I'm currently the editor of the Immunizations
directory in the dmoz Open Directory
Project.
If you know a related website which isn't listed here please notify me.
Many thanks for your co-operation !
Vaccines remain a small part of the overall drug market, just $9
billion in sales compared to global pharmaceutical sales of $550
billion, they make up a fast-growing segment, increasing 26% between
1999 and 2003. Large pharmaceutical makers are attracted to vaccines
because they can't be easily replaced by generics and they provide a
long-term income stream. The large capital investment needed to
manufacture vaccines also makes it difficult for competitors to jump
into the market. And vaccine development is more predictable than
other drugs, allowing companies to smooth out product development
cycles. In 1967, there were 26 vaccine manufacturers in the US
market, but by 2002 there were only 12ref,
but concern about an avian flu pandemic and flu shot shortages in
2004, along with the development of new vaccines – including
products that attack meningitis and cervical cancer – are drawing
big pharmaceutical companies' attention back to vaccines after
decades of retrenchment. Liability remains a problem. In 1986,
Congress created the Vaccine Injury Compensation Program (VICP), a
no-fault system for resolving claims, but lawsuits continue to
plague vaccine makers. The liability environment has gotten worse :
there has been a flurry of lawsuits, and the injury compensation
program in the U.S. is being circumvented in creative ways. For
example, families of children with autism who believe childhood
immunizations led to their children's condition have not filed suits
that argue the vaccines themselves caused autism. They argue instead
that it is the vaccine additive thimerisol, which is not covered by
the VICP. To encourage production of pandemic vaccines, Senators
Hillary Rodham Clinton (D-NY) and Pat Roberts (R-Kan.) have
introduced legislation, known as the Influenza Vaccine Security Act,
that shifts liability from pharmaceutical companies to the federal
government for personal injury or death resulting from the
manufacture, administration, or use of qualified pandemic influenza
technologies.
Perhaps in no area is the divide between the developed and
developing worlds as striking as it is for vaccines: While
healthcare consumers in economically advantaged nations worry
about risk, in developing nations compelling need forces a focus
on potential benefit. People in the United States want a quick
solution, not prevention, so they prefer drugs to vaccines.
Elsewhere, people are afraid of drugs and side effects, and prefer
vaccines. Adding to the imbalance is that the same disease can
have markedly different outcomes depending on the healthcare
infrastructure of a nation. Constraints on vaccine use are complex
and intertwined, involving sociology, economics, politics,
science, and technology. Success of the chickenpox vaccine
highlights the different mindset in the developed and developing
worlds : the vaccine has a very low incidence of side effects and
treats a usually mild disease, but what sells it most, though, is
that if your child has chickenpox, you're home for a week (can you
afford to miss a week of work?!). Creating a vaccine is expensive
: a phase III clinical trial alone can take > 3 years and cost
$50-300 millionref.
For a company to take the plunge, a safe and effective product and
a large, continual market are critical.
Retractions :
1968 : diptheria, pertussis, tetanus (DPT)-intramuscular
polio (safety and efficacy)
1999/2000 : U.S. Public Health Service and other
organizations ask for removal of thimerosal preservative from
vaccines for infants
People avoid vaccines for several reasons. The paramount reason,
fear (vaccinophobia), knows no geographic or cultural
boundaries. But vaccines work : in USA ...
When a disease is caught by
person-to-person contact, as are sexually transmitted viruses,
it spreads through a social network that looks like a disorderly
grid. Each person represents a node in the grid, linked
to others with whom they have had potentially infectious
contact. In recent years, researchers have realized that disease
spread can depend strongly on what this network looks like - on
how the nodes are linked. Many human networks - including some
webs of sexual contacts and the Internet - seem to take on a
form called scale-free. Here a few very highly connected
nodes, dubbed 'hubs', bind the network together. Hubs are
shortcuts between any 2 nodes, giving rise to the small-world
effect popularized in the notion of us all being a maximum of
six degrees of separation from anyone else. In such networks,
infection does not travel as traditional epidemiological models
imply. Even slow-spreading diseases can reach epidemic
proportions. Epidemics were long thought to occur only if the
dissemination rate exceeds a certain threshold value. In
principle, epidemics in a scale-free network can be quashed by
identifying and immunizing just the hubs. This is an appealing
method, as it cuts costs. In practice, however, hubs can be very
hard to find. As a result, some epidemics, such as the spread of
computer viruses and measles, currently rely on random
immunization - virtually the entire population is treated.Rather
than simply immunizing random individuals, it might be more
effective to treat a random selection of the acquaintances of
individuals picked at random. This sounds as if it leaves just
as much to chance. But it doesn't. In a scale-free social
network - a web of friendships, say - anyone connected to
another person by a friendship tie is not representative of the
average. Most nodes have very few connections. So if you know
for sure that someone is part of a friendship circle, they are
more likely to be a hub than is another person selected at
random. In a standard mathematical model of the spread of
infectious disease, the strategy of random-acquaintance
immunization requires only about 50% of a population to be
treated to substantially reduce the chance of an epidemicref.
Vaccines can be made against ...
neoplastic cells (tumour immunity)
infective microorganisms
Requirements for successful specific immunotherapy :
target cell :
transcribes and translates a relevant protein antigen
protein is accessible to peptide-processing machinery
protein incorporates epitopes that can be presented by
relevant MHC molecules
intact and unihibited antigen-processing pathway (including
MHC presentation)
protein ineffectively cross-presented for induction of
immunity (or there would be no need for immunotherapy)
susceptible to effector mechanisms (such as apoptosis and
terminal differentiation)
does not secrete or express local inhibitors of effector
function
immune effector system : naive T cells with appropriate
T-cell receptors for target antigen
intervention (vaccination) induces :
sufficient quantity of effector cells
trafficking to target tissue
appropriate effector mechanisms
responses of sufficient duration
The development
of successful vaccines requires the inclusion of a mixture of
epitopes for the induction of an effective immune response that
can protect against pathogens with high mutation rates.
cover the genetic differences of the population in MHC
haplotypes
Unfortunately, the application of such vaccine cocktails can lead to
the occurrence of immunodominance
(ID),
indicating that the immune response is limited to one epitope or a
small portion of the bona fide T cell epitopes administered.
The administration of rIL-12 during
some consecutive days initiated before immunization counteracts
immunodominance thanks to a transient depletion of B cells, T cells,
macrophages, and DCs in the spleen.
The introduction of rotavirus vaccination in developing countries
is politically difficult in light of its withdrawal from use in
the USAref.
The issue goes beyond one of political correctness. The article
glosses over the moral and ethical issues involved in the trial of
this vaccine in poor countries. The question of how many serious
side-effects are acceptable to save a life has been discussed by
us elsewhereref.
The risk-benefit equation answers the question "Is the cure
(prevention) worse than the disease?" It is true that developing
countries, in which the risk of death from disease is greater than
in developed countries, are more tolerant of preventive measures
with side-effectsref.
We here seek to ask a more fundamental question: is it ethically
justifiable to conduct trials of expensive vaccines such as that
for rotavirus in developing countries? Glass and colleagues
note that, traditionally, vaccines are tested by multinational
manufacturers in the USA and Europe and only later in developing
countries as supply and competition increase and the cost of the
vaccine decreases. We argue that ethically, too, this is the right
way to go about it. The Helsinki Declaration suggests that trials
be done in populations who are directly to use the drug, and that
particular attention must be paid when trials involve vulnerable
sectors such as prisoners and those of low socioeconomic status.
It has been reported that it is easy to recruit participants for
trials in developing countries, and that the cost of research is
halvedref.
A major saving, we dare say, is in the provision of compensation
for adverse effects, which is less likely to be claimed by the
indigent population in poor countries. This is what makes drug
companies press countries such as India to change their law and
allow unfettered research by foreign manufacturersref.
We suggest that if a vaccine is not affordable to the population
at its current price, trials of the vaccine in that population run
counter to the Helsinki Declaration. The rotavirus vaccine costs
US$38 per dose and is administered in three doses. For India's
yearly birth cohort of 25 million, these three doses will cost
$2850 million. According to Health Information of India 2000 and
2001, the Ministry of Health, and the Family Welfare Government of
India, the health and family welfare budget outlay for the year
2002-03 was $1440 million. Rotavirus vaccination, which costs two
times the entire health budget, prevents just 1·5% of the deaths
that occur in children younger than 5 years (see below). The
expenditure is thus difficult to justify. It could be argued that
the health budget needs to be enlarged. However, a more absolute
measure of affordability comes from looking at the intervention
against the per-capita gross national product of the countryref.
Under-5 mortality in India is 98 per 1000 livebirths, and neonatal
death is responsible for 49 deaths. Since rotavirus vaccine given
at 3 months of age is unlikely to prevent neonatal deaths, we are
potentially looking at the remaining 49 deaths per 1000
livebirths. 15% of deaths in under-fives in developing countries
are due to diarrhoea, and 20% of them could be due to rotavirusref.
In effect, rotavirus vaccine can prevent 1·5 deaths per 1000
livebirths. Given the life expectancy of about 60 years in India,
we can assume that this intervention results in 90 life-years
saved. The cost of the vaccine itself (not counting the cost of
administering the three doses) comes to $1266 per life-year saved
(cost of vaccines for 1000 infants divided by 90); the yearly per
capita income in India is only $450. The vaccine cannot therefore
be recommended as cost-effective or affordableref
and so it is unjustifiable to test the drug in this population.
The stipulations of the Helsinki Declaration will permit the
research only after its price has come down drastically. To do
otherwise is to exploit the economic vulnerability of the
population and to use them as guineapigs. In a Viewpoint,
Roger Glass and colleagues (May 8, p 1547)ref
describe how, despite the setback to children of the developing
world, withdrawal of the Rotashield vaccine (Wyerth-Ayerst, USA)
from the US market ultimately created opportunities to consolidate
efforts to tackle this important public-health problem. This
situation was certainly the case with the Pan American Health
Organization and several of its partners, including the Centers
for Disease Control and Prevention, the Gates Foundation, the
National Institutes of Health, and the Albert B Sabin Vaccine
Institute. This partnership is dedicated to the reduction of
morbidity and mortality from diarrhoea caused by rotavirus
infectionref1,
ref2
which is accountable for about 75 000 admissions and 15 000 deaths
every year in the Americas alone. Much work has been done in Latin
America; however, several challenges remain. As noted in a meeting
held in Lima, Peru, in September, 2003ref,
surveillance systems, similar to those developed for polio and
measles, should be strengthened. More economic studies are needed
to accurately define the cost-effectiveness of vaccine
interventions. This information will be critical for future
decisions among national policy makers. Since the Lima meeting,
substantial inroads have been made. To that end, the Pan American
Health Organization and its partners held a global meeting in
Mexico City on July 7-9, 2004, to review progress towards the
development of a rotavirus vaccine and its introduction in
developing countries. Several ministers of health from Latin
America and the Caribbean attended the meetingref.
Leading global experts will address a broad range of issues
concerning: rotavirus pathogenesis, epidemiology, surveillance,
vaccine adverse events, intussusception background rates in
developing countries, vaccine cost-effectiveness, the results of
new rotavirus vaccines being developed, finances, and
partnerships. The aim of this meeting was not just to share
technical information, but to put forward a call to action that
will ultimately benefit children in developing countries.
Therefore, a Mexico City declaration was launched at the end of
the meeting that will certainly go a long way to galvanise the
political support and commitment to do exactly that. The
declaration and proceedings of the meeting will be published in
the near future.ref
Vaccines rarely provide full protection from disease.
Nevertheless, partially effective (imperfect) vaccines may
be used to protect both individuals and whole populations. Vaccines
designed to reduce pathogen growth rate and/or toxicity diminish
selection against virulent pathogens. The subsequent evolution
leads to higher levels of intrinsic virulence and hence to more
severe disease in unvaccinated individuals. This evolution can
erode any population-wide benefits such that overall mortality
rates are unaffected, or even increase, with the level of
vaccination coverage. In contrast, infection-blocking
vaccines induce no such effects, and can even select for lower
virulence. These findings have policy implications for the
development and use of vaccines that are not expected to provide
full immunity, such as candidate vaccines for anthrax and malariaref.
In areas of high mortality, various vaccines might have
non-specific effects on mortality :
inactivated vaccines such as diphtheria-tetanus-pertussis
(DTP) and inactivated poliovirus (IPV) might amplify mortality
from diseases other than diphtheria, tetanus, pertussis, and
polio[ref1,
ref2,
ref3,
ref4]
Non-specific effects are strongest in the first 3-6 months after
immunisationref
and in girls[ref1,
ref2,
ref3,
ref4,
ref5]
and they are largely determined by the most recent vaccine
received; for example, in Guinea-Bissau, the female-male
mortality ratio was 3.08 (95% CI 1·11-8·56) for children who
received DTP as their last vaccine, but only 0.63 (0.28-1.40)
for those who received measles vaccine lastref.
Results of several studies from West Africa have shown that BCG
could enhance the response to unrelated antigensref.
Prime-boost is a 2-part process :
first, an injection of non-infectious (genetic or protein)
antigen(s) primes the immune system to respond
second, several weeks later, an injection of protein or
attenuated carrier viruses containing antigen gene(s)
substantially boosts the immune response
using the same vaccine preparation (homologous prime-boost)
using different vaccine preparations (heterologous prime-boost) : this is
used to circumvent acquired immunity to the first vector,
which precludes subsequent vaccinations with the same vector.
The boost alone produces a quicker but weaker immune response as
compared with the prime-boost strategy.
The use of paracetamol to prevent fever and fever-induced
seizures in vaccinated infant : antibody geometric mean
concentrations (GMCs) were significantly lower in the prophylactic
paracetamol group than in the no prophylactic paracetamol group
after primary vaccination for all ten pneumococcal vaccine
serotypes, protein D, antipolyribosyl-ribitol phosphate,
antidiphtheria, antitetanus, and antipertactin. After boosting,
lower antibody GMCs persisted in the prophylactic paracetamol
group for antitetanus, protein D, and all pneumococcal serotypes
apart from 19Fref.
Active
pharmaceutical ingredients (API) : vaccines may consist of
:
the Ag(s) against which the immune response has to be mounted
mixed or polyvalent vaccine : a vaccine prepared
from cultures or antigens of more than one strain or species.
...isolated from ...
autogenous vaccine : a vaccine prepared from
microorganisms which have been freshly isolated from the
lesion of the patient who is to be treated with it.
The antigen(s) can be ...
whole
organisms
dead or killed or
inactivated or replication-defective germs : less risks, less effectiveness (i.e.
more doses, longer latency period, shorter protection
time). They are usually administered in 2-3 sequential
doses followed by a booster after 6-12 months.
formol : heat,
oxidation and exposure to aldehydes create reactive
carbonyl groups on proteins, targeting antigens to
scavenger receptors. Formaldehyde is widely used in making
vaccines, but has been associated with atypical enhanced
disease during subsequent infection with paramyxoviruses.
Carbonyl groups on formaldehyde-treated vaccine antigens
boost Th2 responses and enhance respiratory
syncytial virus (RSV) disease in mice, an effect partially
reversible by chemical reduction of carbonyl groupsref
VAQTA®
(Merck & Co.) : 50 U in 1 mL; for use in
patients as young as 12 months; may be administered
concomitantly with live measles, mumps, and rubella
vaccine (MMR-II)
JE-Vax®
(distributed by Aventis
Pasteur Inc. (USA Govt license #1156), Biken
(Japan) and by the Korean GreenCross). This purified
formalin-inactivated JE vaccine made from either the
Nakayama strain or the Beijing strain of JEV
propagated in mouse-brain tissue (Biken and
Kaketsuken) has been successfully used to reduce the
incidence of JE in China (Province of Taiwan),
Japan, the Republic of Korea, Thailand and Viet Nam.
Immunogenicity studies in areas devoid of endemic
transmission have indicated that 3 doses of the
vaccine are required to provide adequate level of
antibody. The preferred primary vaccination series
consists of 3 doses administered at 0, 7, and 30
days, but an accelerated schedule consisting of 3
doses administered at 0, 7, and 14 days can be used
when the longer schedule is impractical or
inconvenient because of time constraints. With
either schedule, the primary series should be
completed at least 10 days before travel to allow an
adequate immune response and monitoring of adverse
events (AE) after vaccination; therefore, JE
vaccination should begin at least 24 days before
travel abroad. Japanese children are usually given
the vaccination 3 times: between 6 months and 7.5
years old, 9 and 12 years old, and 14 and 15 years
old. Between 4.2 million and 4.3 million children
receive the encephalitis vaccine a year. Since 1988,
this vaccine has gradually been introduced into the
EPI in Thailand and administered with the 4th dose
of DTP at 18 months.
Side effects rate (as
pointed out in the insert sheet) : local side effects
>10%, systemic side effects (i.e. fever, which is
indicated may happen even up to 10-14 days after
injection) <0,001% (active reporting system in at
least 66.6%: 3 shots gives 2 opportunities to ask
directly about side effects), ADEM
(a female junior high school student in east Japan's
Yamanashi Prefecture fell into critical condition
after receiving an inoculation in 2004). The current
program of JEV vaccinations has been carried out
routinely in Japan since 1994 : > 10 cases of ADEM
have been linked to the vaccination since 1994.
Surveillance of JE vaccine-related complications in
Japan during the years 1965-1973 disclosed
neurological events (principally, encephalitis,
encephalopathy, seizures, and peripheral neuropathy)
among 1-2.3 per million persons vaccinatedref
(Kitaoka M. Follow-up on use of vaccine in children in
Japan. In: McDHammon W, Kitaoka M, Downs WG, eds.
Immunization for Japanese encephalitis. Amsterdam:
Excerpta Medica, 1972:275-7).
cell culture-derived vaccines : 2 variants
are in advanced stages of development in Japan
(undergoing Phase III trials), and licensure is
expected as early as 2006. It is reasonable to believe
that the decision to suspend vaccination with
mouse-brain derived vaccines in Japan was related to
the short timeline for new vaccine licensure in Japan.
another formalin-inactivated JE vaccine is
prepared in China from the P3 strain of JEV
propagated in primary Syrian hamster kidney-cell
cultures. This strain is more immunogenic and
confers greater protection in mice than the Nakayama
strain. This used to be the most widely used JE
vaccine worldwide.
other inactivated JE vaccines have been developed
using better standardized cell substrates, including
Vero cells. Vero cell-derived inactivated JE
vaccines have been developed in China where the
vaccine is now licensed, as well as by Biken and
Chemo-Sero Therapeutic Research Institute in Japan.
The SA 14-14-2 strain also has been adapted
to growth on primary dog-kidney cells and on Vero
cells at WRAIR for use as an inactivated
vaccine. Phase I and II studies of an inactivated SA
14-14-2 strain propagated in Vero cells have been
carried out, showing excellent safety and
immunogenicity profiles (Intercell, Vienna). A Phase
III trial of the vaccine is scheduled to start in
2005.
Currently, there is no JE vaccine which is
WHO-prequalified. Only the Nakayama strain inactivated
mouse brain-derived vaccine is internationally registered,
while there are several vaccines produced in a number of
countries and used locallyref
single-shot vaccine under development by SingVax in
Singapore and Octoplus
in the Netherlands. The work will utilise OctoPlus’
proprietary delivery systems for the controlled
release of drugs and antigens, and the PER.C6®
technology licensed by SingVax from Dutch
biotechnology company Crucell, for the manufacturing
of JE viral particles
anti-Rift
Valley
fever virus
vaccine : 3 injections separated by 1 month each.
Effective for < 1 year. A live vaccine prepared from
Smithburn's attenuated strain of RVF virus has been used
for the control of RVF in non-pregnant cattle and sheep
in endemic areas and during outbreaks, while inactivated
vaccines for use in pregnant animals and in RVF-free
countries are prepared from virulent field strains. RVF
vaccines have been extensively applied in RVF-infected
countries, such as South Africa (where both live and
inactivated vaccines are commercially produced),
Zimbabwe, Kenya, Egypt and Saudi Arabia. For example,
Egypt's annual mass vaccination during 2004 included
> 7 million vaccinations, of which 1,986,825 were in
cattle, 1,259,195 in buffaloes, 3,170,183 in sheep,
935,128 in goats and 95,308 in camels. Both attenuated
and killed vaccines are applied. Egypt's last RVF
outbreak was reported in July 2003. Israel, an RVF-free
country, carried out preventive vaccination against RVF
during the years 1979 -1981 in the face of the RVF
panzootic in neighboring Egypt. The entire country's
ruminant population and camels were vaccinated with a
commercial inactivated vaccine and earmarked; the
country remained free of disease. No vaccinations have
been carried out since. According to OIE's manual of
Diagnostic Tests and Vaccines for Terrestrial Animals,
an inactivated experimental RVF vaccine has been used
for 25 years in humans with considerable success to
protect persons at risk. This vaccine is currently
produced on diploid cells. However, the limited
availability of the vaccine precludes its use in the
general population. 2 new vaccine candidates produced
from human RVF virus isolates are undergoing extensive
testing with a view to replacing existing animal
vaccines. The 1st, MV P12, is a mutagen-derived
strain of virus found protective in young lambs and in
cattle, but its safety for pregnant animals is still
under investigation. The 2nd candidate is Clone 13,
a small plaque variant that did not react with 2
specific monoclonal antibodies and which has undergone
testing in lambs, sheep and young and adult goats with
promising results. Further information, including
description of live and inactivated vaccine production
and testing and data on the above mentioned experimental
vaccines, is available in chapter 2.1.8 of OIE's Manual
of Diagnostic Tests and Vaccines for Terrestrial Animalsref
anti-influenzaviruses
A
and B
vaccine (see also protein
subunit vaccine, attenuated
vaccine and DNA
vaccine)
(Francis, T., Jr., Salk, H. E., Pearson, H. E., and
Brown, P. N. Protective effect of vaccination against
induced influenza A. Proc. Soc. Exper. Biol. & Med.
1944, 55, 104-105; Commission on Influenza. A clinical
evaluation of vaccination against influenza. Preliminary
report. J. Am. Med. Assoc. 1944, 124, 982-985) : for the
last 30 to 40 years, flu virus has been grown in 8-9
days old fertilized hen eggs injected by needle with a
tiny bit of flu virus, which then grows in the egg and
harvested 1-2 days later. A single egg is needed
to make one dose of vaccine containing a multitude of
flu viruses, and major flu vaccine makers like Aventis
Pasteur and Chiron Corp. need tens of millions of eggs
every year (Chiron uses 100,000 a day at the peak of
production) : these have to be ordered months in
advance, which makes it difficult to produce a fresh
batch of vaccine at the last minute and sometimes,
chicken disease outbreaks can kill huge numbers of
animals, hurting egg production. About 4% of the
population is allergic to eggs and many of these people
can't get a flu shot : however some offices sometimes
give the flu vaccine even to patients who are allergic
to eggs because the danger to them from the flu virus is
even greater than the danger from the vaccine. To make a
suitable vaccine strain, researchers inject the
circulating virus, such as Fujian, and another,
fast-growing flu strain into eggs, where the 2 mix and
match their genes. From the eggs, scientists aim to pull
out a new fast-growing reassorted virus - called a seed
strain - which carries the HA and NA genes from
the year's strain. Vaccine manufacturers need to receive
the seed strain in time to grow it up in tens of
millions of eggs, a process that is proven, efficient
and reliable, but takes up to 6 months. Problems growing
the year's strain could be bypassed using :
reverse genetics to rapidly engineer the seed
strain in the laboratory by stitching together
the viral genes they want, and then use it to
mass-produce the vaccine in hens' eggs. Influenza
vaccines made using reverse genetics have not yet
progressed through clinical trials, however, and
vaccine manufacturers might be dissuaded from using
reverse genetics because they would owe licensing fees
to MedImmune, a biotechnology firm based in
Gaithersburg, Maryland that holds patents on the
technique
mammalian cell cultures (Vero cell culture
vaccine is in development by Baxter and Chiron)
The target of vaccination is achieving a
hemagglutination-inhibition (HAI) titer > 1:40. 1
i.m. injection containing 15 µg of HA for each
represented strain per 0.5-ml dose without adjuvant
induce HAI titers > 1:40. When flu vaccines are
well-matched to the prevailing flu strains, the shots can
prevent flu for 1 year in 70-90% in adultsref1,ref2
and 30-40% in elderlies. Well-matched shots may prevent
flu in only 30-40% of nursing home residents, but they can
reduce the death rate from influenza and pneumonia in that
population by 80%. As compared with an i.m. injection of
full-dose (15 µg x3) influenza vaccine, an intradermal
injection of a reduced dose (6 µg (40% of the usual dose)
x3ref
or 3 µg (20% of the usual dose) x3ref)
results in similarly vigorous antibody responses among
persons 18 to 60 years of age but not among those over the
age of 60 years (significant only for antigen to the H3N2
strain). Local pain is significantly more common in the
i.m. group than in the intradermal group among subjects
who were 18 to 60 years of age but not among subjects who
are over 60 years old. Signs of local inflammation are
significantly more common among subjects in the
intradermal group than among those in the intramuscular
group, in both age groups.
Indications : CDC Priority
groups for vaccination with inactivated influenza vaccine
:
all children aged 6-59 months : disease
prevention authorities in the USA and Canada are
considering extending their influenza vaccination
programme to children under 2 years, although a recent
systematic review found little evidence to support the
moveref.
A close look at data from 24 studies showed that live
attenuated vaccines work best in children, reducing
the risk of confirmed influenza by 79% (relative risk
0.21, 95% CI 0.08 to 0.52)—but only in children
over 2 years. As expected, live attenuated
vaccines were less effective against unconfirmed
"influenza-like" illnesses, reducing the risk by only
38% in children over 2 years (relative risk 0.62, 0.57
to 0.67). Inactivated vaccines don't seem to work
as well as live attenuated vaccines, and in a
review at least, did not work at all in children under
2. Few studies looked at complications such as chest
infections, acute otitis media, or hospital admission,
and those that did found no difference between
children who had been vaccinated and those who had
not. The authors found no data at all on mortality.
Despite evidence that vaccinating schoolchildren
against influenza is effective in limiting
community-level transmission, the USA has had a
long-standing government strategy of recommending that
vaccine be concentrated primarily in high-risk groups
and distributed to those people who keep the health
system and social infrastructure operating. Because of
2005 influenza vaccine shortage, a plan was enacted to
distribute the limited vaccine stock to these groups
first. This vaccination strategy, based on direct
protection of those most at risk, has not been very
effective in reducing influenza morbidity and
mortality. Although it is too late to make changes for
the 2005 season, the current influenza vaccine crisis
affords the opportunity to examine an alternative for
future years. The alternative plan, supported by
mathematical models and influenza field studies, would
be to concentrate vaccine in schoolchildren,
the population group most responsible for
transmission, while also covering the reachable
high-risk groups, who would also receive considerable
indirect protection. Vaccinating 60% of schoolchildren
in the USA would dramatically reduce the transmission
of influenza. Children are the primary transmitter and
they link all the other groups in the population. In
conjunction with a plan to ensure an adequate vaccine
supply, this alternative influenza vaccination
strategy would help control interpandemic influenza
and be instrumental in preparing for pandemic
influenza. The effectiveness of the alternative plan
could be assessed through nationwide community studiesref.
Influenza control based on mass vaccination of
schoolchildren was implemented in Japan in the 1960s
and was associated with a decrease in the overall
mortality rate. The program was discontinued in 1994.
The discontinuation was followed by a seasonal
increase in the mortality rate. Lately, young children
and elderly persons have been receiving influenza
vaccines. It is likely that discontinuation of mass
vaccination of schoolchildren was responsible for the
increase in influenza-associated deaths among young
children in the 1990s. The recent increase in
influenza vaccinations among young children, together
with the routine therapeutic use of neuraminidase
inhibitors, has led to a decrease in the
influenza-associated mortality rateref.
Beginning with the 2004/2005 influenza season, the
Advisory Committee on Immunization Practices (ACIP)
recommends that all children aged 6 to 23 months and
close contacts of children aged 0 to 23 months receive
annual influenza vaccinationref.
ACIP continues to recommend that all people aged >6
months with certain chronic underlying medical
conditions, their household contacts, and health-care
workers receive annual influenza vaccinationref.
The composition is decided by consensus among an
international group of influenza experts. The decision
has to be taken in February in order to give the
manufacturers sufficient time to gear up and produce
the vaccine. Data from a surveillance led the ACIP in
2005 to expand its recommendations to include persons
with conditions that compromise respiratory function,
such as neuromuscular disordersref.
In February 2006, the ACIP voted to expand annual
vaccine recommendations to include all children 6 to
59 months of age. This last recommendation will be
published in the 2006 recommendations of the ACIP on
the prevention and control of influenza..
adults aged > 65 years : over the past 4
decades, vaccines have been used to reduce the effects
of influenza in elderly individuals. In 2000, 40 of 51
developed or rapidly developing countries recommended
vaccination for all individuals aged 60–65 or olderref,
and, in 2003, 290 million doses of vaccine were
distributed worldwideref.
According to Centres for Disease Control (CDC), the
main aim of vaccination in elderly individuals is to
reduce the risk of complications in those who are most
vulnerableref1,
ref2.
As such, they define 2 high priority
groups—individuals aged 65 years or older, and
residents of nursing homes and long-term care
facilities. 2 systematic reviews of the effects of
influenza vaccines in elderly people have been
publishedref1,
ref2.
The firstref
was done more than a decade ago, and the secondref
has several methodological weaknesses—namely, the
exclusion of studies with denominators of < 30 and
pooling of studies of different design—and includes
only 15 studies (Rivetti D, Demicheli V, Di
Pietrantonj C, Jefferson TO, Thomas R. Vaccines for
preventing influenza in the elderly. Cochrane Database
Syst Rev 2005; 1:CD004876; Thomas R, Jefferson T,
Demicheli V. Influenza vaccination for healthcare
workers who work with the elderly. Cochrane Database
Syst Rev 2005; 2:CD005187)
observational studies report that influenza
vaccination reduces winter mortality risk from any
cause by 50% among the elderly. Influenza
vaccination coverage among elderly persons (65
years) in the USA increased from between 15% and 20%
before 1980 to 65% in 2001. Unexpectedly, estimates
of influenza-related mortality in this age group
also increased during this period. Researchers tried
to reconcile these conflicting findings by adjusting
excess mortality estimates for aging and increased
circulation of influenza A(H3N2)
viruses. Researchers used a cyclical regression
model to generate seasonal estimates of national
influenza-related mortality (excess mortality) among
the elderly in both pneumonia and influenza and
all-cause deaths for the 33 seasons from 1968 to
2001. Researchers stratified the data by 5-year age
group and separated seasons dominated by A(H3N2)
viruses from other seasons. For people aged 65 to 74
years, excess mortality rates in A(H3N2)-dominated
seasons fell between 1968 and the early 1980s but
remained approximately constant thereafter. For
persons 85 years or older, the mortality rate
remained flat throughout. Excess mortality in A(H1N1)
and B seasons did not change. All-cause excess
mortality for persons 65 years or older never
exceeded 10% of all winter deaths. Researchers
attribute the decline in influenza-related mortality
among people aged 65 to 74 years in the decade after
the 1968 pandemic to the acquisition of immunity to
the emerging A(H3N2) virus.
Researchers could not correlate increasing
vaccination coverage after 1980 with declining
mortality rates in any age group. Because < 10%
of all winter deaths were attributable to influenza
in any season, researchers conclude that
observational studies substantially overestimate
vaccination benefitref.
Numerous studies have shown that influenza
vaccination works -- including to help protect the
elderly from serious illness and hospitalizations --
but the degree to which it works varies from year to
year and can be difficult to measure. For example,
influenza seasons differ each year in length and
severity, and the health status of individuals also
matters. The authors in no way imply that the
elderly should not receive influenza vaccine.
Rather, the study concludes that the vaccine may
prevent fewer deaths among the elderly than previous
studies would have suggested. Another reason for the
apparent relatively poor performance of influenza
virus vaccines in the elderly is semantic. Any
febrile infection is described initially as flu-like
and, in the case of upper respiratory tract
infections, the assumption is that (in the absence
of laboratory diagnosis) the infection is caused by
influenza virus. Whereas in the elderly in some
years other respiratory tract viruses, respiratory
syncytial virus in particular, can be the cause of
extensive outbreaks described as flu
according to reliable evidence, the effectiveness
of trivalent inactivated influenza vaccines in
elderly individuals is modest, irrespective of
setting, outcome, population, and study design. In
view of the known variability of incidence and
effect of influenza, we constructed a large number
of comparisons and strata to reduce to a minimum
possible heterogeneity between studies and to aid
comparability. Despite our attempts we noted
significant residual between-studies heterogeneity
that could be explained only in part by different
study designs, methodological quality, settings,
viral circulation, vaccine types and matching, age,
population types, and risk factors. We think the
residual heterogeneity could be the result of the
unpredictable nature of the spread of influenza and
influenza-like illness and the bias caused by the
non-randomised nature of our evidence base. The
findings of the cohort studies that we included are
likely to have been affected to a varying degree by
selection bias; differential uptake of influenza
vaccines is linked to several factors (anxiety over
unwanted effects, disease threat perception,
societal and economic conditions, education, health
status) and hence to outcome. Indeed, one cohort
studyref,
had real difficulties in achieving high coverage in
those most at need. Differential vaccine uptake and
the resulting selection bias is the most likely
explanation for the high effectiveness of influenza
vaccines in preventing deaths from all causes. A
further example of the potential effect of such bias
is the apparently counterintuitive effectiveness of
the vaccines in elderly individuals living in the
community. In this population, the vaccines are
apparently ineffective in the prevention of
influenza, influenza-like illness, pneumonia,
hospital admissions, or deaths from any respiratory
disease, but are effective in the prevention of
hospital admission for influenza and pneumonia and
in the prevention of deaths from all causes. That
such differences are the result of a baseline
imbalance in health status and other systematic
differences in the two groups of participants cannot
be discounted. Evidence from randomised controlled
trials, in which bias is reduced to a minimum, is
scant and badly reported. Unfortunately, because of
the global recommendations on influenza vaccination,
placebo-controlled trials, which could clarify the
effects of influenza vaccines in individuals, are no
longer possible on ethical grounds. Whatever the
causes of observed variability, we believe that the
decision to vaccinate against influenza cannot be
made on the basis of the results from single
studies, reporting observations from a few seasons,
but that it should be taken on the basis of all
available evidence. The conclusions drawn from
studies done in individuals who live in long-term
care facilities are different to those drawn from
studies in individuals who live in the community.
Whereas studies done in residents of care homes
often indicate the inevitably improvised nature of
efforts to study the effect of vaccines during an
epidemic often concurrently in several locations,
the resident population is usually more consistent
than that in the community: older, with similar
viral exposure and risk levels. Despite a remaining
heterogeneity and an overestimation of the effects
as a result of study design, it is possible to
detect a gradient of effectiveness, in which
vaccines have little effect on cases of
influenza-like illness, but have greater effect on
its complications. This finding suggests that
control through vaccination is a possibility. The
effectiveness of vaccines in the community, however,
is modest, irrespective of adjustment for systematic
differences between vaccine recipients and
non-recipients. The difficulties of achieving good
coverage in those who most need it, or the diluting
effect on vaccines for influenza of other agents
circulating in the community (causing influenza-like
illness, clinically indistinguishable from
influenza), might be to blame. Researchers noted
empirical proof of both, with differential vaccine
uptake among the same population linked to age, sex,
and health status, and a low effect on
influenza-like illness throughout our datasets, even
in periods of supposedly high influenza viral
circulation when the proportion of cases of
influenza-like illness caused by influenza and the
possible benefits of vaccination are highest. On the
basis of these observations, we believe efforts
should be concentrated on achieving high vaccination
coverage in long-term care facilities coupled with a
systematic assessment of the effect of such a
policy. One possible way to improve this strategy
might involve the vaccination of carers in an effort
to reduce transmission (Thomas R, Jefferson T,
Demicheli V. Influenza vaccination for healthcare
workers who work with the elderly. Cochrane Database
Syst Rev 2005; 2:CD005187). The effect of
vaccination of high risk groups should also be
further assessed (Poole PJ, Chacko E, Wood-Baker
RWB, Cates CJ. Influenza vaccine for patients with
chronic obstructive pulmonary disease. Cochrane
Database Syst Rev 2000; 3:CD002733; Cates CJ,
Jefferson TO, Bara AI, Rowe BH. Vaccines for
preventing influenza in people with asthma. Cochrane
Database Syst Rev 2003; 4:CD000364; Tan A, Bhalla P,
Smyth R. Vaccines for preventing influenza in people
with cystic fibrosis. Cochrane Database Syst Rev
2000; 1:CD001753). Finally, investment in the
development of better vaccines than available at
present should be linked to better knowledge of the
causes and patterns of influenza-like illnesses in
different communities. This partnership could lead
to the inception of a more comprehensive and perhaps
more effective strategy for the control of acute
respiratory infections, relying on several
preventive interventions that take into account the
multi-agent nature of influenza-like illness and its
context (such as personal hygieneref,
and provision of electricity and adequate food,
water, and sanitation)ref.ref
in homes for elderly individuals (with
good vaccine match and high viral circulation) the
effectiveness of vaccines (VE=1–relative risk (RR)
or VE*=1–odds ratio (OR)) against influenza-like
illness was 23% and non-significant against
influenza (RR 1.04). Well matched vaccines prevented
pneumonia (VE 46%) and hospital admission (VE 45%)
for and deaths from influenza or pneumonia (VE 42%),
and reduced all-cause mortality (VE 60%). In elderly
individuals living in the community, vaccines were
not significantly effective against influenza (RR
0.19), influenza-like illness (RR 1.05), or
pneumonia (RR 0.88). Well matched vaccines prevented
hospital admission for influenza and pneumonia (VE
26%) and all-cause mortality (VE 42%). After
adjustment for confounders, vaccine performance was
improved for admissions to hospital for influenza or
pneumonia (VE* 27%), respiratory diseases (VE* 22%),
and cardiac disease (VE* 24%), and for all-cause
mortality (VE* 47%). In long-term care facilities,
where vaccination is most effective against
complications, the aims of the vaccination campaign
are fulfilled, at least in part. However, according
to reliable evidence the usefulness of vaccines in
the community is modestref.
improvement in the immune response to
influenza virus vaccination in the elderly
represents the primary unmet need in influenza virus
vaccination. A booster immunostimulating (IS)
patch for transcutaneous immunization (TCI)
developed by IOMAI
Corp. in Gaithersburg, Maryland, resembles a
large sticking plaster pasted over the skin puncture
left by the jab : it contains Escherichia
coli labile enterotoxin (LT) used as an
adjuvant and increases the number of
antigen-specific T-lymphocytes by up to 50-foldsref.
The skin patch might also be used to boost the
response to other types of vaccination. Many other
research groups are seeking ways to enhance the
influenza vaccination for the elderly, using a range
of different adjuvants and ways to deliver them.
Some are adding them directly to the vaccine; others
are wafting them up the nose
ambulatory individuals 65 years and older (N =
202) were assigned randomly to receive a single
intramuscular injection of the 2001-2002 formulation
of trivalent inactivated influenza vaccine
containing 15, 30, or 60 µg of hemagglutinin per
strain (up to 180 µg total per dose) or placebo.
Clinical and serologic responses were assessed
during the month after immunization. Increasing
dosages of vaccine elicited significantly higher
serum antibody levels, frequencies of antibody
responses, and putative protective titers after
vaccination. Mean serum hemagglutination inhibition
antibody titers 1 month after immunization in groups
given 0-, 15-, 30-, and 60-µg dosages were 23, 37,
50, and 61 against influenza A/H1N1;
43, 86, 91, and 125 against influenza A/H3N2;
and 10, 14, 18, and 24 against influenza B,
respectively. Mean serum hemagglutination inhibition
and neutralizing antibody levels against the 3
vaccine antigens in participants given the 60-µg
dosage were 44% to 71% and 54% to 79%, respectively,
higher than those in participants given the standard
15-µg dosage, and the 60-µg dosage level nearly
doubled the frequency of antibody responses in
those whose preimmunization antibody titers were
in the lower half of the antibody range.
Dose-related increases in the occurrence of
injection site reactions were observed (P<.001),
but all dosages were well toleratedref
persons aged 2-64 years with underlying chronic
medical conditions,
all women who will be pregnant during influenza
season,
residents of nursing homes and long-term care
facilities,
children 6 months-18 years of age on chronic aspirin
therapy
health-care workers with direct patient care
out-of-home caregivers and household contacts of
children aged <6 months.
The WHO Recommendations for Influenza Vaccine Composition
for the southern hemisphere for 2005 (southern hemisphere
winter) are the following :
an A/New Caledonia/20/99(H1N1)-like
virus;
an A/Wellington/1/2004(H3N2)-like
virus;
a B/Shanghai/361/2002-like virus. Currently used
vaccine viruses include B/Shanghai/361/2002,
B/Jilin/20/2003 and B/Jiangsu/10/2003
The composition of the trivalent inactivated vaccine
(TIV) for the 2004/05 season (Northern Hemisphere
winter) was announced by the WHO in Geneva on Fri 13 Feb
2004 :
an A/New Caledonia/20/99(H1N1)-like
virus will be retained as the H1N1
component of the vaccine
an A/Fujian/411/2002(H3N2)-like
virus. A/Kumamoto/102/2002 is also available as a
vaccine virus. Because of the growth properties of the
A/Wyoming/3/2003 and B/Jiangsu/10/2003 viruses, US
vaccine manufacturers are using these antigenically
equivalent strains in the vaccine as the H3N2
and B components, respectively.
a B/Shanghai/361/2002-like virus : candidate
vaccine viruses include B/Shanghai/361/2002 and
B/Jilin/20/2003, which is a B/Shanghai/361/2002-like
virus
In 2005, > 10,000 influenza viruses from all continents
were isolated and characterized by the WHO/National
Influenza Centers. These laboratories, which are located
in > 80 countries, form the backbone of the global
influenza surveillance program. Based on that assembled
information, WHO on Fri 10 Feb 2005 published its
recommendations on the formulation of the influenza
vaccine for the Northern Hemisphere. 2005 analysis, which
concluded on Thu 9 Feb 2005, was conducted by members of
the WHO Collaborating Centers on Influenza and has
recommended that vaccines to be used in the 2005-2006
season (Northern Hemisphere) should contain the followingref1,
ref2
:
an A/New Caledonia/20/99(H1N1)-like
virus
an A/California/7/2004(H3N2)-like
virus (candidate vaccine viruses are being developed);
The decision on A(H3N2) candidate vaccine viruses was
postponed pending the identification of a suitable
high growth reassortant. Based on the results of
antigenic and genetic analyses and growth in hens'
eggs, obtained by WHO Collaborating Centers for
Reference and Research on Influenza and Reference
Laborat
(A/California/7/2004-like) virus and A/PR/8/34, is
suitable as a candidate A(H3N2)
vaccine virus
a B/Shanghai/361/2002-like virus (the currently
used vaccine viruses are B/Shanghai/361/2002,
B/Jiangsu/10/2003 and B/Jilin/20/2003ref).
Influenza
B viruses circulating worldwide can be divided into 2
antigenically distinct lineages: B/Yamagata/16/88 and
B/Victoria/2/87. Before 1991, B/Victoria lineage
viruses circulated worldwide; from late 1991 to early
2001, no viruses of the B/Victoria lineage were
identified outside Asia. However, since March 2001,
B/Victoria-lineage viruses have been identified in
many countries outside Asia, including the USA.
Viruses of the B/Yamagata lineage began circulating
worldwide in 1990 and continue to be identified. The
type-B component of the 2005-06 influenza vaccine
(B/Shanghai/361/2002-like) belongs to the B/Yamagata
lineage.
On Feb 19 the FDA advisory panel voted to change the
current vaccine'san A/California/7/2004(H3N2)
strain to a different H3N2 strain
known as A/Wisconsin(H3N2) strain.
Experts also recommended a shift from the less common
B/Shanghai/361/2002 strain to B/Malaysia/2506/2004,
antigenically equivalent to B/Ohio/1/2005. The panel
recommended no change to the current vaccine's A/New
Caledonia/20/99(H1N1) strain. <
1% of all U.S. flu cases this year were caused by
Influenza B viruses. But experts are still considering the
possibility of recommending a "quadrivalent, or 4-strain,
vaccine in the future that contains two types of Influenza
B virusref1,
ref2,
ref3,
ref4,
ref5
This decision presupposes that the avian influenza A(H5N1)
virus currently circulating in East Asia will remain
confined to avian hosts and will not acquire by mutation
or sub-unit reassortment properties facilitating
human-to-human transmission, thereby becoming a novel
pandemic virus. A/California influenza virus, discovered
by officials in Santa Clara County late in 2004, already
represents 20% of influenza cases in USA in the 2004/005
season. The California strain has popped up in Canada,
Mexico, Europe, Asia, Africa and Pacific islands, so that
WHO is predicting that it will be the dominant influenza
virus strain next fall and winter. This rapid spread has
led WHO to recommend that the A/California strain will
replace the H3N2 component of the
vaccine; i.e. the A/Fujian/411/2002(H3N2)
virus. These recommendations are used by pharmaceutical
manufacturers to update the composition of the influenza
vaccines they produce. This annual adjustment is necessary
to match the vaccine with the changing viruses expected to
be circulating during the coming influenza season.
Recommendations for the composition of the vaccine to be
used in the Southern Hemisphere will be made at a meeting
in September 2005. While influenza vaccine coverage has
improved significantly in the last 10 years, the vaccine
is not reaching everyone in the high risk categories.
These categories, defined by WHO, include the elderly,
those who are at increased risk because they have other
respiratory or cardiovascular disease, and health care
workers. However, influenza vaccine use in developing
countries remains minimal to nonexistent. In 2004, WHO's
Member States set a goal of 60% coverage for those in
these high risk groups and 75% coverage by 2010. Since
young children can develop severe disease, some countries
have also started including vaccination of children as
part of their national influenza policy. Vaccinating
children may not only reduce their disease burden, but it
may also reduce transmission to the elderly and others at
increased risk. The current influenza season is now
approaching its peak. All elderly persons or those with a
particular risk of influenza should be vaccinated.
For the 2005/2006 influenza vaccine, 4 manufacturers
expect to provide influenza vaccine to the U.S.
population. Sanofi Pasteur, Inc., projects production of
up to 60 million doses of trivalent inactivated influenza
vaccine (TIV). Chiron Corporation projects
production of 18-26 million doses of TIV. GlaxoSmithKline,
Inc. projects production of 8 million doses of TIV.
MedImmune Vaccines, Inc., producer of the nasal-spray,
live attenuated influenza vaccine (LAIV), projects
production of approximately 3 million dosesref.
Because of the uncertainties regarding production of
influenza vaccine, the exact number of available doses and
timing of vaccine distribution for the 2005/06 influenza
season remain unknown. As a result, CDC recommends that
only the following priority groups receive TIV before
October 24, 2005: persons aged >65 years with comorbid
conditions; residents of long-term--care facilities;
persons aged 2-64 years with comorbid conditions; persons
aged >65 years without comorbid conditions; children
aged 6-23 months; pregnant women; health-care personnel
who provide direct patient care; and household contacts
and out-of-home caregivers of children aged <6 months.
These groups correspond to tiers 1A-1C in the previously
published table of TIV priority groups in the event of
vaccination supply disruptionref.
Beginning 24 Oct 2005, influenza vaccine should be made
available to all persons. Healthy persons aged 5-49 years
who are not pregnant, including health-care workers who
are not caring for severely immunocompromised patients in
special-care units, can receive LAIV at any timeref.
Vaccination Recommendations for Persons Displaced by
Hurricane Katrina : on 6 Sep 2005, CDC issued interim
vaccination
recommendations for persons displaced by Hurricane Katrinaref.
Any displaced persons aged >6 months living in crowded
group settings should be administered influenza vaccine;
children aged <8 years should be administered 2 doses,
at least 1 month apart.
Influenza surveillance reports for the USA are posted
online weekly during October-Mayref.
Unperfectly matched vaccines
:
as the 2003/2004 season progressed,
A/Fujian/411/2002 (H3N2)
viruses, which were antigenically distinguishable from
the vaccine strain A/Panama/2007/99 (H3N2),
became predominant in the USA (the 1st cases turned up
in early October 2003 in Texas: 82% of isolatesref),
resulting
in a less than optimal match. An initial study to
assess the effectiveness of the 2003/2004 influenza
vaccine against ILI in health-care workers did not
demonstrate effectiveness; however, preliminary
analyses of 3 additional unpublished studies of
influenza vaccine effectiveness among children and
adults in the US were presented at the ACIP meeting on
23 Jun 2004, and all demonstrated vaccine
effectiveness. Influenza experts at the WHO knew the
Fujian strain was circulating when they met in
February 2003 to decide which strains to include in
this season's Northern Hemisphere shot, but
laboratories in the WHO's network failed to find a
Fujian strain that would grow in fertilized hens' eggs
in time to include in this season's vaccine.
Approximately 83 million doses of vaccine were
administered, in a near-record. Studies showed reduced
efficacy: estimated efficacy against ILI in those
vaccinated before 1 Nov was 13% and after 1 Nov was 3%ref.
It should be noted that in a study of patients aged
greater than 65 years, TIV was effective in preventing
61% of influenza-related deaths when the vaccine and
circulating strains were well-matched and 35% when
they were not well-matchedref.
The Pneumonia & Influenza death curves (P & I)
contained in 2003 report indicate that the epidemic
peaks of P&I deaths were markedly increased from
the 3 prior seasons (albeit less than for the
1999/2000 peak). This can be taken as additional
circumstantial evidence that last year was more
severe, probably contributed to by a
less-than-efficacious vaccine.
the predominant flu virus around the globe in 2004
is A/Fujian, and the vaccine Americans are seeking
today is a perfect match for it. But,
A/Wellington/1/2004(H3N2)-like
virus is gaining ground. Tests suggest that 43% of
recent New Zealand flu cases spring from the new
strain, or variants of it. A/Wellington has even
turned up about as far from the South Pacific as is
geographically possible: in Norway. The late season
surge of A/Wellington was so worrying that the WHO, on
8 Oct 2004, recommended that 2005 flu vaccine for the
Southern Hemisphere, which is shipped in March, be
reformulated to protect against it. Laboratory animal
tests suggest that the current vaccine -- which
targets A/Fujian -- is about 2/3rds less effective in
stirring antibodies against A/Wellington than it is
against the targeted strain. Despite the late
emergence of the new flu strain, influenza was
unusually mild throughout the Southern Hemisphere from
May through October 2004.
Shortages :
CDC predicted in May 2004 that 6-8 million doses of
thimerosal-free flu vaccine would be produced for
people concerned about the preservative. 90 millions
of high-risk people need flu shots in USA, with only
60 million doses available : 12 millions of doses
remained unused in 2002. The average flu shot costs 20
US$, while a year's supply of Viagra costs US$ 3,500.
Oxford-based Chiron and Aventis Pasteur are each
expected to produce roughly 50% of the projected 100
million doses for USA in 2004-2005 season, while
MedImmune is likely to supply about 3 million doses of
the intranasal vaccine FluMist. Chiron Corp. announced
on Aug 2004 that it was delaying release of its flu
vaccine doses until early October because some lots of
vaccine didn’t meet sterility standards. The company
said it expected to ship 46-48 million doses, down
from the 50 million doses predicted previously. Chiron
said its planned "late-season delivery" of 2 million
Fluvirin doses for the CDC stockpile for the Vaccines
for Children program remains on schedule : those doses
are in addition to the 46-48 million produced for
general distribution. Chiron says that it then
performed careful safety tests, and showed that the
problem was confined to a few batches, with the vast
majority of the vaccine is safe. But on 5 Oct,
Britain's Medicines
and Healthcare products Regulatory Agency (MHRA)
informed Chiron that it had safety concerns about the
entire production facility in Speke, Liverpool and
suspended the firm's licence for 3 months. UK health
authorities, which use 5 other suppliers, say they
have made alternative arrangements to make up for the
loss of Chiron's near 20% share of the National Health
Service's (NHS) supplies (2.4 million out of 14
million doses). The announcement means a huge vaccine
shortfall is probable in the USA, where Chiron was due
to supply nearly half of the 100 million doses
expected. To a lesser extent, the ban will also affect
Britain. Health authorities will prioritize remaining
stocks of the vaccine to those who most need them,
probably health workers, children, the elderly and
those with illnesses that make them susceptible to
infection. The department is also talking to the only
other major flu vaccine manufacturer, the French
company Aventis Pasteur, to see if it can make up some
of the shortfall. But experts say it will be difficult
to produce a large batch of the vaccine in time to
meet demand by the start of the flu season. Known in
the industry as FDA Form 483, the FDA warned that the
plant had failed to follow its own procedures to
investigate sterility problems. For instance,
bacterial contamination was found in a room that was
supposed to be sterile, even after the room was
fumigated. Even then, the company failed to document
the impact of this sterility failure on its product.
The company also failed to use proper storage
temperatures for its vaccine, failed to properly
follow procedures for cleaning and maintaining
equipment, failed to properly review production
records for accuracy, and failed to take corrective
action after experiencing alerts of contamination.
Ultimately, the company found Serratia bacteria in
nine of its 100 flu vaccine lots. Because the plant
had failed to keep adequate records of each vaccine
batch, it could not trace where the problem started,
nor determine if the other 91 lots were contaminated.
As a result, none of the batches was safe to use. The
discovery meant the loss of half of the flu shots for
the United States and about 10% to 20% of the United
Kingdom's doses. Poor inspections by under-trained
inspectors only make companies feel they have done
sufficient work, and that is what gives rise to GMP
noncompliance problems. On Dec 8 U.K. regulators have
extended the initial suspension of Chiron's license to
make flu vaccines, scheduled to end Jan. 4, until
March 2005 to allow time to fix the manufacturing
flaws, but possibly jeopardizing 2005-2006 supply. The
same day U.S. health officials announced an agreement
to buy 4 million Fluarix doses from GlaxoSmithKline
Plc. ID
Biomedical Corp. signed distribution agreements
with 3 wholesalers to supply flu vaccine to the U.S.,
possibly starting as early in 2005. If the shipments
start later, the total value of the purchases under
the agreements may be about $2.3 billion if the
vaccine is ready for U.S. use by the 2007-2008 flu
season. As of the week ended Nov. 27, Minnesota and
Washington had reported flu cases, and New York
reported more cases around the state. 35 other states,
Washington, D.C., and New York City had sporadic
reports of flu cases. The estimates are that somewhere
between 42- and 50 million people would meet
high-risk, or high-priority criteria, and request
vaccination. There are currently 22.4 million doses of
flu vaccine produced by Aventis Pasteur USA that have
not been shipped. In addition to the doses of flu
vaccine, there is a federal stockpile of oseltamivir,
and there are plans to add up to 5 million treatment
courses of rimantadine to the stockpile as well.
High-risk children, the elderly (> 65 years of age,
with a focus on institutionalized elderly), and the
military would be included in the 1st wave of
vaccinations to be offered. The implications of this
current vaccine shortage/crisis are potentially highly
significant in terms of expected P&I deaths this
coming year in the USA. As a result of the vaccine
shortage, the CDC is planning to teach people how to
protect themselves through hygiene and ‘cough
etiquette’ : you should avoid touching your eyes, nose
or mouth and if you do get flu, stay at home so that
you don’t infect others. Complete projected figures
regarding the effects of the vaccine shortage on the
UK and other countries that were dependent upon this
manufacturer are not presently available for
review/discussion. The UK Department of Health said of
the 14 million doses of flu vaccine they had ordered,
Chiron had only been due to supply 2.4 millionref. In
the USA the dearth of flu vaccine is having one small,
unforeseen benefit: people are flocking to join
clinical trials of new ways to defeat the disease and,
perhaps, fuelling advances in protection. But even
infants, the elderly and others at high risk are
struggling to find supplies and reports abound of long
lines outside clinics. Despite the shortage, some
research groups are still able to run clinical trials
that aim to figure out how best to use the existing
vaccine. And some are testing experimental drugs or
vaccines for the future. One trial, headed by
virologist Pedro Piedra at Baylor College of Medicine
in Houston, Texas, is testing whether the spread of
the influenza virus can be curbed by blanket
vaccination of all school-age children in a local
area. Children are the most likely to get infected and
to pass on the disease to others, so the researchers
hope to discover whether it makes sense to target this
group with vaccines in the future. Because the trial
is pretty much the only way many families can find a
jab for their kids, Piedra says the group has
immunized around 3,000 children in 10 days, a process
that would normally take > 6 weeks. The interest in
clinical trials is also helping those testing
experimental vaccines, such as those that are grown in
cells cultured in the laboratory rather than in hen
eggs. John Treanor at the University of Rochester, New
York, is recruiting around 400 healthy adults aged
< 49 who are willing to receive a syringe-full of a
vaccine grown in insect cells with the baculovirus
protein expression system (e.g. Protein
Sciences : FluBlŘk™, Recombinant
Neuraminidase (rNA) and SARS), which was tested
in the elderly last year. At least one company is
willing to take any number of healthy people into
their trial. GenoMed,
based in St Louis, Missouri, wants to test whether ACEI(binding
receptors
on WBCs inducing apoptosis and dampening an overactive
immune response and can actually ease symptoms) can
also fight flu. The company already has preliminary
evidence that the therapy wards off West
Nile
virus (WNV),
and the opportunity to test it on flu during the
current shot shortage was too good to pass up. Anyone
interested can enrol by printing a form from the
company's website and taking it to their doctor in
order to get a prescription for the drugs; the company
then sends follow-up e-mails to check on subjects'
progress. About 100 people have shown an interest so
far. Although the approach is experimental, the drugs
are widely used and safe enough to pose little risk
Acambis is working on a vaccine based on M2 protein,
which does not mutate : so a single shot of the vaccine
could protect a person against all strains of influenza
virus.
The 10 influenza A (H1N1) 2009
monovalent vaccines produced by 7 different
manufacturers are made from a single influenza virus
strain that is an A/California/7/09-like virus
intramuscular injectable vaccines
influenza
A
(H1N1) 2009 Monovalent
Vaccine (CSL Limited; FDA-approved for USA)
(Panvax®
egg-derived; similar to Afluria®) (0.5
mL preservative-free, single-dose, pre-filled
syringe. 5 mL multi-dose vial containing 10 doses.
Thimerosal, a mercury derivative, is
added as a preservative; each 0.5 mL dose contains
24.5 mg of mercury) :
18 years of age and older
influenza
A
(H1N1) 2009 Monovalent
Vaccine (Novartis Vaccines and Diagnostics
Limited; FDA-approved for USA, EMEA-approved
for France, The Netherlands, Switzerland and
Japan) (Focetria®
egg-derived with adjuvant; Celtura®
cell-derived with adjuvant; Fluvirin®
without MF-59, for USA) (prefilled single dose
syringe, 0.5-mL. Thimerosal, a mercury derivative used
during manufacture, is removed by subsequent
purification steps to a trace amount (< 1 mg mercury per 0.5-mL
dose); multidose vial, 5-mL. Contains thimerosal,
a mercury derivative (25 mg
mercury per 0.5-mL dose)) : 4 years of age and
older.
influenza
A
(H1N1) 2009 Monovalent
Vaccine (Sanofi Pasteur, Inc.; FDA-approved for
USA; EMEA-approved for France, Brazil, Mexico)
(Humenza®with MF-59, Panenza®without
MF-59;
egg-derived; similar to Fluzonet®)
(prefilled syringe, 0.25 mL, no preservative;
distinguished by a pink syringe plunger rod;
Prefilled syringe, 0.5 mL, no preservative (3) ;
single-dose vial, 0.5 mL, no preservative;
Multi-dose vial, 5 mL, contains thimerosal as a preservative. Each 0.5 mL
dose contains 25 mcg mercury.) : 6 months of
age and older (6 through 35 months of age
(0.25 mL dose, intramuscular injection): Two
0.25 mL doses approximately one month apart.)
Celvapan®
(Baxter; EMEA-approved for France, Italy, UK,
Ireland, New Zealand) produced from cell cultures,
without MF-59
Pandemrix®(GlaxoSmithKline; EMEA-approved for France,
UK, Belgium, Italy, Finland, Canada, Mexico and
Japan) egg-derived, with MF-59
PanFlu® (Sinovac
Biotech, also known in China as Beijing Kexing
Bioproducts; China-approved for Mexico)
? : a
randomized, placebo-controlled, double-blind
clinical trial of the influenza A (H1N1) 2009
monovalent, split-virus vaccine was developed by
Hualan Biological Bacterin Company
(China-approved) showed that a single dose
of 15 µg of HA antigen without alum adjuvant
induces a typically protective immune response in
the majority of subjects between 12 and 60 years
of age. Lesser immune responses were seen after a
single dose of vaccine in younger and older
subjectsref.
intranasal spray vaccine
influenza
A
(H1N1) 2009 Monovalent
Vaccine (MedImmune LLC) (similar to Flumist®)
(prefilled single-dose intranasal sprayer
containing 0.2 mL suspension) for the active
immunization of individuals 2-49 years of age;
contraindicated in children and adolescents (2-17
years of age) receiving aspirin therapy or
aspirin-containing therapy, because of the
association of Reye’s syndrome with aspirin and
wild-type influenza infection.
Groups recommended to receive 2009 H1N1
vaccine first are:
pregnant women
people who live with or care for infants younger
than 6 months of age
health care and emergency medical personnel
anyone from 6 months through 24 years of age
anyone from 25 through 64 years of age with
certain chronic medical conditions or a weakened
immune system
As more vaccine becomes available, these groups should
also be vaccinated:
healthy 25 through 64 year olds
adults 65 years and older
Pregnant or breastfeeding women can get inactivated 2009
H1N1 flu vaccine. Inactivated 2009 H1N1 vaccine may be
given at the same time as other vaccines, including
seasonal infl uenza vaccine.
In 1976, an earlier type of swine flu vaccine was
associated with cases of Guillain-Barré Syndrome (GBS).
If GBS has occurred within 6 weeks of previous influenza
vaccination, the decision to give Influenza A (H1N1)
2009 Monovalent Vaccine should be based on careful
consideration of the potential benefits and risks
Epidemiology:
the vaccine alone costs about 7 cents per bird, not
counting the labor of injecting or the monitoring
that should accompany it.
Hong Kong : in 2002
began vaccinating their poultry with an
inactivated oil-adjuvant H5N2
Mexico strain vaccine commonly used elsewhere to
protect against imported virus : it provides
cross-protection and effectiveness in 80% of
chickens against infection from the the 1997 H5N1
strain. Vaccination in the region is said to be
very widespread, probably in reaction to the
wholesale destruction of Hong Kong's chickens
after the H5N1 cases in
people in 1997. In that occasion at 3 farms
chickens in infected sheds were culled, but
chickens in other sheds were inoculated with a
vaccine based on the H5N2
strain. The virus spread to additional sheds on 2
of these farms, killing some of the recently
vaccinated chickens, but 18 days after
vaccination, when immunity had developed, there
were no new cases of disease among the vaccinated
birds; intensive monitoring found no evidence of
asymptomatic shedding. In early 2003, Hong Kong
added universal vaccination to its control
measures. Unvaccinated "sentinel" chickens are
placed within each flock, and there is regular
serologic and virologic testing. When H5N1
swept through neighboring China early this year,
Hong Kong remained virus-free.Hong Kong's
experience is not easily translated to other
countries, however. Hong Kong's poultry industry
is limited to just 150 farms and a handful of
families raising backyard chickens. The territory
is small and has an infrastructure capable of
fully monitoring the use of vaccines. In January
2004 Hong Kong began requiring all imported
poultry to be vaccinated with an inactivated H5
vaccine.
China : currently
officially applied; in 2002 poultry farmers in
southern mainland China began vaccinating their
poultry with an H5N1killed
virus vaccine made at the National Veterinary
Research Institute at Harbin to protect against
imported virus : it provides cross-protection and
effectiveness in 80% of chickens against infection
from the the 1997 H5N1strain.
Vaccination is compulsory in a radius of 5 km
around infected or suspected premises. Several of
the vaccines in use are based on the H5N1
strain itself, making it difficult to track the
disease. And the use of unvaccinated sentinels and
the serological and virological monitoring is
spotty at best. The National Emergency Plan
Against HPAI has inoculated poultry flocks in
areas susceptible to avian influenza infection.
China has also inoculated poultry flocks on
breeding farms, large-sized egg layer farms and in
areas with a high concentration of water
bodies. Poultry in certain areas designated
"no enforced inoculation areas" or "no disease
infected areas" have not been inoculated.
Other areas apply voluntary inoculation.
From February 2004 to January 2005, China has
inoculated a total of 2.68 billion birds -- mainly
chickens, ducks and geese. The objective of
China's poultry vaccine is to inactivate the
highly pathogenic avian influenza (HPAI) virus H5N2.
During 2004, this vaccine played an important role
in HPAI elimination and prevention in China. The
vaccine is only manufactured at the plants
designated by the Chinese Government. The National
Reference Laboratory has also developed 2 new
vaccines. One is a recombinant AI H5N1
virus inactivated vaccine, and the other is a H5N1
fowl pox live virus vaccine. They are highly
efficient, safe and can be produced
cost-effectively. The vaccines passed the Ministry
of Agriculture's new animal drug evaluation and
verification process at the end of 2004. The
recombinant H5N1 virus
inactivated vaccine even works better against the
HPAI because its protective period for chickens is
longer, and it is especially effective for
waterfowl immunity. The vaccine can efficiently
stop the spread of the HPAI virus. Now, it
is widely used for waterfowl inoculation in water
concentrated areas in South China. In order to
strengthen disease control and guarantee
inoculation quality, the Ministry of Agriculture
has carried out regular inoculation supervision
and evaluation through sampling serum and pathogen
tests among inoculated poultry flocks. Up to now,
we have not isolated any H5N1virus
from our inoculated poultry flocks. At the same
time, some provinces in South China have adopted a
measure of placing inoculated poultry in highly
exposed areas to watch the result of infection.
Results of 3 vaccines currently used in China:
A. AI
inactivated vaccine (H5
sub-type, N-28 strain) (seems to be a
traditional inactivated oil emulsion H5
LP vaccine. Based upon a H5N2
LP virus, it has been widely used in China
during 2004 as a DIVA (Differentiating Infected
from Vaccinated Animals) vaccine)
1) Seed
virus: A/Turkey/England/N-28/73, low virulent
strain imported from Weybridge Laboratory Lab
in Britain.
2)
Result: The antibody level reached the highest
rate, namely 8 log2, during the 5th week after
vaccination. This rate was maintained for 4
weeks. The antibody protective level can
be sustained into the 23rd week after
vaccination.
3)
Feature: The Ministry of Agriculture approved
this vaccine as a new bio-product for animal
inoculation in December 2003. This
vaccine was widely used in China during the
outbreaks of HPAI at the beginning of 2004.
B. Recombinant
AI virus inactivated vaccine (H5N1sub-type,
Re-1 strain)
1) Seed
virus: Artificially modified conventional seed
virus A/Goose/Guandong/1996 (H5N1),
which is representative for the antigen in
China, to make H5N1
virus inactive through recombination with
human flu virus.
2)
Result: The antibody reached highest level of
9 log2 during the 3rd week after vaccination.
This rate was maintained for 4 weeks.
The antibody protective level can be sustained
into the 25th week after vaccination.
3)
Feature: MOA approved this vaccine as a new
bio-product for animal inoculation in January
2005. It works efficiently for avian
influenza, it helps poultry organs generate
high levels of antibodies and the protective
period lasts longer. The laboratory
experiments proved that waterfowl inoculated
with this vaccine are free of AI infection or
infectivity. Many countries in the world
now use this method to try to develop
vaccines, but only China has succeeded and put
the vaccine into commercial production.
The inactivated H5N1 vaccine
used in China was produced from a recombinant
strain of LPAI (H5N1)
constructed by reverse-genetic techniques. The HA
and NA were taken from a local prevalent dominant
strain of H5N1 (the sites
related to the high pathogenicity in HA was
blocked/deleted), and the other 6 genes were taken
from the PR8 strain (previously isolated from
humans). This recombinant can grow well in Vero
cells and chicken embryo. The use of this
recombinant as a vaccine candidate has been
subject to extensive debates among Chinese
scientists; a lot of concern was expressed
regarding the potential for a 'gene switch' for
the vaccine strain and field HPAI viruses and
regarding bio-safety procedures. Detailed
information on the vaccine would have allowed a
serious look at relevant potential risks. However,
the vaccine has been widely used nationwide and
the outcome is not known.
C. Recombinant
fowl pox virus live vaccine for AI (H5
sub-type)
1) Seed
virus: Use A/Goose/Guangdong/1996 (H5N1)
as part of gene donor to make a recombinant
fowl poxvirus for a live vaccine.
2)
Result: The antibody reached the highest level
of 7 log2 during the 2nd week after
vaccination. The antibody protective level can
be sustained into the 26th week after
vaccination.
3)
Feature: The Ministry of Agriculture approved
this vaccine as a new bio-product for animal
inoculation in January 2005. It helps
create antibodies against the antigen of
specific proteins. Therefore, it is good
to differentiate immunity and field
infection. Mexico also has this kind of
vaccine and widely uses it.
D. bivalent Avian influenza/Newcastle
disease vaccine, has been developed by the
Harbin Veterinary
Research Institute in northeast China's
Heilongjiang Province and quickly put into
production before thorough bio-safety studies. The
new vaccine is safer, more convenient to use and
cannot kill newborn chicks, attributes that made
it more attractive to farmers than a vaccine they
were already using. The vaccine can be injected,
given as nasal spray or as eye drops, or put into
water supplies and immunizes birds against bird
flu and Newcastle disease. China will produce 1
billion doses by the end of 2005. Production of
the live vaccine costs 20% as much as inactivated
vaccines on the market, has a longer shelf
life of 18 months, and 70-80% effectiveness. The
Chinese bivalent vaccine might be related to a
previously published paper on experimental
recombinant NCD/AI vaccine. A recombinant vaccine
(rNDV-AIV-H7) was constructed by using
a lentogenic paramyxovirus type 1 vector
(Newcastle disease virus [NDV] B1 strain, similar
to LaSota) with insertion of the hemagglutinin
(HA) gene from avian influenza virus (AIV)
A/chicken/NY/13142-5/94 (H7N2).
The
recombinant virus had stable insertion and
expression of the H7 AIV HA gene as
evident by detection of HA expression via
immunofluorescence in infected Vero cells. The
rNDV-AIV-H7 replicated in 9-10 day
embryonating chicken eggs and exhibited
hemagglutinating activity from both NDV and AI
proteins that was inhibited by antisera against
both NDV and AIV H7. Groups of 2-week-old white
Leghorn chickens were vaccinated with transfectant
NDV vector (tNDV), rNDV-AIV-H7, or
sterile allantoic fluid and were challenged 2
weeks later with viscerotropic velogenic NDV
(vvNDV) or highly pathogenic (HP) AIV. The
sham-vaccinated birds were not protected from
vvNDV or HP AIV challenge. The transfectant NDV
vaccine provided 70% protection for NDV challenge
but did not protect against AIV challenge. The
rNDV-AIV-H7 vaccine provided partial protection
(40%) from vvNDV and HP AIV challenge. The
serologic response was examined in chickens that
received 1 or 2 immunizations of the rNDV-AIV-H7
vaccine. Based on hemagglutination inhibition and
enzyme-linked immunosorbent assay (ELISA) tests,
chickens that received a vaccine boost
seroconverted to AIV H7, but the
serologic response was weak in birds that received
only one vaccination. This demonstrates the
potential for NDV for use as a vaccine vector in
expressing AIV proteinsref.
The Chinese scientists applied a similar approach
starting with LaSota strain of NDV, inserting an H5
gene (from which virus strain?) instead of H7.
It would be helpful to obtain data on their work,
particularly the methods and results of challenge
trials, hopefully with better results than the
ones obtained by the experimental rNDV-AIV-H7
vaccine.
During 2005, the
Chinese Government will invest over RMB 5 billion
(approximately USD 600 million) in animal disease
control. China uses the 3 kinds of poultry
vaccines, approved by MOA between Dec 2003 and Jan
2005, for AI prevention.
Indonesia :
currently officially selectivelyapplied in regions
where the virus has appeared. Several of the
vaccines in use are based on the H5N1
strain itself, making it difficult to track the
disease. And the use of unvaccinated sentinels and
the serological and virological monitoring is
spotty at best
Thailand forbids it
as it is worried that vaccination might enable the
virus to circulate silently among vaccinated
birds, exposing farm hands and families to
infection.
Products
:
the application of
AI vaccines with a heterologous neuraminidase (not
N1, in the current case; e.g.
oil-adjuvant H5N2 Mexico
strain) is meant to enable their use as natural
"marker" vaccines or differentiating infected
from vaccinated animals (DIVA). This method
has been advocated and applied in recent years in
several countries, initially Northern Italy) :
there will be cross protection, in theory, but the
shedding of the wild virus might not be prevented.
an inactivated vaccine, based upon an H5N2
virus isolated from ("carrier") geese in Foshan,
1996, developed by Chinese scientists and
announced on 16 Mar 2004 by China's Ministry of
Agriculture (probably as they have done for some
5 or 6 years). It can remain effective within an
animal's immune system for as long as 10 months
An outbreak of avian influenza (AI) caused by a
low-pathogenic H5N2 type A
influenza virus began in Mexico in 1993 and several
highly pathogenic strains of the virus emerged in
1994-1995. The highly pathogenic virus has not been
reported since 1996, but the low-pathogenic virus
remains endemic in Mexico and has spread to two
adjacent countries, Guatemala and El Salvador.
Measures implemented to control the outbreak and
eradicate the virus in Mexico have included a
widespread vaccination program in effect since 1995.
Because this is the first case of long-term use of
AI vaccines in poultry, the Mexican lineage virus
presented us with a unique opportunity to examine
the evolution of type A influenza virus circulating
in poultry populations where there was elevated herd
immunity due to maternal and active immunity. The
coding sequence of the HA1 subunit and the NS gene
of 52 Mexican lineage viruses that were isolated
between 1993 and 2002 were analyzed. Phylogenetic
analysis indicated the presence of multiple
sublineages of Mexican lineage isolates at the time
vaccine was introduced. Further, most of the viruses
isolated after the introduction of vaccine belonged
to sublineages separate from the vaccine's
sublineage. Serologic analysis using
hemagglutination inhibition and virus neutralization
tests showed major antigenic differences among
isolates belonging to the different sublineages.
Vaccine protection studies further confirmed the in
vitro serologic results indicating that
commercial vaccine was not able to prevent virus
shedding when chickens were challenged with
antigenically different isolates. These findings
indicate that multilineage antigenic drift, which
has not been observed in AI virus, is occurring in
the Mexican lineage AI viruses and the persistence
of the virus in the field is likely aided by its
large antigenic difference from the vaccine strainref.
an (homologous?) H5N1
fowlpox vaccine (inactivated/ live-attenuated?
origin? adjuvants?) developed by Chinese
scientists and announced on 16 Mar 2004 by China's
Ministry of Agriculture. Probably it is produced
by taking the H5 gene from H5N1
outbreak virus and inserting it into fowlpox virus
(as David Swayne did in the USA in 1997) and using
it as a live fowlpox/AI vaccine, as has been used
in Mexico since 1997. It can remain effective
within an animal's immune system for as long as 10
months
Vietnamese researchers injected a vaccine based
on weakened H5N1 bird flu
virus on 3 monkeys early in Feb 2005, and 3 weeks
later found the monkeys were healthy and had
produced antibodies. Vietnamese researchers hope
to have a vaccine ready for testing on humans in
2004
for humans : the only
difference is that when we vaccinate with annual
flu, people have one shot because they already have
some background immunity. Here, we know the
population is totally naďve, so it's difficult to
raise a protective immune response. Because H5N1
is so deadly in chicken embryos, reverse genetics is
required to prepare the prototype H5N1
virus for vaccine production, which requires growth
in chicken eggs : reverse genetics will remove a
stretch of 4-5 basic amino acids at the HA cleavage
site that allows the virus to replicate in every
organ of a chicken's body (rather than only in the
epithelial tissues (respiratory and intestinal)
normally infected) and merges the NA and
modified HA genes from H5N1
with the other 6 viral genome segments from
(A/PR8/34)[H1N1], a
rapidly growing "master" strain of virus commonly
used to make vaccines. The reassortment prototype
virus can be rescued in 1 week : after that comes
amplification in embryonated hen's eggs, followed by
safety testing in chickens and in ferrets. Within 4
weeks sufficient amounts of safety-tested prototype
vaccine virus will probably be available for the
necessary 1 to 2 months of clinical trials. The
resulting virus is recognized by the human immune
system and causes a protective immune response but
no disease. Vaccine developers :
in 1998, an American
company announced the production of an
experimental batch of an H5N1
human vaccine, and, according to their
communication, delivered > 1000 doses of the
new vaccine to the NIH for use in trials
in May 2004 the
NIAID contracted 2 suppliers of the annual
influenza vaccine to prepare 16,000 doses of an
investigational H5N1 avian
influenza vaccine. To make the vaccine, virus was
taken from a patient who died in February 2004 in
Vietnam and altered with reverse genetics to
reduce pathogenicity.
Sanofi
Pasteur (USA, France) : in March 2005,
Sanofi Pasteur had 8,000 doses ready to be
shipped to the NIH to begin clinical trials. A
phase I trial started in March 2005 involved 450
healthy adults in Rochester, New York; Baltimore
and Los Angeles a French vaccine company that is
now part of Aventis. The government could decide
to release the product under emergency
conditions if an A(H5N1)
influenza pandemic struck before the testing
process was completed. Although cautioning that
the vaccine has not been fully tested, the
initial test findings have given the federal
government enough confidence to start the
process of adding millions more doses of the
vaccine to the 2 million it has bought. The
present supply is stored in bulk form, and they
cannot put it in vials until they find out what
the right dose is. The manufacturer needs to
know the dose and regimen to determine how much
more vaccine it can produce and make available
to the USA and other customers. NIH announced on
Aug 2005 preliminary results of tests in 115
people of a vaccine against the H5N1
avian flu virus, showing that 2 large doses
should protect adults from infection. But
critics point out that the large amounts needed
mean the hundreds of millions of doses needed to
tackle a pandemic could never be produced.
Vaccines that work at much lower doses are
urgently needed. The NIAID tested 4
concentrations of vaccine on 452 healthy adults.
The drug was made by the pharmaceutical company
Sanofi Pasteur's facility in Swiftwater,
Pennsylvania. 2 shots at 90 µg of flu
antigen each were needed to produce an immune
response likely to confer protection - the
highest concentration tested. Annual flu
vaccines typically use a single shot of
15µg. Needing 2 doses of 90µg is the
worst-case scenario. If the entire US vaccine
production system, which can produce 180 million
seasonal flu vaccines, was devoted entirely to
making pandemic vaccine at this concentration,
it could make enough for 15 million people:
barely 5% of the US population. The US
government plans to stockpile the vaccine to
protect first-responders in the immediate
aftermath of a pandemic. It has bought 2 million
H5N1 vaccines from Sanofi
Pasteur, and says it intends to buy 20 million
more. But given the test results, these would
only protect 330,000 to 3.4 million people, far
short of the 20 million US goal. Sanofi Pasteur
will double its capacity to produce flu vaccine
in the USA and France in 3-4 years time. But
that would not be enough to produce sufficient
vaccines unless the dose was < 15 µg. Critics
argue that the vaccine must be changed to work
at much lower doses : this is difficult, as
people have no natural immunity to avian flu.
Lower doses can be used for seasonal flu jabs,
as people have a natural exposure to such
viruses in their daily lives, giving them a low
level immune response. Results from earlier
trials suggest that low doses might work in
combination with an adjuvant : but regulatory
agencies treat adjuvanted vaccines as new
products, and so require a lengthy approval
process. NIAID will now start tests of 3
adjuvants : they will also investigate other
dose-reducing strategies such as injecting the
vaccine into skin or muscle. The institute will
also test the vaccine in children and the
elderly. An immune response in healthy adults
does not guarantee that the vaccine will work in
these other groups. In the meantime, experts
caution that enthusiasm over early results might
do more harm than good, making policy makers and
others responsible for pandemic preparedness
feel optimistic, and reluctant to speed up
urgent pandemic preparedness.
Chiron
(USA)'s half of the vaccine supply has been
delayed due to problems at its Liverpool
facility used to produce its commercial flu
vaccine. They are manufacturing the clinical
supply of H5N1 in
Liverpool, UK, in the same location that makes
our commercial vaccine, Fluvirin, but in a
different part of the facility : the US and
France have each contracted with Sanofi Pasteur
to produce 2 million doses of the prototype
vaccine.. But tests of the Chiron vaccine have
not started because of delays related to prior
contamination found in Chiron's plants. The
NIAID has 8000 doses of the Chiron human A(H5N1)
vaccine and hopes to start testing it in
volunteers in late fall. The tests will follow
the same steps taken with the Sanofi-Pasteur
vaccine
This approach is
disadvantaged by the lapse of time between choice
of vaccine strain and appearance of a pandemic
virus which may have diverged by progressive
genetic mutation, or may even have acquired
non-homologous H (and/or N) antigens by
reassortment.
ID
Biomedical Corp. (Canada) announced in Jan
2005 that it had begun development of a mock
vaccine against H5N1 using
the genetically modified rH5N1
reference strain from the UK's National Institute
for Biological Standards and Control
National
Institute for Biological Standards and Control
(NIBSC) in Potters Bar, London, UK and St Jude Children's
Research Hospital in Memphis, Tennessee, USA
: an H5N1 candidate human
vaccine was developed in 2003. The strain was
based on the virus isolated in February 2003 from
a human case in Hong Kong. The candidate prototype
vaccines have already undergone basic tests to
ensure safety and effectiveness, genetic
stability, and antigenic homogeneity
Sinovac
(China) is currently advancing its inactivated H5N1
vaccine (PanFlu®) through the various
stages of pre-clinical studies. On March 25 2004,
Sinovac received a reassortant influenza strain (NIBRG-14)
for developing a Pandemic Influenza Vaccine (H5N1)
from the British National Biological Standard and
Control (NIBSC), which is the WHO International
Laboratory for Biological Standards.
Vietnam : Hanoi-based Vaccine and Biological
Products No. 1 Company will test a homegrown bird
flu vaccine on humans and poultry in summer 2005
after successful tests on mice and monkeys. The
trials will be conducted in August on a group of
10 to 20 people to check the vaccine's
effectiveness and safety. The vaccine, which has
been successfully tested on mice and monkeys, will
later be given to 200-300 other people who are
healthy and have close contact with poultry. The
same vaccine also will be tested on poultry in
June. If the results are successful, the company
hopes to mass produce the vaccine for humans and
poultry in early 2006. The trials are expected to
be completed before January 2006.
Australia ?
GlaxoSmithKline
: prepandemic influenza vaccine H5N1
(Prepandrix®;
AS03-H5N1 vaccine] is a split virion, inactivated
vaccine containing H5 hemagglutinin antigen
adjuvanted with a novel 10% oil-in-water
emulsion-based adjuvant system (AS03). It is
approved in the EU for use as an active
immunization against H5N1 subtype influenza A
virus (influenza A/H5N1 virus) in adults aged
18-60 years. The recommended dosage in this
population is two doses of 0.5 mL containing 3.75
microg of H5 hemagglutinin, administered > or
=21 days apart. Adjuvantation of H5N1
vaccine with AS03 allows for a reduction in the H5
hemagglutinin dose required to elicit an adequate
immune response, and administration of two doses
of the adjuvanted vaccine met all criteria for the
licensure of influenza vaccines set out in
European Committee for Proprietary Medicinal
Products (CPMP) and US FDA documents.In two
clinical trials, two doses of AS03-H5N1
vaccine containing 3.75 microg of H5 hemagglutinin
induced an immune response in healthy volunteers
aged 18-60 years against the homologous, clade 1
vaccine strain, A/Vietnam/1194/2004, and the
heterologous, drifted, clade 2 nonvaccine strains,
A/Anhui/1/2005, A/Indonesia/5/2005, and
A/turkey/Turkey/1/2005. This cross-clade response
persisted for > or =6 months following
administration of the first vaccine dose in the
majority of vaccine recipients. In addition,
AS03-H5N1 vaccine protected against lethal
challenge with A/Vietnam/1194/2004 or
A/Indonesia/5/2005 in animal studies. The vaccine
was generally well tolerated and adverse events
were transient and predominantly of mild to
moderate severity.AS03-H5N1
vaccine has demonstrated antigen dose-sparing
properties and cross-clade reactive immunity in
clinical trials and challenge studies in animal
models. Enrolled in the study were 451 healthy
adults 18 to 64 years of age who received two
doses of the vaccine without adjuvant, each of
which contained 90, 45, 15, or 7.5 µg of
hemagglutinin antigen, or placebo. The vaccine was
produced from a human isolate (A/Vietnam/1203/2004
[H5N1]) of a virulent clade
1 influenza A (H5N1) virus
with the use of a plasmid rescue system, with only
the hemagglutinin and neuraminidase genes
expressed. The rest of the genes were derived from
an avirulent egg-adapted influenza A/PR/8/34
strain. The hemagglutinin gene was further
modified to replace 6 basic amino acids associated
with high pathogenicity in birds at the cleavage
site between HA1 and HA2. Immunogenicity was
assessed by microneutralization and
hemagglutination-inhibition assays with the use of
the vaccine virus, although a subgroup of samples
were tested with the use of the wild-type
influenza A/Vietnam/1203/2004 (H5N1)
virus. Although the 1203 vaccine was safe, with an
unremarkable adverse-event profile, its
immunogenicity was poor to moderate at best. In
fact, in only one group did > 50% of the
subjects reach the immunogenicity threshold
(defined a priori) of an antibody titer > 1:40
(typically thought of as seroprotective) — the
subjects who received two doses of 90 µg each 28
days apart — a total dose 12 times that of
seasonal influenza vaccines. Notably, the current
worldwide manufacturing capacity for influenza
vaccine is estimated at only 900 million doses (at
the dose level of 15 µg). The requirement of 2
doses of 90 µg per person means that only 75
million persons (1.2% of the world's population)
could be fully immunized, and of those, only half
would achieve seroprotection. Thus, vaccines must
contain much less influenza hemagglutinin to be
widely useful as a global public health measure.
And there are some additional provisos. An
antibody titer of 1:40 does not guarantee
protection from infection. People with lower
titers show protection against influenza, and
people with higher titers can have symptomatic
infection. Moreover, the assumption that a titer
of 1:40 is seroprotective is based on circulating
strains of seasonal influenza. Whether the same
will prove to be true for new influenza viruses in
people whose immune systems have not been primed
is unknown. However, even moderate levels of
seroprotection could be useful for the public
health by preventing or decreasing
transmissibility, severe symptoms, complications,
or death. An important issue is whether the 1203
vaccine offers cross-protection against other H5N1
strains of influenza Aref.
Studies of different dose levels of vaccines
administered with MF59 (a licensed adjuvant in
Europe), aluminum hydroxide, or other adjuvants
are urgently neededref.
We know from previous work that new hemagglutinin
proteins (including H5) in people who
have not been primed are poorly immunogenicref1,
ref2.
In recognition of this fact, the Department of
Health and Human Services and the National
Institutes of Health have funded studies of >
30 candidate vaccines. Early results from some of
these trials should be available in the next 6 to
12 months. Previous studies of a new influenza A
(H5N3) vaccine administered
with MF59 adjuvant showed that vaccine
administered without adjuvant was poorly
immunogenic but that vaccine administered with
MF59 adjuvant in two doses, each as low as 7.5 µg,
was highly immunogenic and resulted in
cross-neutralizing antibodies against influenza A
(H5N1)ref1,
ref2.
Studies of an influenza A (H2N2)
vaccine administered with alum adjuvant had
similar results: hemagglutination-inhibition
titers increased significantly at doses as low as
1.9 µgref.
The immediate development and testing of such
antigen-sparing vaccines administered with
adjuvant are imperative both to improve
immunogenicity and to increase the number of doses
available (if lower doses are effective). In
addition, live attenuated cold-adapted influenza
vaccines are safe, are immunogenic, and have the
relevant advantage of cross-protection against
heterologous influenza strains — suggesting a
promising avenue to the development of pandemic
vaccines. A contract for the development of such
vaccines has been awarded to MedImmune. Other
approaches to vaccine development involve DNA,
adenovirus vectorsref,
and cell-culture manufacturing techniques to
increase the speed and capacity of vaccine
production. These approaches are promising,
particularly since reverse-genetics reassortant
vaccine candidates can be generated within weeksref
The H5N1
from the outbreaks in Viet Nam and South Korea in
late 2003-2004 has a different genetic sequence and
antigenicity from the 2003 H5N1
strain in Hong Kong =>
the H5 strains
currently causing disease in South-East Asia are
recognised poorly by antiserum generated against
2003's H5vaccine strains, and so the
entire process is being repeated at NIBSC, at CDC
in Atlanta, and at St Jude Children's Research
Hospital in emphis. The minimum time to generate
the new strain is about 1 month. On Feb 13, 2004
the NIBSC has generated a reassortant candidate
vaccine strain containing the HA and NA of a human
H5N1 influenza virus
isolated recently in southeast Asia
(A/Vietnam/1194/04) (the other 6 viral genome
segments were supplied by the laboratory virus
A/PR8/34).
it seems probable
that the Chinese H5N1
vaccine is also not a very close antigenic match
for the Viet Nam virus. A flu vaccine will allow
flu virus for which it is not a close antigenic
match to continue to circulate at low levels in
vaccinated flocks. So the Chinese vaccine could
allow the Viet Nam virus to spread if it is
present. This could continue unnoticed, without
mass disease outbreaks to give the virus's
presence away, until it reached an unvaccinated
flock. These would tend to be in smallholdings,
and would probably be ducks, because they
traditionally do not get sick with flu and are
probably not commonly vaccinated. So the discovery
of H5N1 in a duck
smallholding in Guangxi is interesting. The
currently circulating H5N1,
like the related one that caused an outbreak in
Penfold Park, Hong Kong in 2003, is unique in that
it kills ducks as well as a variety of other
birds. This might make it less likely that wild
birds are mainly responsible for carrying the
virus over long distances. It is interesting to
speculate what selective pressures an H5N1
virus circulating at subclinical levels in very
large numbers of partially-immunised chickens
might be subject to, and how that might relate to
the emergence of the current outbreaks
It is possible that there is cross-protection in
adults to the N1 component of H5N1
that is attenuating their presentation : the
neuraminidase protein is associated with severity of
influenza illness, so it is possible that there is
protection against N1 in adults from their
cumulative experience with human N1
influenza viruses that could be resulting in milder
illness from this avian strain. Perhaps
immunologically naive young children do not have the
benefit of this broad cross-protection from other N1
exposure (influenza A (H1N1)
virus first emerged in 1918 -- the most severe of
known influenza pandemics -- a highly virulent strain.
N1 subtypes have been co-circulating with
other influenza viruses since 1977, but H1N1
viruses cause less extensive or widespread outbreaks.
It may be that younger persons have not had the
benefit of cumulative opportunities for antigenic
exposure and resulting cross-protection. When
Influenza H1N1 reached England
in 1977, nearly everyone infected with it (and
confirmed by a laboratory) had been born after 1956,
when the H1N1 virus had
previously disappeared, having circulated from
1947-1956. In fact, in 3 consecutive years we had
infections with H1N1, H3N2,
and then both together. Age distributions of those
affected in these years showed this very nicely: H1N1
<25y, H3N2 the usual J-shaped
curve, and both an amalgam of the 2 distributions. In
contrast to the neutralizing, infection-preventing
antibody induced to the major antigen of the influenza
virus -- the hemagglutinin (HA), antibody to the NA is
infection-permissive, yet disease-suppressive, and it
has been repeatedly demonstrated in experimental
animals that this effect results from partial
suppression of virus load over a wide range of
antibody concentrations. There is epidemiologic
evidence that the impact of the H3N2
1968 pandemic was blunted by pre-existing encounter of
humans with the N2 NA in the H2N2decade
following
the pandemic introduction of H2N2
virus in 1957. The evolutionary rate of NA
antigenicity is slower than that which occurs with the
HA. This could have implications for
protective/preventive approaches : could vaccination
with already on hand H1N1 human
strains attenuate disease due to H5N1,
if not prevent it altogether? However, there is
another possible explanation for the greater
susceptibility of children to new influenza strains
and even subtypes. Immunity can be directed to
antigens conserved between viruses that do not share
neuraminidase antigens, for example nucleoprotein
(NP), matrix (M), and the polymerases. This broad
cross-protection, termed heterosubtypic immunity,
has been studied in animals for decades and can be
mediated by T-cell immunity as well as in some cases
antibodies (see Epstein, S.L. Control of
influenza virus infection by immunity to conserved
viral features. Expert Rev. Anti-Infect. Ther. 1(4):
89-100, 2003). Can this form of immunity protect
against highly pathogenic H5N1
viruses? Vaccination to NP and M was indeed shown to
protect mice against lethal challenge with H5N1
virusref
: do humans have heterosubtypic immunity? Dr. Suzanne
Epstein conducted a study of archival records from the
Cleveland family study during the 1957 pandemic. The
antigenic shift in 1957 was from H1N1
to H2N2, thus no shared NA.
Nonetheless, records suggest an effect of prior
immunity, perhaps accumulated immunity to conserved
components. In particular, adults differed from
children in the effect of prior infection, with
children getting flu again in 1957 despite earlier
bouts but adults rarely getting it again. This work is
not yet published. More investigation of the multiple
possible explanations for the age incidence data is
needed. Another factor to consider in relation to
age-related cross-protection is the concept of original
antigenic
sin (OAS)
first described by Francis in 1953: the serological
response of an individual to influenza A virus
infection is dominated throughout life by the nature
of the antibody produced in response to the first
influenza A virus infection. It is a characteristic of
viruses for which there are cross-reacting antigenic
types. Consequently the cross-reacting responses of
adults will vary and relate to the serotype of
influenza A virus that was predominant when they were
young. However, the relationship is not
straightforward. Powers and Belsheref
observed that elevated titers of antibodies to
heterologous antigens were present both before and
after vaccination in higher proportions of middle-aged
and elderly than young adults following vaccination
with a current vaccine, whereas antibodies to more
recent antigens were prevalent in all age groups.
Notably, vaccine responses to heterologous viruses
were consistently reduced in frequency and magnitude
with advancing age. Also, within each age group,
antibody responses against progressively older
heterologous antigens tended to diminish. These
authors concluded that preferential orientation of
secondary antibodies toward priming epitopes (OAS) is
not responsible for the age-related impairment of
antibody responses to influenza vaccine. Antigenic and genetic characteristics of H5N1
viruses and candidate H5N1
vaccine viruses developed for potential use as
pre-pandemic vaccinesref
: this WHO document describes the current status of
the development of new candidate H5N1
vaccine viruses and is intended to provide guidance
for national authorities and vaccine companies on the
selection of candidate viruses for use in vaccine
development. The selection of H5N1
vaccine viruses should consider the geographical
spread, epidemiology, and antigenic and genetic
properties of recently circulating H5N1
viruses.
H5N1 vaccine viruses
developed for potential use as pre-pandemic
vaccines : the development of representative
pre-pandemic H5N1 candidate
vaccine viruses by the WHO Global Influenza
Programmeref
is being conducted as one step in an overall
strategy for pandemic preparedness. This summary
presents the current status of the development of
new candidate H5N1 vaccine
viruses and is intended to provide guidance for
national authorities on the production of
pre-pandemic vaccine. The H5N1
viruses chosen for development of pre-pandemic
candidate vaccine viruses are representative of
antigenically and genetically distinct groups of
viruses that have infected humans primarily
through contact with ill or dead H5N1-infected
birds. These representative candidate H5N1
vaccine viruses have been prepared by reverse
genetics and safety tested prior to release for
production of pilot vaccine lots that may be used
for experimental studies and for stockpiling by
governments in advance of a possible H5N1
pandemic, should such a national policy exist.
Companies are recommended to consult individual
national authorities on the H5N1
strains to be used. Decisions should be based on
the epidemiology of the circulating H5N1
viruses that are described below. Comparison of
the previously developed (clade 1 rg
A/Vietnam/1194/2004 and rg A/Vietnam 1203/2004)ref
and new candidate H5N1 vaccine viruses and studies
of cross-reactivity of these pre-pandemic vaccine
viruses and their relationship to newly emerging H5N1
viruses are ongoing, and will be reported
periodically by WHO.
genetic characteristics of recent H5N1
viruses : the haemagglutinin (HA) sequences of the
majority of H5N1 viruses
circulating in avian species during the past 3
years separated into 2 distinct phylogenetic
clades (genetic groups)ref.3
Clade
1 viruses circulating in Cambodia, Thailand and
Viet Nam were responsible for human infections in
those countries during 2004 and 2005. Clade 2
viruses circulated in birds in China and Indonesia
during 2003-2004 and subsequently during 2005-2006
spread westwards to the Middle East, Europe and
Africa. This latter genetic group of viruses has
been principally responsible for human infections
during the later part of 2005 and 2006. Six
sub-clades of clade 2 have been distinguished, 3
of which (subclades 1, 2 and 3) also differ in
geographical distribution and have been largely
responsible for human cases in Indonesia, in
countries in the Middle East, Europe and Africa,
and in China, respectively. Figure 1 in the
original document is a phylogenetic tree showing
the relationships of some 60 strains comprising
the 2 major clades and the 3 sub-clades.
antigenic characteristics of recent H5N1
viruses : the antigenic relationships between the
HAs of human isolates representative of clade 1
and 3 subclades of clade 2 were compared by
haemagglutination inhibition (HI) tests using
post-infection ferret antisera. Reciprocal
cross-reactions in HI tests demonstrated antigenic
similarity of HAs within the same genetic clade
and distinguished representatives of different
clades with the exception of viruses from the Karo
clusterref
represented by A/Indonesia/CDC625/2006. Viruses
from this family cluster were antigenically
distinguishable from the majority of human
isolates represented by A/Indonesia/5/2005 and
A/Indonesia/CDC357/2006 (subclade 1), and appeared
antigenically more closely related to H5N1
viruses in subclade 2. In the original document
These data for 14 strains representing the 2 major
and 3 sub-clades are compiled in the form of a
table, illustrating striking differences in
haemagglutination inhibition titres
new candidate vaccine viruses : viruses
representative of subclade 1 (A/Indonesia/5/2005)
and subclade 2 (A/Bar headed
goose/Qinghai/1A/2005, A/Whooper
swan/Mongolia/244/2005 and A/turkey/Turkey/1/2005)
were selectedref
for the preparation of reverse genetics modified
reassortant vaccine viruses using the laboratory
reference strain A/PR8/34 as donor of the
polymerase, nucleoprotein, matrix and
non-structural protein genes. HI analysis
confirmed that the reassortant candidate vaccine
viruses were antigenically similar to the parent
viruses and the majority of recent isolates within
the same clade. On the basis of more recent data,
a subclade 3 vaccine virus is also being prepared
from A/Anhui/1/2005.
recommended use of candidate pre-pandemic H5N1
vaccine viruses : pre-pandemic vaccines have been
produced by manufacturers using clade 1 viruses (rg
A/Vietnam/1194/2004 (NIBRG-14) and rg
A/Vietman/1203/2004 (CDCRG-1 and SJRG-161052).
Clinical trials have been conducted or are under way
in several countries and stockpiling of clade 1
vaccines has begun in some countries. Because it is
not known if the next influenza pandemic will be
caused by H5N1 viruses or
which of the clades or subclades of H5N1
would be responsible, should one occur, clinical
trials using clade 1 viruses should continue as an
essential element in pandemic preparedness to
maximize data available on priming, cross-reactivity
and cross-protection by vaccine viruses from
different clades and subclades. On the basis of the
geographical spread, the epidemiology, and the
antigenic and genetic properties of the H5N1
viruses isolated from humans during the past 12
months, national authorities may recommend the use
of one or more of the following H5N1
candidate vaccine viruses for pilot lot vaccine
production and subsequent stockpiling of vaccines,
should relevant national policies exist:
An A/Indonesia/5/2005-like virus
An A/Bar headed goose/Qinghai/1A/2005-like
virus (Candidate vaccine viruses also include
A/turkey/Turkey/1/05 and A/Whooper
swan/Mongolia/244/2005)
An A/Anhui/1/2005-like virus (Candidate
vaccine virus in preparation)
Vaccines for avian influenza typically are aimed at
hemagglutinin or neuramidase on the outside of the virus
capsid. A major problem with such an approach is that
the genes coding for these proteins have a very rapid
mutation rate, forcing commercial producers to wait for
mutations to occur before developing effective new
versions of standard vaccines. However, a recent study
has revealed that the 1918 flu virus, like the H5N1
AI virus, has an E627K mutation in its PB2
component, which is located inside the virus capsid.
Other research has indicated that this mutation strongly
influences the virulence of H5N1.
It seems reasonable to believe that the constancy, over
> 80 years, of the E627K mutation could be exploited
to begin developing a vaccine now, rather than waiting
for new mutations. The peptide sequence, DTVQIIKLL,
present in the PB2 protein of the H5N1
virus, would be expected to bind to HLA-A26 restricted
immune system cell surface receptors. Hence, the bound
peptide might be capable of stimulating protection from
CTLs. Should the present hypothesis be confirmed in
laboratory studies, and an effective vaccine developed
for individuals expressing the HLA-A26 receptor; further
research would be indicated. This research would be
aimed at determining whether molecular modifications to
the DTVQIIKLL peptide could make it effective with other
members of the HLA-A1 supertype to which HLA-A26
belongs. In addition to allowing vaccine development to
begin now, this peptide-based approach would have the
advantage of avoiding the use of dangerous, live, avian
influenza virus during mass productionref.
The pandemic vaccine could largely be provided in
multi-dose vials, and avoid an important bottleneck
linked to filling and packaging of single-dose vials or
syringes which would thereby maximizing the number of
doses that can be made available. Moreover, single dose
presentations would be more costly and create
substantial difficulties from a storage (cold room
capacity) and logistics point of view. When a vaccine is
supplied in multi-dose vial, it is normal practice not
to provide needles and syringes. IFPMA IVS ITF members
propose to follow this normal practice when distributing
a pandemic vaccine. In order to be fully prepared for a
pandemic situation, IFPMA IVS ITF suggests that each
government/country should clearly anticipate its needs
for needles and syringes and take the appropriate
measures to secure supplies in advanceref.
Commercialized formulas :
split-virus vaccine (SVV)
: the inactivated virus is chemically disrupted, and
then further purified. The split virus vaccine is less
reactogenic (associated with fewer side effects) than
the whole virus vaccine, especially in children and
young adults. For this reason, only split virus
vaccines are recommended for use in children under 13
years of age.
Begrivac® (Behringwerke =>
Chiron, globally)
preservative containing
preservative-free
Elvarix® (VEB Sachsisches
Serumwerk Dresden)
Fluarix®(GlaxoSmithKline
Inc.,
made by its German subsidiary Sachsisches Serumwerk)
: a 1,000-person (aged 18-64) phase III clinical
trial started in Dec 2004 at 4 U.S. hospital centers
-- the University of Rochester Medical Center, the
University of Maryland School of Medicine,
Cincinnati Children's Hospital, and Baylor College
of Medicine. Approved by FDA for use in adults
Sanofi Pasteur, Inc. is the 1st leading flu
vaccine manufacturer worldwide, which makes about
45-50% of the world's supply
Fluzone® (Sanofi Pasteur)
Imovax Gripe® (Sanofi
Pasteur)
Istivac® (Sanofi Pasteur)
MFV-Ject® (Sanofi Pasteur)
Vaxigrip® (Sanofi Pasteur)
Baxter : PreFluCel® : phase
II/III clinical trial in Europe was suspended in Dec
2004 due to a higher than expected rate of mild
fever and associated symptoms in the clinical trial
participants.
Chiron, based in California, is the 2nd leading
flu vaccine manufacturer worldwide. Chiron makes 4
influenza vaccines :
Fluvirin® (Evans Medical,
Servier => Chiron), the top flu vaccine in
northern Europe and the No. 2 vaccine in the US.
Adinvira A+B® (Imuna)
Admun® (Duncan)
Admune GB® (Duncan)
Alorbat® (Asta Pharma)
Biaflu Zonale® (Farmabiagini)
Flubron® (Pfizer)
Flugen® (?, UK)
Fluogen® (Parke Davis)
FluShield® (Wyeth-Ayerst)
Fluviral® (Armand-Frappier)
Gripax® (Hebrew University)
Gripe® (?, Spain)
Gripovax® (GlaxoSmithKline)
Grippe® (?, France)
HIS® (Serbian Institute)
Inflexal® V (Swiss Serum and
Vaccine Institute) : A virosomal influenza vaccine,
with a composition in accordance with annual
recommendations of the WHO
Influmix® (Schiapparelli)
Influpozzi Zonale® (Ivp)
Influvac S® (Duphar)
Influvirus® (Ism)
Invirin® (GlaxoSmithKline)
Isiflu Zonale® (Isi)
MFV® (Servier)
Miniflu® (Schiapparelli)
Munevan® (Medeva)
Mutagrip® (Aventis Pasteur)
Nivgrip® (Nicolau Institute of
Virology)
Sandovac® (Sandoz)
Vaxihaler-Flu® (Riker) :
inhaler
Side effects :
atypical lymphoid infiltrations arose within the
influenza inoculation sites of two adult female
patients. One patient developed a low-grade cutaneous
marginal
zone B-cell lymphoma (MZL)
that was responsive to local excision and radiation
therapy despite spread to a distant cutaneous site.
The second patient's clinical course was characterized
by a locally aggressive, histologically reactive
inflammatory reaction responsive only to radiation
therapy after multiple failed attempts at surgical
resectionref
false positive results in HIV serological
testing due to cross-reactivity between the
transmembrane domain of HIV-1 env protein and HAref
anti-polioviruses 1, 2
and 3
vaccine (inactivated polio vaccine (IPV))
(see also attenuated
vaccine) : developed by Jonas Salk in 1957.
Viruses cultured on primary Cercopithecus
aethiops (African green monkey) kidney (CMK)
cells and killed by formalin. 4 intramuscular injections
at month 1, 2, 3, and age 1. Effective for > 5 years
in 100%.
Purivax®
(Merck) : no longer in use (1956 to 1965)
IPV-Virelon®
(Chiron, Italy)
Virelon C®
(Chiron, Germany)
The polio vaccine used in the USA from 1955 to 1963 was
found in 1960 to be contaminated with SV40, which resists
to formol inactivation of polioviruses. The tainted
vaccine was never recalled. It may have been given to 10
million to 30 million Americans. Vaccines made after 1961
were free of the virus. There is no doubt that SV40 causes
4 cancers in rodents (osteosarcomas, ependymoma,
mesothelioma, and non-Hodgkin's lymphoma) : the virus has
been detected in tumor cells from people with the four
cancers that develop in rodents. Further CMK cells are
often contaminated by simian
cytomegalovirus
(SCMV)
in lots of vaccine manufactured prior to 1992 : SCMV DNA
but not infective forms have been found in CSF from
patients with encephalopathies.
anti-rabies virus
vaccine (see also DNA
vaccine)
: intramuscular injections at day 0, 7 and 21-28.
Booster every 2 year. Effective for 2-3 years. The
original rabies vaccine discovered by Louis Pasteur was
administered to Joseph Meister. It can be preparated on
cultures of :
human diploid embryo lung cells (human diploid
cell vaccine (HDCV)) : inactivated with
propiolactone, much lower incidence of adverse
reactions than the previously used...
Imovax Rabies®
/ Imovax Rage® (Aventis Pasteur
Swiftwater, PA) : on April 2, 2004 following the
discovery through routine testing of a
non-inactivated Pitman-Moore virus (the attenuated
vaccine strain) in a single product lot which was
not distributed, some lots of Imovax®
Rabies, Rabies Vaccine (Human Diploid Cell) that
were produced during the same period as the lot that
contained noninactivated Pitman-Moore virus were
recalled as a precautionary measure :
Country / Lot
Angola / X0713-4
Australia / X0713-1,
X0074-3, X0074-4
Botswana / X0713-4
Croatia / X0074-1
Denmark / X0253-2
Chad / X0074-1
Germany / X0071-2,
X0253-4
Hong Kong (China) /
X0074-1
Ireland / X0071-6,
X0712-1
Italy / X0253-6,
X0253-8
Malawi / X0713-4
Mozambique / X0713-4
New Zealand /
X0713-1, X0074-3, X0074-4
Netherlands /
X0071-3
Norway / X0253-1
Nigeria / X0074-1
Oman / X0074-1,
X0074-5
Spain / X0071-1
Switzerland /
X0071-7, X0253-5, X0253-7
United Arab Emirates
/ X0074-1, X0074-5
United Kingdom /
X0071-6
United States /
W1419-2 (expiration date : 12/6/2005), W1419-3
(expiration date : 12/6/2005), X0667-2 (expiration
date : 6/24/2006), X0667-3 (expiration date :
6/24/2006), distributed in the U.S. from September
23, 2003 through April 2, 2004
Zambia / X0713-4
Zimbabwe / X0713-4
The lots being recalled
passed all release tests, including testing to
confirm the absence of live virus. All purchasers
and distributors of vaccines from the recalled lots
are being notified. Health care providers will
notify any recipients of the recalled vaccine of
next steps, which may include the recommendation
that some individuals receive additional doses of
vaccine and, if appropriate, rabies immune globulin.
hamster kidney
Semple
rabies vaccine is composed of rabies
virus-infected sheep or goat brain inactivated with
phenol and is administered daily after exposure for
14-21 days. It has been abandoned because 1 case in
220 immunized individuals develop Semple rabies postvaccinial
autoimmune
encephalomyelitis (SAE) 10-14 days after
vaccination : it is mediated by IgM antibodies to myelin
basic protein (MBP), GM1 or GD1a
gangliosides and Th1 lymphocytes reactive
against MBP.
primary cultures of chicken fibroblasts
(purified chick embryo cell (PCEC) vaccine (PCECV))
: a lyophilized vaccine inactivated with b-propiolactone
fetal rhesus lung : rabies vaccine adsorbed (RVA)
: the virus is inactivated by b-propiolactone
and
concentrated by adsorption to aluminum phosphate
purified vero cell rabies vaccine
(PVRV)
Abhayrab® (source : Human
Biologicals Institute, Ooty, India) : pre-exposure
study was undertaken on 60 healthy volunteers (Group
I) with vaccination on days 0, 7 and 21. A group of
75 patients of category II (Group II), 67 of
category III (Group III) were given post-exposure
prophylaxis and 88 patients of category III were
administered with rabies immunoglobulins (Group IV)
along with post-exposure prophylaxis as per WHO
recommendations with a booster on day 90. The
volunteers and patients vaccinated showed very few
adverse side effects. The blood samples collected
from volunteers (Group I) on days 14, 35 and 365 and
patients (Group II–IV) on days 14, 30, 90 and 365
showed geometric mean titres (GMT) of >0.5 IU/mlref
Sinovac Biotech
Co Ltd (Beijing, China : in collaboration with
the Chinese Academy of Medical Sciences, has been
funded with $2.2 million in grants from the Chinese
government) began the world's first clinical trial on
May 22, 2004 : the first person in the world to
receive the vaccine was Lan Wanli, a university
student based in Beijing. At June 2004, 4 volunteers
(3 men and 1 woman, all University students) were
injected. A second batch of 36 volunteers, aged 21 to
40, was vaccinated at the Sino-Japanese Friendship
Hospital in Beijing between 22 May and August 2004,
developed antibodies, and experienced only some fever
and discomfort. Phase I trials completed by end of
March 2005 The vaccine appears to be safe, but the
researchers do not yet know whether it will provide
protection against SARS by stimulating the production
of protective antibodies. Scientists in Beijing will
carry out the phase II trials among volunteers aged 20
to 60 to test the effectiveness of the vaccine in 300
human volunteers : the persistence of antibodies will
be monitored over a 9-month period after the vaccine
is administered. Whether it can conduct Phase III
trials may depend on nature: Large-scale, conventional
Phase III trials can begin only if another outbreak
creates a large pool of infected people. Scientists in
Singapore cloned the surface protein of a coronavirus
into Lactobacillus casei bacteria. This was
then fed to mice which developed resistance to
infections.
inactivated anti-bacterial
vaccines (bacterin)
polybacterial immunostimulators
oral
Alvakol®
Biostim® (source : Aventis
Pharma) : a broad-spectrum antigenic preparation
from Klebsiella
pneumoniae
Broncasma Berna® (source :
Swiss Serum and Vaccine Institute, Berne) : a 1-ml
dose contains 50 x 106 pneumococcal types
I, II, and III; 40 x 106 streptococci;
500 x 106 staphylococci; 60 x 106Moraxella
catarrhalis; 20 x 106Gaffkya
tetragena; 250 x 106Pseudomonas
aeruginosa; 40 x 106Klebsiella
pneumoniae; and 40 x 106Haemophilus
influenzae serotype B (Hib) and conservans (maximum 0.4%
phenol). The usual vaccine regimen consists of 5
escalating doses: 0.1 ml, 0.3 ml, 0.5 ml, 0.7 ml,
and 1.0 ml. It has been safely used throughout the
world for 30 years for the prevention or treatment
of recurrent tonsillitisref
(0.05 mL given once every 4 to 14 days (average once
a week) on 3 to 20 occasions (average 8)), chronic
sinusitis and nasal allergyref,
chronic lower respiratory infectious diseaseref,
noncholesteatomatous chronic
suppurative
otitis mediaref
(7 0.05-ml injections), recurrent hordeolumref
OM-85 Broncho-Vaxom (BV)®,
Imocur®(source : Fournier or
Zambon, France): lysates from eight
pneumotropic bacteria for recurrent acute
respiratory tract infections (RARTIs)
Dentavax® : killed cells from
Klebsiella
pneumoniae, Streptococcus
pyogenes, Staphylococcus
aureus, Candida
albicans and Lactobacillus
acidophilus and their lysates for the
prophylaxis and treatment of inflammatory
periodontal diseases. The stimulating effect of the
preparation was evaluated in 12 volunteers immunized
for 10 consecutive days. On days 7, 14, 21, 28 and
49 after the last immunization peripheral blood (PB)
lymphocyte subsets, T lymphocyte activation and PB
phagocytic activity, were studied by flow cytometry.
PB lymphocyte proliferative responses to PHA, rIL-2,
LPS and D were evaluated radiometrically. The
production of TNF-a in
supernatants of in vitro stimulated
lymphocytes and specific IgA, IgM and IgG antibodies
in serum and saliva was determined by ELISA.
Ultrastructural morphologic changes in T and B
lymphocyte populations were also investigated.
Although no significant changes in the levels of
basic lymphocyte subsets were detected, the
early/late (CD57+/CD57-) CD8 T
effectors ratio was increased at the end of the
studied period, as were the percentage of
PHA-responding (CD69+) T cells and PB
phagocytizing cells. The most prominent
lymphoprolipherative responses were measured upon
costimulation with LPS+D and PHA+D on day 21.
Electron-microscopic studies demonstrated a
significant effect of D on both T and B cell
activity. TNF-a
concentration increased progressively from day 7
till the end of the investigation. Maximal
concentrations were observed after stimulation with
D and LPS. An increased level of specific salivary
and serum antibodies against the components of D was
found, with highest levels between days 7 and 21.
Specific secretory IgA predominated in saliva as
compared to IgM and IgGref
Factor R® :
ImmunoRx® (Munogen) : killed
and freeze-dried lysates and bacterial bodies of Lactobaccillus
bulgaricus and ...
OK-432 / NSC-B116209
(Picibanil®): prepared from a strain of
group A Streptococcus
pyogenesby treatment with heat and
penicillin, its main ingredient is the lipoteichoic
acid (LTA)-related molecule (OK-PSA), which
binds to TLR4
Omnadin® :
Ribomunyl®
is an immunostimulant that was developed and
commercialized in the 1980s in France and has
subsequently been made available in a large number
of countries. The formulation is composed of
proteoglycans from Klebsiella
pneumoniae and of ribosomes from 4 of
the most commonly encountered bacterial strains in
recurrent respiratory tract infections. It works on
different mechanisms in innate immunity
(phagocytosis, cell adhesion, dendritic cell
maturation, Toll-like receptors, interferon
production, proinflammatory cytokines, activation of
natural killer cells), as well as in adaptative
immunity (polyclonal activation of T and B cells,
specific immunoglobulin A immune response in an
integrated view of the mucosal immune system, and Th1/Th2
regulation and balance). The effect of this
immunostimulant on anti-infectious responses can be
explained, not only by a stimulation of the
antibacterial defense directly assumed by innate
immunity, but also by a stimulation of the specific
(adaptative) immune response related to the
activation of dendritic cells, of which the pivotal
role in T-cell differentiation is already well
known. This supports the potential of bacterial
immunostimulants such as Ribomunyl® in
anti-infective therapyref
intramuscular administration 3 times at
weekly intervals, booster injection after 6
monthsref
p.o. ?
vaginal mucosal self-administration at 0, 1,
2, 6, 10 and 14 weeks : of patients receiving 6
immunizations 55% did not experience an
infection in next 6 months, whereas 78% of
primary immunization and 89% of placebo treated
women had UTIs. No women had significant adverse
effects. Furthermore, in patients who were
re-infected, the median infection-free period
was 160 days in the booster group versus 59 days
in the primary group and 35 days in the placebo
groupref.
LW 50020: multibacterial
lysate vaccine for administration consisting of
antigens of 7 bacteria commonly involved in
respiratory tract infections (RTIs), including
recurrent tonsillitis
Luivac® (source : Sankyo,
Tokyo, Japan)
Paspat oral® (source :
Altana Pharma or Luitpold Werk, Munich))
anti-Bordetella
pertussis vaccine : containing
agglutinogens 1, 2 and 3. Each 0.5 mL dose contains not
less than 41.U of pertussis vaccine and not more than
20,000 million organisms. Thimerosal
is added to a final concentration of 0.01%. Store
between 2°C and 8°C and protect from light. Do not
freeze. This vaccine should not be used if it has been
frozen.
Protocol : 3 x 0.5 mL deep
subcutaneous or intramuscular injection at intervals of
not less than 4 weeks (usually at weeks 8, 16 and 24).
Boosters after 1 and 5 years. Routine pertussis
immunization is recommended for all children under 6,
except when a specific contraindication exists.
Contraindications : history
(or family history) of convulsions, epilepsy, cerebral
irritation in the neonatal period or any other disorder of
the CNS, infection, severe allergy, acute illnesses
Side effects : mild in ~ 20%
(erythema at the site of injection during the 24 hours
following vaccination, transient fever, restlessness,
irritability, crying or loss of appetite a few hours after
vaccination). About 0.1% of infants experience convulsions
10-14 days after receiving the vaccine and in a very small
number of cases (1 in 20,000-50,000) postvaccinial
autoimmune
encephalomyelitis
occurs : reactogenicity mainly depends on presence of
pertussis toxin and LPS.
anti-Salmonella
typhi, Salmonella paratyphi A and Salmonella
paratyphi B
vaccine (TAB vaccine) (see also attenuated vaccine)
: either acetone-dried or phenol-inactivated. 2
subcutaneous injections separated by 1 month. Boosters
every 3 yrs. It confers about 70 per cent protection,
which can be overcome by a large challenge. Immunization
is recommended only for exposure due to travel,
epidemic, or household contact with a carrier. No longer
used due to short protection and side effects.
T.A.B.® (Institute Pasteur)
TAB® (Pharmaceutical Industries
Corporation)
TAB Vaccine® (?, Egypt)
Titifica® (?, Italy)
Typhoid Vaccine® (Wyeth-Ayerst)
Typhopara-typhoidique® (?,
France)
anti-Vibrio
cholerae injectable vaccine (contains 4 . 109
vibrios serogroup O1 Inaba and Ogawa serovars / mL)
(see also DNA
vaccine)
: 2 subcutaneous or intramuscular doses separated by
1-6 weeks. Boosters every 6 months. Side effects
within 2 dd. It doesn't protect from infection because
it doesn't induce IgA production, so does not reduce
carrier status, fecal shedding of bacteria or reduce
disease transmission..
Vibriomune® (Duncan, Flockhart)
anti-Vibrio
cholerae oral vaccine => induces IgA production (Cholerix®)
: 1011 vibrios as
above + 1 mg B subunit of cholera toxin in a buffered
solution ingested with water. Effective in 40÷65% (no
in babies and individuals with O blood group), it
protects only for 3-6 months.
cholera-toxin B subunit,
killed whole-cell (rBS-WC)
oral cholera vaccine : contains inactivated whole cells
of the classic and El Tor biotypes of V.
cholerae, serotypes Inaba and Ogawa, as well
as recombinant cholera-toxin B subunit.
International health experts carried out the world's
first mass cholera vaccination in Esturro (Beira,
Mozambique's second-largest city, population
21,818), from December 2003 to January 2004. 50,000
people received 2 doses of the oral vaccine. They
then assessed vaccine protection in a case–control
study during an outbreak of El Tor Ogawa cholera in
Beira between January and May 2004. A year later,
researchers have determined that receipt of one or
more doses of rBS-WC vaccine was associated with 78%
protection (95% confidence interval, 39 to 92%
P=0.004). The vaccine was equally effective in
children younger than five years of age and in older
persons and was 90% protective against cholera of
life-threatening severity. The study could pave the
way towards expanded use of vaccines against
cholera, a major public health threat in about 50
poor countries around the globe. The vaccination was
carried out by IVI, the World Health Organisation,
the Mozambique Health Ministry, Medecins Sans
Frontieres and others, with doses donated by SBL
Vaccines in Sweden. The experiment also proved for
the first time that the vaccine can protect
HIV-infected individuals against cholera : it is
remarkable that such a high level of protection was
observed in Beira, a population where 20-30% of
adults are living with HIV. Beira was chosen for the
experiment because of the high levels of cholera -
between 4,000 and 5,000 cases annually among its
population of 500,000ref
anti-Yersinia pestis
vaccine : it contains at the time of manufacture
1.8-2.2 x 109 per mL of formaldehyde-killed
plague bacilli in sodium chloride injection, USR. The
product may also contain trace amounts of: beef heart
extract, yeast extract, the peptones and peptides of soya
and casein, agar and not more than 0.019% formaldehyde. It
is preserved with 0.5% phenol and supplied in a 20 mL
vial. Store at 2-8°C (35-46°F). Do not freeze.
Indications :
laboratory and field personnel who are working with
Y. pestis organisms resistant to antimicrobics
persons engaged in aerosol experiments with Y.
pestis
persons engaged in field operations having
occupational or avocational exposure to wild rodents
in plague enzootic areas. where prevention of exposure
is not possible (such as some disaster areas) and/or
at times when regular sanitary practices are
interrupted
Contraindications :
hypersensitivity to any of the product constituents,
severe thrombocytopenia or any coagulation disorder that
would contraindicate intramuscular injections, severe
febrile illness, same occasion as typhoid or cholera
vaccines (to avoid the possibility of accentuated side
effects), pregnants (unless clearly needed)
Protocol : intramuscular
injections into the deltoid muscle.
dose number
age <1
age 1-4
age 5-10
age >10
1
0.2 mL
0.04 mL
0.6 mL
1.0 mL
2 (after 1-3 months
0.04 mL
0.08 mL
0.12 mL
0.2 mL
3 (3-6 months after the second injection)
0.04 mL
0.08 mL
0.12 mL
0.2 mL
boosters
0.02-0.04 mL
0.04-0.08 mL
0.06-0.12 mL
0.1-0.2 mL
The series of 2 injections will produce adequate
protection in the vast majority of human beings who have
never received this vaccine : however 7% of the
individuals fail to produce detectable Ab even after the
second booster dose, but some may produce an adequate
response following the third injection. The mean titer of
antibody to F1 capsular antigen determined by PHA test, is
1:25, 1:140, and 1:576 at 15, 105, and 285 days,
respectively. It protects for 6-12 months and increases
the chances of recovery in those vaccinated individuals
who may develop the insect-borne (bubonic) form of the
infection, but is not effective against pulmonary pestis.
Booster injections of 0.1-0.2 mL should be administered at
6-month intervals to individuals remaining in a known
plague area : the smaller dose should be approached as the
total number of such injections increases. It should be
noted, however, that booster doses at intervals > 6
months, e.g., 1-2 years, may be appropriate for persons
who have received > 3 booster doses at 6-month
intervals. In persons who have an unusually high risk of
infection or who have a history of serious reactions to
the vaccine, PHA should be determined in order to govern
the frequency of booster doses.
Side effects :
local (subside within 2 days)
erythema and induration at the site of injection
(~ 10%)
tenderness and edema
sterile abscesses
systemic effects (~ 10%, persist for only a few
days)
The increased frequency and severity of adverse reactions
following repeated doses appear to depend on the number of
doses received the method by which the doses are
administered, and the reactivity of the individual.
Commercialized formulae :
Sampar® (Aventis Pasteur)
Vaksin Sampar® (Perum Bio Farma)
anti-Rickettsia
prowazekii vaccine : a
formalin-inactivated vaccine of chick embryo origin
Cox vaccine : cultivated on fertile egg
membrane
Weigl vaccine : cultivated in vivo on Pediculus
humanus corporis, phenol-killed gut extract
Protocol : 2 intramuscular
injections separated by 1 month. Effective for 10 years in
a limited number of vaccinated people : booster every 6-12
months. . Efficacy of this vaccine has not been
established and it is no longer available in the United
States. A live vaccine containing the attenuated Madrid
E strain is protective but can cause mild
symptomatic infection; it also is not generally available.
anti-Rickettsia
rickettsii vaccine : grown in yolk
sacs of embryonated chicken eggs; it had limited
effectiveness and is no longer available. A new chick
embryo cell culture vaccine is under investigation.
Protocol : 2 intramuscular
injections seprated by 1 month. Effective for 2 years.
Commercialized formulae :
Vax-Spiral® (Finlay Vaccunas y
Sueros Centro de Investigacion)
killed but metabolically active (KBMA)
bacteria : this strategy simultaneously takes
advantage of the potency of live vaccines and the safety of
killed vaccines. Genes required for nucleotide excision
repair (uvrAB) were removed, rendering
microbial-based vaccines exquisitely sensitive to
photochemical inactivation with psoralen and long-wavelength
ultraviolet light. Colony formation of the nucleotide
excision repair mutants was blocked by infrequent, randomly
distributed psoralen crosslinks, but the bacterial
population was able to express its genes, synthesize and
secrete proteins. Using the intracellular pathogen Listeria
monocytogenes as a model platform, recombinant
psoralen-inactivated Lm uvrAB vaccines induced
potent CD4+ and CD8+ T-cell responses
and protected mice against virus challenge in an infectious
disease model and provided therapeutic benefit in a mouse
cancer model. Microbial KBMA vaccines used either as a
recombinant vaccine platform or as a modified form of the
pathogen itself may have broad use for the treatment of
infectious disease and cancerref.
attenuated live germs (live vaccine /
replicative vaccine) :
a vaccine prepared from live microorganisms or viruses
that have been attenuated but that retain their ability to
reproduce and immunogenic properties. They are usually administered
in a single dose. Not to administer to
immunocompromised subjects or to females that could become
pregnant within 3 months ! Virulence reversion risk,
frequent side effects. They need low temperature storage.
Attenuation (lessening of virulence) may be obtained by
...
Anyway these vaccines are actually cocktails containing
complete repertoires of antigenic forms of the
corresponding germ : administering a complete repertoire of
antigenic variants confers immunity simultaneously against all
variants thus preventing the microbe varieties from
persisting. Of course, instead of an increase in antigenic
heterogeneity during "attenuation", some antigenic variants
might overpower others; in any case, success in achieving a
complete repertoire will depend on the choice of experimental
conditions (e.g. duration of the disease or even the health
conditions of the animal used). This corresponds to the
present severe difficulty of empirically finding the right
method of "attenuation". Understanding vaccines as multivalent
strains not only substantiates the fact of the very existence
of vaccines, but also explains some well-known phenomena which
otherwise are treated as pure paradoxes :
antigenic switching was always considered a nearly
fatal obstacle to creating vaccines. It is therefore
unclear how immunologists of the past, unaware of the
existence of this problem, nevertheless succeeded in
designing effective vaccines for antigenically unstable
microbes.
vaccines for rabies or smallpox were isolated from
their "wild" relatives more than century ago and have
since evolved in absolutely independent directions. This
obviously led to increasing differences between 'wild'
viruses and vaccines and consequently to loss of antigenic
similarity. But, in fact, no worsening of vaccine quality
over time has been reported.
any real vaccine includes different antigenic variants
present in concentrations differing by several orders of
magnitude. For live vaccines this is not significant as
any small population will yield its own wave of
parasitemia providing sufficient specific immunity. But
for inactivated vaccines the quality of the immunity
elicited is obviously proportional to the concentration of
antigen, so the protective effect of such vaccine will not
be uniform for different antigenic variants.
the gradual transmutation over time of virulent
microbes into vaccines is quite incompatible with what we
would expect from viruses, as even a single mutation
usually means an abrupt change in virus properties, so
coexistence of various sets of viral forms with continuous
change in virulence seems a miracle. But as population
overgrowth is described by an exponential function,
collecting vaccine after a few attenuation cycles ensures
that most variants are represented and the formers are
still present. A classical quantitative illustration of
this transmutation phenomenon is the so-called fixation of
rabies virus described by Pasteur : after transmission
from a dog followed by sequential passages in rabbits, the
duration of incubation abruptly decreases from about 20
days to about 10 days after first 2-3 passages and then
for a very long time this value approaches a stable value
of about 7 days.
Some examples :
live attenuated anti-viral
vaccines
anti-flavivirus
vaccines : without effective antiviral drugs,
vaccination offers the best chance of decreasing the
incidence of these diseases, and live virus vaccines are
the most promising and cost effective. However,
flaviviruses can recombine, which raises the possibility
of recombination between a vaccine strain and wild-type
virus resulting in a new virus with potentially
undesirable properties, but steps can be taken to
minimise risk. The development of non-live flavivirus
vaccines should be encouragedref.
a live attenuated SA14-14-2 vaccine
produced in primary hamster kidney cells. > 200
million doses have been given without any recorded
severe side effectsref.
It has an excellent safety record, and, in studies
to date, no severe adverse events have been reportedref1,
ref2,
ref3.
The vaccine's use outside China has been limited,
initially because of questions about the novel cell
line that is used (primary hamster kidney cell);
however, these issues have been resolved, and the
vaccine has now been licensed in Nepal (given to
children aged 1–15 years in the Terai region of
Nepal in July 1999 afforded sustained high
protection ref1,
ref2),
Sri
Lanka, South Korea, and most recently, India. China
distributes its own vaccine widely since 1988ref.
China agreed to make some 13 million doses for India
at a discounted price -- about 180 million rupees
(USD 3.8 million), about 13.80 rupees (29 cents) per
child. Since May 2005, nearly 11 million children
aged 1 to 15 years have been vaccinated against JEV
in high-risk areas of 4 northern India states : at
least 1 death and close to 200 addition serious
neurologic reactionsref.
Human clinical trials carried out in China, Korea
and Nepal have demonstrated 85-100% seroconversion
rates in JE non-immune subjects and 96-99%
protective efficacy in JE-endemic areas after 1
single vaccination. Persistence of neutralizing
antibody has shown to be 88.8% in vaccinated
subjects after 6 years in a JE non-endemic area
after 2 doses of vaccination. The duration of
protective efficacy has been demonstrated > 12
years in one area and 5 years in another area
following an immunization schedule of 1 primary dose
at 1 age and 1 booster dose at 2 ages. Data
collected from several provinces have shown evident
decline of JE morbidity in regions where vaccination
campaigns with SA14-14-2 live vaccine had been
carried out compared with the local historical data
and with neighboring counties where no vaccination
was conducted during the same periodsref.
In a June 2005, the WHO Global Advisory Committee on
Vaccine Safety (GACVS) reviewed the safety issues
related to the JE SA 14-14-2 vaccineref
: of 522 vaccinated children actively monitored for
adverse events for 4 weeks after vaccination,
approximately 10% developed fever > 38°C and a
cough. Redness and swelling at the site of injection
were observed in < 1%. These findings are
consistent with those reported from China. GACVS
acknowledged the excellent safety and efficacy
profile of the SA 14-14-2 vaccine but nonetheless
recommended more detailed study of the following:
the safety profile in special risk groups including
immunocompromised people and pregnant women; whether
viral shedding occurs in vaccinees and the potential
implications of such shedding; further analysis of
sequential or co-administration of JE and measles
vaccines; the interchangeability of inactivated and
live JE vaccines; the safety of vaccine
administration to infants aged under 1 year; and the
implications for the efficacy and safety of the
vaccine in infants with maternal antibodies against
JE virus. SA 14-14-2 was obtained after 11
passages in weanling mice followed by 100 passages
in primary hamster kidney cells at the National
Institute for Control of Pharmaceutical and
Biological Products (NICPBP) in Beijing in the early
1970s. This strain was shown to be safe and
immunogenic in mice, pigs, horses and humans.
Expanded field trials in southern China involving
more than 200 000 children confirmed the strain
safety and yielded efficacies of 88–96% over 5
years. The SA 14-14-2 strain also elicits
seroconversion rates of 99–100% in nonimmune
subjects. The live attenuated SA 14-14-2 vaccine is
produced on primary hamster kidney cells,
lyophilized, and administered subcutaneously to
children at 1 year of age and again at 2 years in
annual spring campaigns. Currently, > 60 million
doses are distributed annually in southern and
western China, and the vaccine is exported to Nepal
and the Republic of Korea. Efforts are ongoing to
produce the vaccine to GMP standards.
Side effects : following
an extensive investigation of 504 adverse events
reported through the AEFI system (including 22 deaths)
and 29 additional cases identified through active
case-finding, the committee found no link between JEV
vaccine and the serious illnesses or deaths temporally
associated with immunization in India in 2006. 9.3
million children from 11 districts in 4 states were
vaccinated in 2006 campaigns. Of these beneficiaries,
533 total adverse events (including 22 deaths) were
recorded. The most common adverse events (75% of
reported cases) involved mild systemic reactions
(fever, acute respiratory infection, vomiting, and/or
rash). Case investigations and laboratory tests
following adverse events reported during the 2006
campaigns were inadequate, and the committee
recommends strengthening case recording, sample
collection, data analysis, epidemiological
investigation, and causality assessment. The frequency
of 22 deaths among the vaccinated cohort of 9.3
million children aged 1 to 15 years calculates to a
rate of 0.00024%. By comparison, the probable
frequency of death among children of this age range in
the general population is 0.009
percent. /2 Therefore, adverse events following JE
vaccination do not seem to cause excess mortality.
Seasonal outbreaks of JE and acute encephalopathy in
targeted districts (specifically those in Northern
India) may have caused infection prior to vaccination
and resulted in deaths due to naturally occurring
infection rather than infection caused by
vaccination with the live, attenuated virus. Consensus
statements from several global meetings of the World
Health Organization have identified human vaccination
as the only effective long-term control measure
against JE and have recommended that at-risk
populations receive a safe and efficacious vaccine
through the national immunization program. The
Government of India is currently conducting a
follow-up study to evaluate long-term vaccine safety
and serious adverse events occurring up to 12 months
following vaccination. During the first 4 weeks
following vaccine administration, no serious adverse
events were recorded among the study population.
Subjects will be monitored
at several intervals throughout the 12 months
following vaccination. The following contacts are
available to provide further information and answer
any questions related to vaccination with the live,
attenuated SA 14-14-2 JE vaccine
ChimeriVax-JE® (Bharat Biotech
International Limited and Acambis Plc) is a new
chimeric vaccine based on the YFV
17D vaccine that comprises the prM and E
coding sequences of the JEV SA 14-14-2 strain
inserted in Phase into the 17D YFV strain genome.
The resulting virus can be cultivated on Vero cells,
has proved to be highly immunogenic in rhesus
monkeys and to protect against intracerebral and
intranasal challenges with wild-type JEV. The
prototype vaccine, ChimeriVax-JE (Acambis), has been
tested successfully in 99 adults in the USA, showing
good safety and immunogenicity; 94% of the vaccinees
developed JEV-neutralizing antibodies after a single
dose. There was no interference with chimeric
vaccination by prior immunity to YF, but a slight
interference was noted in persons given YF 17D 30
days after ChimeriVax-JE. The vaccine is under Phase
II clinical trials with promising early results. A
first paediatric evaluation of the vaccine is
scheduled for 2005 in Thailand
poxvirus vectors (NYVAC, ALVAC) expressing
the prM, E, NS1 and NS2A proteins have been tested
in monkeys and in humans, but their development was
stopped.
anti-dengue virus vaccine (see also DNA
vaccine)
: up to 90% seroconversion rates in a phase I trial of
live-attenuated dengue-virus vaccines in childrenref.
VDV3, a clonal derivative of the Mahidol
live-attenuated dengue 3 vaccine was prepared in Vero
cells. Despite satisfactory preclinical evaluation,
VDV3 was reactogenic in humans. While no variations
were seen in serum IL-12 or TNF-a
levels, a high IFN-g
secretion was detected from Day 8, concomitant to IFN-a, followed by IL10. Specific Th1
and CD8 responses were detected on Day 28, with high
IFN-g/TNF-a ratios. Vaccinees exhibited
very homogeneous class I HLA profiles, and a new HLA
B60-restricted CD8 epitope was identified in NS3.
Among other factors, adaptive immunity may have
contributed to reactogenicity, even after this primary
vaccination. In addition, the unexpected discordance
observed between preclinical results and clinical
outcome in humans led us to reconsider some of our
preclinical acceptance criteriaref.
anti-yellow
fever
virus (YFV) vaccine : chick embryo
origin, 1 subcutaneous injection with Rockefeller
17D strain. Effective for > 10 years in 100%
: booster every 10 years.
Amaril®
(Aventis Pasteur)
Arilvax® (Wellcome; Purdue
Pharmaceuticals PLC, The Netherlands)
There are only 4 manufacturers whose YF vaccine has been
prequalified by WHO as of 7 Jan 2005ref
::
Aventis Pasteur, France
BioManguinhos, Brazil
Institut Pasteur Dakar, Senegal
Evans Vaccines, (formerly Medeva), U.K.
Aventis Pasteur USA & the Institute of Poliomyelitis
& Viral Encephalitis, Moscow, Russia, have been
removed from the list. Colombia and India produce YF
vaccines, but these have not been prequalified by WHO.
Yellow fever vaccine has been successfully used to
prevent the disease since 1937. Yellow fever vaccine
associated viscerotropic disease (YFV-AVD) and neurotropic
disease (YFV-AND) have been recently identified in
various countries. Previously post-vaccination multiple
organ
system failure
was recognised as a rare serious adverse event of yellow
fever vaccination and 21 cases of postvaccinial
encephalitis
had been recorded. However, reports of YFV-AVD, after
administration of 17D-204 and 17DD
vaccines, suggest we need to revisit the vaccine's
safety profile, specifically with attention to
host-dependent risk factors. Since 1996, 9 cases of
YEL-AVD, a disease clinically and pathologically
resembling naturally acquired yellow fever, have been
reported in the USA; an additional 14 cases have been
identified worldwide as of July 2004. 14 (61%) of these
cases have been fatal. In several cases for which tissue
samples were available, results of IHC indicated viral
dissemination throughout the body, including to the
liver, lungs, spleen, lymph nodes, brain, and smooth
muscle; however, in many cases, tissue samples were not
available for histopathological review or detection of
virus. In the USA, the reported incidence of YEL-AVD is
about 3 cases per million civilian doses distributed; a
similar incidence has been reported in the UK. In a
review of reports made since 1990 to the US Vaccine
Adverse Event Reporting System, a passive reporting
system, advanced age was shown to be a risk factor for
YEL-AVD; individuals aged older than 60 years seem to be
at increased risk. Because of the low incidence of
YEL-AVD, identifying risk factors is challenging.
However, 4 (17%) of the 23 vaccinees reported with this
syndrome had a history of thymus disease, suggesting
that thymic dysfunction is an independent risk factor
for YEL-AVD. One fatal case of YEL-AVD involved a
67-year-old woman from the USA. The patient had a
history of thymectomy, for a malignant thymoma, about 2
years before vaccination. A 2nd US case involved a
70-year-old man with a history of hyperthyroidism,
myasthenia gravis, and thymectomy for thymoma 20 years
before vaccination. This patient survived. The 3rd
individual was a 50-year-old man from Switzerland who
had a history of thymectomy due to thymoma 8 years
before vaccination. He also survived. The 4th individual
was a 44-year-old man who developed fatal YEL-AVD with
fulminant hepatic failure after yellow fever vaccination
in Colombia. 2 years previously, he had had a thymectomy
due to benign thymoma. The thymus is important in
regulating the integrity of T-cell and B-cell function.
Thymic tumours are rare and are associated with
various autoimmune disorders. When thymectomy is
undertaken to suppress such autoimmune disorders,
administration of serum immunoglobulin is recommended to
protect against infectionref.
In an adult mouse model, immune suppression induced by
antithymocyte serum potentiated lethal yellow fever 17D
infectionref.
Thymomas are also associated with reduced numbers of
circulating B lymphocytes and hypogammaglobulinemia in
adults. The incidence of thymoma increases with age
above 40 years up to age 80 yearsref,
and there is also thymic involution during normal aging.
This suggests that changes in the thymus may contribute,
in part, to the increased risk of YEL-AVD observed in
elderly individuals. A retrospective study looked at the
effect of vaccination with live viral vaccines in
children with DiGeorge syndrome, which is associated
with thymic hypoplasia and diminished T-cell counts.
These children did not have a higher rate of adverse
events when compared with reports in the general
population; however, children included in the
study did not have low T-cell counts, and yellow fever
vaccine was not one of the live vaccines assessed in the
studyref.
Yellow fever vaccine provides essential protection to
people traveling to, or living in, areas where yellow
fever is endemic or epidemic. However, health-care
providers should carefully consider the benefits and
risks of vaccination for elderly travelers, and should
ask about a history of thymus disorder or dysfunction,
irrespective of age, including myasthenia
gravis,
thymoma,
thymectomy,
or DiGeorge
syndrome,
before administering yellow fever vaccine. If travel
plans cannot be altered to avoid yellow fever-endemic
areas, people with a history of thymus disease should
consider alternative means of yellow fever prevention,
including use of insect repellents, containing N,N-diethyl-m-toluamide
(DEET)
and permethrin, and other behaviors to reduce mosquito
bites. For countries that demand a yellow fever
vaccination certificate, it is possible for physicians
to provide a letter showing that the vaccine is
medically contra-indicated. However, this does not
guarantee that a country will accept such a waiver.
Health-care providers should be encouraged to report all
cases of yellow fever vaccine-associated adverse events,
so more information can be gathered about risk factors
for YEL-AVDref
[ref1,
ref2,
ref3,
ref4].
A
26-year-old woman from Onuba, Spain, was admitted on 21
Oct 2004 to Juan Ramon Jimenez Hospital in Huelva
because of fever and multi-organ failure, having had, in
addition to fever, malaise, vomiting, and diarrhea
during the previous days : she died from yellow fever
stemming from a post-vaccination reaction. Since she was
about to travel abroad, the patient was also vaccinated
for diphtheria and tetanus on 14 Oct 2004 at the
External Sanitation Services in Huelva. This case does
not seem to correspond to problems with the vaccine
(contaminated batches), or with manufacturing problems,
but is a consequence of a special interaction between
the virus in the vaccine and the host; since, in rare
cases, there might be an inability by the host to
generate an adequate immune response to the virus.
Shortages :
in February 1999, for a few weeks YF vaccine was
not been available in the UK owing to a production
failure
since July 2004 in Israel
in South Africa repeated shortages since 2000 to
2005
in Italy in 2005
in New Zealand in 2005
anti-chikungunya
virus
vaccine : a phase II, randomized, double-blind,
placebo-controlled, safety and immunogenicity study of a
serially passaged, plaque-purified live chikungunya
(CHIK) vaccine in 73 healthy adult volunteers. 59
volunteers were immunized one time subcutaneously with
the CHIK vaccine, and 14 were immunized with placebo
(tissue culture fluid). Vaccinees were clinically
evaluated intensively for one month and had repeated
blood draws for serological assays (50% plaque-reduction
neutralization test) for 1 year. Except for transient
arthralgia in 5 CHIK vaccinees, the number and severity
of local and systemic reactions and abnormal laboratory
tests after immunization were similar in CHIK vaccinees
and placebo recipients. 57 (98%) of 58 evaluable CHIK
vaccinees developed CHIK neutralizing antibody by day
28, and 85% of vaccinees remained seropositive at one
year after immunization. No placebo recipients
seroconverted. This promising live vaccine was safe,
produced well-tolerated side effects, and was highly
immunogenic. An isolate from a patient in Thailand, CHIK
strain 15561, was used to develop a small lot of vaccine
1st passaged in green monkey kidney (GMK) cells and then
formalin-inactivated before administration to 16
volunteersref.
The vaccine produced no untoward reactions and was
highly immunogenic. The current live vaccine (lot 1-85,
TSI-GSD-218) was developed at the U.S. Army Medical
Research Institute of Infectious Diseases and was
produced at the Salk Institute, Swiftwater, PA from a
lot of the GMK-passaged, strain 15561 inactivated
vaccine by subsequent serial passage in MRC-5 cellsref.
The live vaccine proved to be safe and immunogenic in a
phase I trial in 15 alphavirus-naive volunteersref.
The current phase II, randomized, double-blind,
placebo-controlled trial was designed to provide
additional safety and immunogenicity data for live CHIK
vaccine TSI-GSD-21ref.
The US Army discontinued development of such a vaccine
in the 1990's, reportedly because of changing budget
priorities. However, on 14 Sep 2006 the US Embassy in
Paris announced there would a resumption of development
of a vaccine, in collaboration with the US Military
Infectious Disease Program and the US Department of
Health & Human Services, the French Ministry of
Health, and Inserm and the Institut Pasteur. This
announcement followed an agreement on 6 Sep [2006] to
allow transfer of research records, vaccine supplies,
and seed stocks for manufacturing vaccine, from the US
to the Frenchref.
Also, on 25 Oct 2006 a news story in Indiaref
said that the BCG Vaccine Laboratory in Chennai had been
sequencing different strains of the chikungunya virus
and had applied for a patent to manufacture vaccine(s)
against the virus for commercial sale. However, it is
not clear to what extent the news story was an
indication of real progress in independently developing
a vaccine, as distinct from publicity to encourage
investment in the laboratory's efforts.
FluMist® (Wyeth Lederle+ Aviron => MedImmune Inc.;
$46 wholesale). Cold-adapted (ca) for nasal
spray administration (survives in the cool nasal
passages but dies off in the warmer lung tissues).
Only for use in healthy people ages 5 to 49, as it is
linked with an increase in episodes of asthma and
wheezing in children under 5.
CAIV-T is an investigational intranasal,
cold-adapted trivalent influenza vaccine. It is the
next-generation, refrigerator-stable formulation of
FluMist®, which is a frozen, live
attenuated cold-adapted trivalent influenza vaccine.
To date, the safety, tolerability and efficacy of
CAIV-T has been studied in both healthy and at-risk
populations between the ages of 6 weeks and 98
years.
anti-human
parainfluenza virus type 1 (rHPIV1)
live attenuated vaccine candidates was evaluated
for attenuation, immunogenicity, and protective efficacy
in African green monkeys (AGMs). Temperature sensitive
(ts) and non-ts attenuating (att) mutations in the P/C
and L genes were introduced individually or in various
combinations into rHPIV1, including the CR84G and
HNT553A mutations identified in the present work and the
CF170S, LY942A, and LL992C mutations identified
previously. The rHPIV1 vaccine candidates exhibited a
spectrum of attenuation in AGMs. One genetically and
phenotypically stable vaccine candidate,
rCR84G/F170SLY942A/L992C, was attenuated and efficacious
in AGMs and is a promising live attenuated intranasal
HPIV1 vaccine candidate suitable for clinical evaluationref
human rotavirus (serotype G1, P1A[P8]) :
RIX 4414 strainref
has been developed from the parent vaccine strain
89-12ref1,
ref2,
ref3
(Rotarix®; source : AVANT
Immunotherapeutics (formerly Virus Research
Institute) and GlaxoSmithKline
(GSK)) is given at 2 and 4 months of age, with
efficacy of 76.6%. Very recent data obtained with
Rotarix® support the suggestion that
factors other than neutralizing antibody can play
important roles in protection against rotavirus
disease after live rotavirus immunizationref.
It will be rolled out without the approval of the
FDA or the EMEA. Although some of the Phase III
trials involving 60,000 infants were conducted in
Finland, GSK hasn't asked Finnish authorities for
approval. Instead, the trials were done under the
auspices of the Mexican government, for approval in
Mexico and other Latin American countries. GSK is
trying to target an emerging middle class that
supports a private healthcare industry. The strategy
was successful in that the Phase III trial had
promising results. Of the 30,000 infants given the
vaccine in the trial, only six cases of
intussusception were reported. Of the same number of
children in the control group who were given a
placebo, only seven cases of intussusception were
reported. As a result, the Mexican government
approved RotaRix and it went on sale in January of
2005. It will target developing nations market (up
to 100 millions infants per year), with an estimated
revenue potential of up to $ 250 million per year.
Clinical trials with the HRV vaccine in Finnishref
and Latin Americanref
(Brazilian, Mexican, and Venezuelan) infants showed
that two doses were well tolerated and immunogenic.
In phase 2 clinical trials, the efficacy of the
vaccine against severe rotavirus gastroenteritis
reached 90-100%ref1,
ref2,
ref3.
Protection started as early as the first dose,
lasted until the subjects were up to 2 years of age,
and was demonstrated against both G1P[8] and G9P[8]
rotavirusesref1,
ref2,
ref3.
A phase III RCT showed that the efficacy of 2 doses
the vaccine against severe rotavirus gastroenteritis
and against rotavirus-associated hospitalization was
85% and reached 100% against more severe rotavirus
gastroenteritis. Hospitalization for diarrhea of any
cause was reduced by 42%. During the 31-day window
after each dose, 2 vaccine recipients and 7 placebo
recipients had definite intussusception (difference
in risk, –0.32 per 10,000 infants)ref
human rotavirus vaccine 89-12 (after 33
passages in cultured monkey kidney cellsref)
is efficacious in preventing diarrhoea caused by
rotavirusref.
This strain was selected because natural infections
with 89-12-like rotaviruses provided 100% protection
over 2 yearsref1,
ref2,
ref3.
multivalent human-animal reassortant rotavirus
vaccines (HRRV) : reassortant rotavirus between
simian rotavirus RRV or bovine rotavirus WC3 and human
strain rotaviruses have been extensively tested as
candidate vaccines
tetravalent
rhesus-human reassortant rotavirus vaccine
(RRV-TV) (RotaShield® ;Wyeth Lederle
=> BIOVIRx)
: rhesus rotavirus with a gene replaced by VP7
from a human strain (40% efficacy). An estimated 1.8
million doses of rotavirus vaccine have been
administered to infants since it was licensed on
August 31, 1998 to the October 15, 1999 withdrawalref1, ref2,
ref3,
ref4,
ref5
(within the next 9 months, > 600,000 infants had
received at least 1 dose of the 3-dose vaccine : 15
cases of intussusception appeared, all of them
within 3 days of vaccinationref),
due
to reports of at least 99 bowel intussusception (with a population attributable
risk of approximately 1 per 10,000 (range of 1 in
5,000 to 1 in 12,000) vaccine recipientsref)
just 1-3 weeks following the vaccine and as many as
10-20 diarrhea episodes a day, making them
dangerously dehydratedref.
> 80% of all cases of intussusception events that
were associated with the vaccine happened with
babies who received the vaccine after 4 months of
age, which was at the far end of the manufacturer's
recommendations. That's because, when the vaccine
first appeared, many doctors were "catching up" with
older babies who didn't have a chance to get the
vaccine in the months before its approval. Further,
overall intussusception rates of children given the
rotavirus vaccine were the same as the baseline
expectation of otherwise healthy children in the
first year of life—about 1 in 3000 : RotaShield®
appears to have triggered an intussusception
response in infants who probably would have had it
anyway. If a vaccine triggers intussusception in
infants who are going to get it anyway, that means
it's not only preventing rotavirus but it's
providing much safer and more watchful conditions
for the intussusception to occur. Today the
consensus is that the rate of RotaShield-associated
intussusception is 1 in 10,000 and probably even
lower. RRV-TV was also associated with fever,
vomiting, diarrhea, abdominal pain, and bloody
stoolsref1,
ref2,
ref3,
ref4.
The vaccine was voluntarily withdrawn from the
market in October 1999ref
oral, live pentavalent (G1, G2, G3, G4 and
P[8]) human-bovine reassortant rotavirus vaccine
(RotaTeq®; source : Merck) is an
attenuated vaccine in phase III clinical trials
containing neutralization proteins representative of
dominant human serotypes. Rotavirus (RV) reassortant
strain WI79-9 consists of a human (strain WI79),
G1-serotype VP7 surface protein on a bovine (strain
WC3) backgroundref1,
ref2.
Phase III trials for RotaTeq have concluded, and the
preliminary results suggest that it prevents severe
rotavirus infections without causing serious side
effects such as intussusception. It had been
expecting to apply for approval by 2006, but in
light of the positive trial results, it will submit
its application in the second quarter of 2005, which
means it could have a full rollout in the United
States by the end of the year. It will still be
several years after a US launch before the company
launches the product in developing nations. It will
target US and European market (8 million infants per
year), with an estimated revenue potential of up to
$1 billion per year
live quadrivalent rotavirus vaccine (QRV)
is a precursor to the pentavalent HRRVref
consisting of bovine-human reassortant rotavirus
serotypes G1, G2, G3, and P1aref
In the Rotavirus Efficacy and Safety Trial (REST)
Study, the 34,035 infants in the vaccine group and
34,003 in the placebo group were monitored for serious
adverse events. Intussusception occurred in 12 vaccine
recipients and 15 placebo recipients within 1 year
after the first dose including 6 vaccine recipients
and 5 placebo recipients within 42 days after any dose
(RR = 1.6). The vaccine reduced hospitalizations and
emergency department visits related to G1–G4 rotavirus
gastroenteritis occurring 14 or more days after the
third dose by 94.5%. In a nested substudy, efficacy
against any G1–G4 rotavirus gastroenteritis through
the first full rotavirus season after vaccination was
74%; efficacy against severe gastroenteritis was 98%.
The vaccine reduced clinic visits for G1–G4 rotavirus
gastroenteritis by 86.0%ref.
Approximately 3.5 million doses of RotaTeq have been
distributed in the USA through 1 Feb 2007. Not all of
these doses have been administered. Since its
licensure on 3 Feb 2006 until 31 Jan 2007, 28 cases of
intussusception have been reported in the U.S. in
infants who received RotaTeq. These cases have been
reported to the Vaccine Adverse Event Reporting System
(VAERS). The reported 28 cases occurred after dose 1,
dose 2 and dose 3. Approximately half of the cases
occurred 1 to 21 days after vaccination, with a range
of 0 to 73 days. 16 of the 28 infants with
intussusception required hospitalization and surgery
on their intestine. The remaining 12 infants had
reduction of the intussusception by contrast or air
enema. No deaths due to intussusception were reported.
The number of intussusception cases reported to date
after RotaTeq administration does not exceed the
number expected based on background rates of 18-43 per
100 000 per year for an unvaccinated population of
children ages 6 to 35 weeks (CDC, unpublished data)ref
natural bovine neonatal virus : 3 other
vaccines are undergoing Phase II trials in India and
could get regulatory approval there within 3 years.
Developers in India are trying a different type of
vaccine, based on strains isolated from infants in
the late 1980s. M.K. Bhan, then at the All India
Institute of Indian Medical Sciences in Delhi, and
C. Durga Rao, a microbiologist at the Indian
Institute of Sciences in Bangalore, each isolated
strains of a rotavirus that was sweeping through
India. Babies infected with those strains tested
positive for rotavirus but had no diarrhea. Both
teams found that large portions of the strains'
genetic sequence were identical to a bovine form of
the virus. Because it's a natural virus, it should
be easy to manufacture. It immunizes the child
against future severe bouts of rotavirus-related
diarrhea without causing diarrhea in the first
place. Bhan notes that they do not expect
intussusception as a side effect, because no data
have shown that the natural neonatal virus leads to
increased risk of intussusception. Despite the
promise of the 2 strains, called 116E (Bhan's
strain) and I321 (Rao's strain), the
samples sat on lab shelves for a decade, because no
company was willing to take a chance on the project.
That changed in 1999, when Krishna Ella stood up at
a medical meeting and announced that his company,
Hyderabad-based Bharat
Biotech International Ltd, would create a
rotavirus vaccine. It was a bold move as the company
was only 2 years old and had just begun to
manufacture its first product, a HBV vaccine. Ella
had fewer than a hundred employees and no experience
in live vaccine development. Today, Bharat
Technologies employs 350, and it has a $10 million
factory dedicated to cranking out a live rotavirus
vaccine. It will soon be producing 3 different
vaccines, the 2 Indian strains and a third strain
(bovine reassortant) that Bharat recently licensed
from the NIH (VP7). The vaccines are being
used in clinical trials that have just begun
(earlier safety trials had already been performed in
the United States). Phase II trials have just begun
in India for all 3 vaccine candidates. The best
performer of those 3 will become Bharat's new
rotavirus vaccine and could be a low-cost competitor
to Rotarix and RotaTeq. A full rollout in India can
begin within 3 years, assuming that at least one of
the three candidates is successful in a Phase III
trial. There used to be no infrastructure for
clinical trials in India : now that they've built
that, they can complete all 3 rounds of trials in 3
years, where it takes a minimum of 5 years in the
West. And they can do it at a fraction of the cost.
Cutting expenses is crucial when it comes to
providing a vaccine for a country like India. 34
million newborns need to be vaccinated every year in
the Indian subcontinent (estimated revenue potential
up to $100 million per year), of which 24.4 in India
(estimated revenue potential up to $75 million per
year), and the government can afford to spend only a
few dollars per inoculation. That's why Bhan hopes
that Bharat and other homegrown biotechs can hit the
threshold of $1 per dose. Western countries can
afford to spend $40 a dose, they can't. Although
Bharat officials think they can hit the $1 mark,
they don't have the same advantages that other
Indian industries offer. Salaries are cheaper in
India, but the real expense of making vaccines is in
capital expenses – equipment and buildings – and
they have no competitive edge over European or
American companies there. Instead, Ella has devised
a business plan to cut development costs by doing
all the clinical trials in India and diluting the
cost of equipment purchases by applying for grants
from nonprofit organizations such as the Gates
Foundation. Once a rotavirus vaccine is rolled out
in India, it could then be distributed in other
Asian countries as well. The competition could drag
prices down to historic lowsref1,
ref2,
ref3
natural lamb virus : LLR (Chinese
government) vaccine is already in use in China (15.6
million vaccinees per year), with an estimated
revenue potential up to $10 million per year.
Animal models : to evaluate
whether the rectal route of immunization may be used to
provide appropriate protection against enteric pathogens
such as rotaviruses (RV), we studied the antibody response
and the protection induced by rectal immunization of mice
with RV virus-like particles (VLP). For this purpose,
6-week-old BALBc mice were rectally immunized twice with
RV 8-2/6/7-VLP derived from the bovine RV RF81 strain
either alone or combined with various adjuvants including
4 toxins [cholera toxin (CT) and 3 attenuated Escherichia
coli-derived heat-labile toxins (LTs), LT(R192G),
LT(R72), and LT(K63)] and two Toll-like receptor-targeting
adjuvants (CpG and resiquimod). 6 weeks after the second
immunization, mice were challenged with murine RV strain
ECw. RV VLP administered alone were not immunogenic and
did not protect mice against RV challenge. By contrast, RV
VLP combined with any of the toxin adjuvants were
immunogenic (mice developed significant titers of anti-RV
IgA in both serum and feces and of anti-RV IgG in serum)
and either efficiently induced complete protection of the
mice (no detectable fecal virus shedding) or, for LT(K63),
reduced the amount of fecal virus shedding after RV
challenge. When combined with RV VLP, CpG and resiquimod
failed to achieve protection, although CpG efficiently
induced an antibody response to RV. These results support
the consideration of the rectal route for the development
of new immunization strategies against RV infection.
Rectal delivery of a VLP-based vaccine might allow the use
of adjuvants less toxic than, but as efficient as, CTref
Oka strain : routinely administered to children in
the United States and Europe to prevent chickenpox. It
is effective and safe but occasionally produces a
rash. The vaccine virus has accumulated mutations during
its attenuation, but the rashes are not explained by their
reversion, unlike complications reported for other viral
vaccines. Indeed, most of the novel mutations
distinguishing the Oka vaccine from the more virulent
parental virus have not actually become fixed. Because the
parental alleles are still present, the vaccine is
polymorphic at >30 loci and therefore contains a
mixture of related viruses. The inoculation of >40
million patients has consequently created a highly
replicated evolutionary experiment that we have used to
assess the competitive ability of these different viral
genotypes in a human host. Using virus recovered from rash
vesicles, it has been shown that 2 vaccine mutations,
causing amino acid substitutions in the major
transactivating protein IE62, are outcompeted by the
ancestral alleles. Standard interpretations of varicella
disease severity concentrate on the undeniably important
effects of host genotype and immune status, yet our
results allow us to demonstrate that the viral genotype is
associated with virulence and to identify the key sites.
These loci have pleiotropic effects on the immunogenic
properties of the virus, rash formation, and its
epidemiological spread, which mould the evolution of its
virulenceref
Varicella-RIT® (GlaxoSmithKline)
Varilrix® (GlaxoSmithKline
Inc.) : PWSO(2000 U / 0.5 mL)SC
Varivax
II® (Merck & Co.) : average
potency of only 1350 pfu per dose. The higher dose
seems to be necessary to overcome the immunosenescence
associated with aging. For this reason, the currently
licensed Varivax is not recommended for zoster
prevention in adults. PWSO(1,350 U / 0.5 mL)SC
Zostavax®
(Merck & Co.) : individual vaccine lots had an
estimated potency ranging from 18 700 to 60 000
plaque-forming units (pfu) per dose (median potency,
24 600 pfu per dose), i.e and immunogenic potency
14-fold greater than Varivax®; in a
randomized, double-blind, placebo-controlled trial
38,546 adults of 60 years of age or older, the use of
the HZ vaccine reduced the burden of illness due to HZ
by 61.1% (P<0.001), reduced the incidence of
postherpetic neuralgia by 66.5% (P<0.001), and
reduced the incidence of HZ by 51.3% (P<0.001).
1 subcutaneous injection. Effective for 6-10 years in 95%.
Side effects in immunocompromised. 3a5crebahnr in Russia.
Vaccination for VZV has now come of age. It is recommended
for healthy children, patients with leukaemia, and
patients receiving immunosuppressive therapy or those with
chronic diseases. The protection induced by the vaccine
seems, to some extent, to include zoster and associated
neuralgia.
Specific PCR tests to differentiate wild-type from
vaccine-strain VZV are available in a few laboratories
around the worldref1,
ref2,
ref3,
ref4.
With these tests, results can be obtained quickly from
specimens obtained from blood, cerebrospinal fluid,
vesicles, and some tissues. Besides these benefits, VZV
viral load can be measured by TaqMan PCR, which helps in
the monitoring of disseminated disease progression and
response to antiviral treatment, among other benefitsref
Primary vaccine failure is the main reason for
breakthrough varicella infection in 15 to 20% of
vaccinees; in 20 of 84 children (24%) who were given one
dose of vaccine, VZV antibodies failed to develop
(Michalik D, LaRussa P, Steinberg S, Wright P, Edwards KM,
Gershon A. Primary immune failure after 1 dose of
varicella vaccine may be the main cause of breakthrough
infections in healthy vaccinated children. In: Proceedings
of the 44th annual meeting of the Infectious Diseases
Society of America, Toronto, October 12–15, 2006). Chaves
and colleagues used an estimate of primary vaccine failure
and cannot distinguish failure to elicit immunity from
waning immunity. When directly tested in a case–control
study, the vaccine's effectiveness did not diminish
significantly over timeref1,
ref2;
although effectiveness decreased 1 year after vaccination,
no further decrease occurred 8 years thereafter, a finding
that is consistent with primary vaccine failure. The
inference that immunity wanes might therefore be incorrect
and discourage vaccination, enlarging the number of
persons who may be susceptible to varicella. Varicella
vaccine is highly effectiveref1,
ref2,
ref3;
a 2-dose regimen is expected to address primary vaccine
failure. Chaves and colleagues found that VZV
vaccine–induced immunity waned over time, and they
recommend a second dose of vaccine. The major concern of
the VZV vaccination program has been that it might
transfer the burden of disease to adults, who are 23 to 29
times as likely as children to die from primary infectionref.
Will the loss of immunity from natural varicella infection
in childhood (especially in the developed world) be at the
expense of higher rates of severe primary varicella among
adults in the future?
Edmonton-Zagreb
(EZ-HT) strain was derived from a clinical
isolate in 1954 and was subsequently passaged in a
variety of cells in tissue culture, resulting in
attenuation of the virus and loss of pathogenicity. In
1989, WHO recommended use of high-titre measles
vaccine (HTMV) at age 6 months for children
living in countries in which the incidence of measles
before age 9 months was high. In 1992, after results
of studies in Guinea-Bissau, Senegal, and Haiti had
shown raised female mortality in recipients of HTMV,
recommendation for this vaccine was rescinded. The
greatly reduced mortality after measles vaccination
has been attributed to prevention of long-term effects
of measles infection. However, although morbidity
might be raised for a few months after measles
infection, results have shown no increase in mortality
after the acute phase of infection. Mild measles
infection might be associated with lower mortality,
thus both measles infection and measles vaccination
might provide beneficial stimulation of the immune
system, which enhances resistance to other infections.
HTMVs seem to result in a high female-male mortality
ratio and an increased mortality when compared with
female recipients of standard-titre measles
vaccine (STMV). In a meta-analysis of West
African studies, girls who received HTMV had a
mortality ratio of 1.86 (95% CI) compared with those
who received standard measles vaccine, whereas boys
had a mortality ratio of only 0.91. The effect was not
seen immediately, but several months later. 2
different hypotheses have been proposed to account for
these surprising observations :
Initially, HTMV was
postulated to have come too close to the natural
disease, thus inducing immune suppression, as
happens in natural measles infection. This
hypothesis does not account for the delayed increase
in mortality and why later, the effect was noted for
girls only. Although measles mortality might be
raised in older girls and women, it is usually not
higher in girls in the first 3 years of life, which
is the period when high-titre vaccines are
associated with increased female mortality. If
anything, boys have higher measles mortality in this
age range. More importantly, measles infection is
usually not associated with long-term excess
mortality. Hence, HTMV does not mimic natural
measles disease. Furthermore, contradictory to the
hypothesis, results of one large trial of HTMV in
Zaire showed no increase in mortality of HTMV
recipients when compared with recipients of medium-titre
measles vaccine (MTMV), and no increase in
female-to-male mortality
in geographical areas
with high childhood mortality standard measles
vaccine was associated with a non-specific benefit
on survival, which was especially strong for girls.
The detrimental effect of HTMV would only be seen in
areas with high mortality, for high-titre vaccine
did not provide the non-specific and sex-specific
benefits of the standard measles vaccine. The
mortality difference would only be seen when girls
in the control groups had received the standard
measles vaccine, and it would not be noted in areas
with low mortality since children in these areas had
no non-specific survival benefit from standard
measles vaccine. However, in the time before
vaccination, girls did not have higher mortality
than boys. Thus, our hypothesis did not fully
explain why girls had a higher mortality than boys
in the high-titre group and why these effects did
not arise in the HTMV trial in Zaire
Since both of these
interpretations are unable to account for all
observations, an alternative hypothesis has been
proposed. In the high-titre trials, many children
received DTP (which has been reported to be associated
with an increase in female mortality) or IPV after
measles vaccination. There is no excess mortality for
high-titre recipients compared with controls in the
period between enrolment and subsequent reception of
DTP or IPV vaccines. Recipients of high-titre vaccine,
after being given DTP or IPV, have a higher
female-male mortality ratio than controls receiving
standard measles vaccine at age 9-10 months, and a
higher female-male mortality ratio than high-titre
recipients who did not receive additional DTP or IPV.
M-Vax® (Lederle) : no longer in
use (1963 to 1979)
NPOTHB KOPH® (?, Russia)
Odra® (?, Poland)
Pfizer Vax-Measles® (Pfizer) :
no longer in use (2/65 to 1970)
Rimevax® (RIT/GlaxoSmithKline)
Rimparix® (GlaxoSmithKline)
Rougeole® (?, France)
Rouvax® (Institute Merieux)
Rubeola 'o Aifombrilla® (?,
Spain)
Rubeovax® (Merck) : no longer in
use (1963 to 1971)
Sarampion Comu'n® (?, Spain)
V.Rouvaux® (?, France)
Vaccinum Morbillorum Vivum®
(Moscow Research Institute)
Vaksin Campak Kerig® (Pasteur
Institute, Perum Bio Farma)
VVR® (Cantacuzino Institute)
Zamovax® (Institute of
Immunology - Croatia)
The secondary immune response was defined by IgG with an
avidity index >32%. A secondary response in infected
children previously immunized was considered as a
secondary vaccine failure. Vaccinated children presented
higher IgG titers and IgG avidity than unvaccinated
children. The proportion of secondary immune responses in
unvaccinated patients was lower than that obtained in
previously vaccinated infected patients. Avidity testing
can be a useful tool to detect secondary vaccine failure
in mumpsref
anti-mumps virus
vaccine (see also killed
vaccine) : since 1990, 3 strains of mumps virus --
the Urabe, the Rubini and the
Jeryl-Lynn vaccine strains -- have been used in MMR triple
vaccines at various times. The Urabe strain was withdrawn
in 1992 after an increased risk of aseptic meningitis was
reported in some countries and replaced by the Rubini
strain in some triple vaccines between 1993 and 1995 and
in turn by the Jeryl-Lynn strain in most current triple
vaccine formulations.
Urabe Am-3 (or AMS) strain. Side effect :
aseptic benign post-vaccinial meningitis (0.4-10 per
million) after 2-4 weeks.
Imovax Oreillons® (Aventis
Pasteur)
Rubini vaccine : attenuation of the wild
virus was performed by isolation and serial passage in
WI-38 human diploid cells, specific pathogen-free
hens' eggs and MRC-5 human diploid cells. Low efficacy
has been shown by the sentinel surveillance system in
Switzerland for 1986-9 and in reports of outbreaks in
Portugal, Italy, and Switzerlandref
Jeryl Lynn B strain. 1 subcutaneous
injection after age 1. Effective for > 10 years in
75-95%. Administered alone ...
Imovax Oreillons® (Institut
Merieux)
Imovax Parotitidis® (Aventis
Pasteur)
Les Oreillons® (?, France)
Mumaten Berna® (Swiss Serum
and Vaccine Institute)
Mumps® (?, Germany)
Mumps, Generic® (?) : no
longer in use (4/74 to 6/78)
... or as MMR.
Recommended for males after puberty.
anti-polioviruses 1, 2
and 3vaccine
(see also killed vaccine)
: developed by Albert Bruce Sabin in 1963 by
culture on human diploid cells, then cultured on primary
Cercopithecus
aethiops (African green monkey) kidney (CMK)
cells. Oral cachets ((trivalent) oral poliomyelitis
vaccine (OPV / TOPV)) at month 3, 5, age 1 and 3.
Obliged vaccination. This vaccine confers both humoral
and intestinal immunity. Long-life effectiveness in
100%. OPV has the disadvantage of
genetic instability, resulting in rare and sporadic
cases of vaccine-associated paralytic
poliomyelitis (VAPP) and the emergence of
genetically divergent vaccine-derived polioviruses
(VDPVs) (risk is estimated as 1 in 2.5 million
recipients, expecially for polioviruses 2 and 3).
Whereas VAPP is an adverse event following exposure to
OPV, VDPVs are polioviruses whose genetic properties
indicate prolonged replication or transmission. 3
categories of VDPVs are recognizedref
:
circulating VDPVs (cVDPVs)
from outbreaks in settings of low OPV coverage
immunodeficiency-associated
VDPVs (iVDPVs) from individuals with primary
immunodeficiencies
ambiguous VDPVs (aVDPVs),
which cannot be definitively assigned to either of
the first 2 categories.
Because most VDPVs are
type 2, the World Health Organization's plans call for
coordinated worldwide replacement of trivalent OPV with
bivalent OPV containing poliovirus types 1 and 3.
in 1963 to 1966 in a region
of the Byelorussian Republic of the former Soviet
Union a widespread circulation and evolution of
independent lineages of vaccine-derived polioviruses
took place. Up to 37% of unvaccinated children had
probably been exposed to 9 strains descended from
the OPV and rapidly mutating or other
vaccine-derived strains of the virus. Some of these
lineages appeared to originate from OPV given to 40
children in the community during this period of
essentially no vaccinations.
in 2000 a back mutation
caused a polio outbreak in Haiti and Dominican
Republic (type-1), followed by similar incidents in
Philippines (type-1)
Egypt (type-2)
Madagascar (5 cases of acute
flaccid paralysis due to type 2 poliovirus were
reported in southern Madagascar in 2001/02)
in 2005 in Madagascar 2
cases of polio were reported : national immunisation
days will be held in August-September 2005, covering
at least 600 000 children aged under 5 in Toliara's
21 districts as well as 6 other districts bordering
the province. Although no case of the disease due to
a wild polio virus has been detected in Madagascar
since 1997,those associated with the virus derived
from the oral vaccine made eradication "more
complex", and had an implication for vaccination
campaigns. It would be of interest to know if
the responsible virus this year is genetically
related to the one that caused the cluster of cases
in 2001/2002, suggesting continued low-level
circulation of the same virus, or if this was a new
episode of reversion to neurovirulence.
If a population's immunity is
boosted regularly, the risk from stopping the vaccine is
low. In Cuba, for example, where doctors do mass
vaccinations twice a year, the live virus dies out of
the population within 3 months because so few children
are susceptible. Continuing such 'pulse' vaccinations is
one option for countries after worldwide eradication.
But researchers fear that diligence will dwindle once
countries see the risk as small. A second option,
already taken up by many developed countries including
Italy and the USA, is cessation of vaccination with OPV,
replacement by IPV, and
the creation of an OPV stockpile for emergency response
in case of the reintroduction of poliovirus into
circulation : in USA no cases of VAPP have been reported
with the sequential IPV-OPV schedule or when IPV was
used exclusively from 1990 through 2003. The injectable
IPV may be safer but is much harder to deliver,
expensive and may not be 100% effective at stopping
transmission of the virus in faecal matter - both
problems for developing countries. The data demonstrate
very high risks associated with both the local cessation
of OPV vaccination and the proposed use of OPV to
control a possible reemergence of poliovirus in the
postvaccination period. The high transmissibility of
OPV-derived viruses in nonimmune population and the
known existence of long-term OPV excretors should be
also considered in assessing risks of the synchronized
global cessation of OPV usageref.
One wonders if this is a case of "seek and ye shall find,"
or if this is an emerging problem associated with the
vaccine. The former seemed to have been preliminarily
ruled out by the failure of a retrospective study of over
2000 AFP-associated poliovirus isolates (performed in the
Philippines) to identify additional VDPV. If it is truly a
low-level occurrence, it may have been missed. If
this is an emerging problem, one wonders why now, after
approximately 50 years of vaccine use, we are seeing this
phenomenon. If one chooses to adjust the date to the
implementation of increased vaccination activities
associated with the polio eradication effort, the time
frame for widespread use is approximately 20 years, when
polio eradication activities in the Americas region
began. At the risk of provoking our readers, this
moderator wonders whether the increased prevalence of HIV
infection might be associated with this observed
phenomenon. There are now greater numbers of
immune-compromised infants who may have been exposed to
the live virus, with resultant chronic infections
postulated to predispose to neurovirulence reversion. This
phenomenon has now occurred (or better stated, "been
documented") in 4 different regions of the world: the
Middle East (Egypt and Israel), the Americas (Hispaniola,
i.e. Haiti & the Dominican Republic), the Western
Pacific (Philippines), and now Africa (Madagascar).
In 2 of the regions (Hispaniola and the Philippines)
circulation of the wild poliovirus had been interrupted
(the last reported case of wild poliovirus-associated
disease in the Americas was in 1991 and in the Philippines
in 1993). In Madagascar, the last documented case of
wild poliovirus circulation was in 1997. In all 4
prior cases, this occurred in pockets of unvaccinated or
incompletely vaccinated individuals (we do not have this
information about the current case(s) in Madagascar but
one might assume this is the case). There was also a case
report of a VDPV type-1 paralytic case in Russiaref
in 1999. In the absence of total interruption of wild
poliovirus circulation worldwide, there is still a need
for intensified vaccination efforts. The risk of disease
is still present, especially in today's environment with
extensive world travel. The occurrence of VDPV in
association with clinical disease is very disturbing, as
it adds another factor to the risk/benefit equation of
vaccination recommendations. As mentioned in an earlier
comment, a cost-efficacy analysis of switching to the
inactivated polio vaccine (IPV) in countries that have
interrupted wild virus circulation [suggests that they
cannot afford it]. Significantly, a switch to IPV would
remove the advantage of flooding the environment with the
vaccine virus (the attenuated very-low-neurovirulence
virus) to further interrupt transmission of wild
poliovirus if introduced, as well as to "vaccinate"
individuals who may not have directly taken the vaccine
themselvesref1Yang C-F, 8366-8377, ref2,
ref3,ref4
Some lots of polio vaccine were found to be contaminated
with SV40, which resists
to formol inactivation of polioviruses.
Sabin viruses may do strange things in the central nervous
system. In a monkey model, we found Mahony (parent of
vaccine type 1 virus, highly neurovirulent) to cause
typical poliomyelitis after ulnar nerve inoculationref.
Sabin type 1 virus, surprisingly, passed from neurone to
neurone in the spinal cord without lysis (non-productive
infection) and without inflammation or neuronophagia, and
no paralysisref.
While provocation polio is well known (from the
1950s, when children given DTP in the UK had some 30 times
higher incidence of polio within the next 30 days)ref1,ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8,
ref9,
ref10,
what is less well known is another form of provocation
called "aggravation" polio (Wyatt HV. Adverse drug
reactions: DPT and poliomyelitis in developing countries.
Current Science, 73 (5): 402-403). Here, a child gets
polio due to wild virus within 48 hours of intramuscular
injection. Always starting in the injected limb, it may or
may not progress to other limbs and is very well
recognized in India prior to prevention by immunization.
The explanation is different from the slow process of
provocation polio. Here, the virus may already be in the
spinal cord, but a non-paralytic disease is perhaps
converted to a paralytic disease? What has surgery got to
do with this? Similar tissue
irritation/damage/inflammation as in
provocation/aggravation? Here, the aggravation picture
fits. Could Sabin virus type 2 have been present in a
non-productive manner in the central nervous system (CNS)?
Could the surgery have aggravated the lesion in nerve
cells? (This is quite different from tonsillectomy and
bulbar polio, wherein direct invasion by the virus via
nerve endings in the pharynx to bulbar region of CNS is
invoked as the mechanism).
Web resources :
Informed Parents Against Vaccine-Associated
Paralytic Polio (VAPP) (IPAV)
Golden
Rice
Report : linking vitamin A distribution to the
Pulse Polio Program in India
anti-rubella
virus
vaccine : 1 subcutaneous injection expecially in
never-infected fertile females (but > 3 months before
undergoing pregnancy !). Booster every 10 years.
Effective for > 15 years in 95%. Side effects :
reversible arthralgia and arthritis. Administered alone.
RA 27/3 strain :
Almevax® (Evans Medical Ltd)
Cendevax® (RIT/GlaxoSmithKline)
: no longer in use (3/70 to 1976)
Ervax® (GlaxoSmithKline Mexico)
Ervevax® (GlaxoSmithKline
Europe)
Ervevax RA 27/3® (GlaxoSmithKline
Belgium)
Gunevax® (Sclavo => Chiron,
Europe and Asia)
HarPaBreHnr B CtauOHAP® (?,
Russia)
Lyovac Meruvax® (Merck) : no
longer in use
Meruvax® (Merck) : no longer in
use (6/69 to ?)
Meruvax II® (Merck) : 9/78
Mot Kopper® (?, Norway)
Roda Hund® (?, Sweden)
R-VAC® (Serum Institute)
Rosolia® (?, Italy)
Rosovax® (Ism)
Roteln® (?, Germany)
Rubavax® (Aventis Pasteur)
Rubeaten Berna® (Swiss Serum and
Vaccine Institute)
Rubella, Generic® (Philips
Roxane, Inc.) : no longer in use (12/69 to 1972)
Rubellovac® (Sclavo =>
Chiron, Germany only)
Rubelogen® (Parke Davis) : no
longer in use (12/69 to 1972)
Rubeola® (?, Spain)
Rubeola® (?, Norway)
Rubeola 'o Aiforbrilla® (?,
Spain)
Rubilin® (Medeva)
Rudivax® (Aventis Pasteur)
Sarampion® (?, Spain)
Sarampion Aleman® (?, Spain)
Zaruvax® (Institute of
Immunology - Croatia)
... or as MMR.
Side effects : arthralgia
(50% of females) or arthritis (10% of females) within 2-6
weeks.
anti-Orthopoxvirus
vaccine (variolation) [see also cross-immunization and
DNA
vaccine]
: in 11th century immunity to smallpox was
conferred by nasal inhaling (Chinese and
Indians) or intravenously injecting (Turks) live
variola from scabs or pustular material taken from a
person with smallpox : since scabs were usually from
people who had survived smallpox, they contained
weakened or dead virus, which had been attacked by the
survivor's immune system. This practice resulted in an
infection that was usually less severe than an infection
acquired naturally by inhalation of droplets : anyway,
if the recipient lacked a strong immune system (e.g. the
local Indian tribes around Fort Pitt, who were
deliberately infected by British conquerors with
blankets laden with pus or fomites : using a
handkerchief was especially diabolical, since the
recipient might well have used it on his own nose,
introducing the virus directly into the respiratory
system) or if the virus were not noticeably weakened, it
had a mortality rate of ~ 1% - an alarming figure, but
far lower than the mortality that resulted from natural
infection by the respiratory route (up to 40%). Those
infected in this manner were capable of transmitting
smallpox by droplet inhalation to others. In 1723 Lady
Mary Wortley Montague (1689-1762 : wife of the British
ambassador in Constantinople, Turkey) introduced
variolation to Western Europe : she had been disfigured
by smallpox and practiced variolation to her children to
protect them. Her supporting helped common people to
ignore anathemas from catholic churchmen, who believed
smallpox was a divine punishment, and hence blamed any
attempt to defeat it.
anti-Salmonella
typhioralvaccine : strain Ty21a
(UDP-Gal-4-epimeraseD). 3 cachets at day 0
(no before month 3 !), 2 and 4. It replicates itself
in the gut for 2÷3 dd.
Lavantuu tirokote® (Central Public Health Lab)
Neotyf® (Biocine) : capsules
Vivotif®(Swiss Serum and Vaccine Institute)
Tyfoid® (?, Sweden)
Typhoral-L® (Swiss Serum and Vaccine Institute;
Chiron, Germany)
Orochol® (Swiss
Serum and Vaccine Institute) : genetically
modified strain CVD103-HgR (a Hg-resistant
derivative of classical biotype Inaba serotype
strain 569B unable to produce A subunit of CT),
which has minimal reactogenicity but low colonization
potential and therefore has to be given in higher
doses. 5 . 108 liophilized and
buffered vibrios in water ingested at empty stomach.
No side effects. Effective (from age 2) from day 6
after vaccination to month 6 in 60-90%
Kolera®
anti-Francisella
tularensis vaccine : at present, no
licensed tularemia vaccine is available in the USA.
However, the live vaccine strain (LVS) vaccine
is available to military personnel under an
investigational new drug (IND) protocol held by the US Army Medical
Research Institute of Infectious Diseases (USAMRIID),
Fort Detrick, Maryland and is available only for at-risk
US military personnel. It is administered via 1
scarification (intradermic injection) using multiple
punctures of a bifurcated needle, similar to vaccinia
inoculation for smallpox. The availability of this
vaccine in the USA for use beyond selected at-risk
groups has been hampered by several obstacles. According
to Colonel David L. Danley, Project Manager, Joint
Vaccine Acquisition Program (JVAP) at Fort Detrick, data
now required for licensure were not adequately
documented during its development, prohibiting plans to
license the current vaccine. Because the "old method of
growth using shaker culture does not meet current good
manufacturing processes required for FDA licensure," the
manufacturing processes and potency of the current LVS
vaccine are being re-evaluated, and "a new process using
fermentation technology will be used," explained David
T. Dennis, MD, MPH, Chief, Bacterial Zoonoses Branch,
CDC. Despite the increased risk of a bioweapons threat
felt after September 11th, further vaccine development
for tularemia remains slow. The projected date of a new
licensed vaccine in the USA is not until 2009. The
current LVS vaccine is based on research that goes back
to the 1960s. It is a descendant of strain 15
developed by the former Soviet Union's Institute of
Epidemiology and Microbiology, Gamalcia Institute, in
Moscow, and sold to the US military in 1956ref.
In the early 1960s, USAMRIID had isolated the LVS strain
for preventive use in at-risk US military personnelref1,
ref2.
Efficacy studies in civilian laboratory employees at
Fort Detrick published in 1977 revealed that the vaccine
was safe and significantly reduced the incidence of
typhoidal tularemia from 5.70 to 0.27 cases per 1000
at-risk employee-yearsref.
Although the incidence of ulceroglandular tularemia was
unchanged by the vaccines, the disease was found to be
milder in the vaccine cohort. I am not aware whether the
vaccine is effective if given postexposure. It induces
5-10 years long CMI in a high percentage of vaccinated.
Worldwide, LVS has since been used as seed stock for
tularemia vaccinesref.
Several limitations of the current LVS tularemia vaccine
indicate a need to move forward on developing an
improved vaccine. One limitation is the current mode of
administration, which requires scarification that is
both cumbersome and difficult to standardize. Further
limitations deal with gaps in understanding the factors
responsible for the virulence and genetic stability of F.
tularensis, as well as which antigens are needed
to produce an effective cell-mediated immunity. It is
not well standardized and contains 2 phenotypes of F.
tularensis. Current research shows that only one
of the 2 phenotypes of LVS, the blue colony type,
appears to be immunogenicref1,
ref2.
A 2nd limitation is confusion over which arm of the
immune system should be targeted. Although it has been
thought that the humoral immune response is not
important in protection against tularemia, a relatively
recent report from the Fort Detrick group has suggested
that this may not be the caseref.
Pooled sera from humans immunized with LVS were found to
fully protect mice against a large lethal challenge of
LVS organisms. New lots of LVS produced in the USA
clearly show immunogenicity in human volunteers,
producing both brisk cell-mediated and humoral immune
responsesref.
In the future, techniques to optimize the appropriate
humoral response may be available. Strategies for
development of a new generation of vaccines include
identification of individual components of F.
tularensis, such as the lipopolysaccharide (LPS)
or various other outer surface proteins, as potential
vaccine components (either native or recombinant). After
identification, these components would then be used as
immunogens, instead of using the entire organism. In
laboratory studies, some of these cell components have
been tested and found to have variable protection in
mice. For instance, one of the membrane proteins of the
F. tularensis that has been studied as a
potential immunogen is a 17-kilodalton lipoprotein,
TUL4. The gene for this antigen has been cloned into a Salmonella
typhimurium mutantref.
In mice immunized with this recombinant vector, both
humoral and cell-mediated immune response to the antigen
developed, and mice were protected from an LVS
challenge. The development of monoclonal antibodies for
use as passively protective agents is another possible
strategy for new vaccine development, according to Dr.
Dennis of the CDC. A number of investigators are
conducting basic research into tularemia, particularly
molecular and sequencing studies aimed at identifying
proteins and antigens for use as vaccine candidates.
Most of this research is being conducted at military
research institutions, including USAMRIID. As one would
expect, since September 11th, information on
manufacturers actively working on a new vaccine is
scarce. In the USA, DynPort
Vaccine Company LLC was awarded a contract to
develop, manufacture, test, and license an LVS vaccine
from the current vaccine material, according to both Dr.
Dennis and Col. Danley at Fort Detrick. DynPort has been
under contract to the USA Department of Defense's
(DoD's) JVAP since 1997 and acts as its executive arm,
says Terry Irgens, President of DynPort. Basic
researchers from institutes such as USAMRIID work
closely with DynPort, which employs over 100 scientists,
physicians, and veterinarians to conduct preclinical and
clinical testing of vaccines. Production and licensure
are also managed by DynPort, whose contract with JVAP
was recently extended to 2012. A proposed licensure date
is June 2009, as previously mentionedref.
Internationally, several efforts are under way to
develop new tularemia vaccines, but with similar limited
information on manufacture and licensure dates. In the
UK, 2 approaches to a new vaccine, use of defined
attenuated mutants and a subunit vaccine (Chemical
and
Biological Defence Establishment, Porton Downs,
England), are in their earliest stages and are not
anticipated for licensure in the UK for more than a
decade, says Col. Danley. Other development efforts are
being conducted in Sweden at the National
Defense Research Establishment, University of Umea,
which recently received a 5-year grant from the US
National Institutes of Health to develop a subunit
vaccine against aerosolized forms of F. tularensis.
In collaboration with Canadian researchers, under the
direction of Dr. Wayne Conlan, Medical Research Council,
Ottawa, Canada, the grant will also compare the efficacy
of these candidate vaccines to those of attenuated
vaccines, said Dr. Anders Sjostedt, who heads the
research group at Umea University. In Moscow, a project
is under way at the Institute
of
Immunological Engineering to develop a chemical
tularemia vaccine based on preparations of
outer-membrane components of F. tularensis. This
group is also working on a project to develop a
molecular vaccine based on LPS-protein complexesrefref
X-ray irradiation-attenuated Plasmodium
falciparum sporozoites has been known for many
years to protect humans from blood-stage P.
falciparum malaria infection and disease
upregulated in infectious sporozoites gene 3
(UIS3)-/-Plasmodium berghei can
be maintained as asexual stages in the red blood cells
of the host with no detrimental effects to the
parasiteref.
This is crucial, as the organism has to infect the
host liver to induce a full immune response, but
cannot undergo early liver-stage development. It will
be crucial to determine whether this gene deletion
attenuation is similarly effective in the most
important human parasite—P. falciparumref
MalariaControl.net,
a new project involving several research institutions in
Europe and Africa, and coordinated by the particle-physics
lab CERN. The organizers are asking members of the public
to download software on to their computers that runs while
machines are idle. The computers signed up to
MalariaControl.net will run a model that has been in
development by Tom Smith at the Swiss Tropical Institute,
Basel, and his colleagues since 2003. The team originally
wanted to predict the amount of protection afforded by a
prototype malaria vaccine in order to decide how effective
it must be before it is worth investing in. The model
attempts to individually simulate malaria infection in
each of 50,000 to 100,000 people over a lifetime. It
simulates how often each individual is bitten, becomes
infected and fights off an infection, plus their age,
health, changing number of parasites in the blood and
level of immunity. It updates this information every 5
days over a population's lifetime, a computing feat that
takes about an hour to tot up on an average PC. To refine
the model, the researchers have to adjust each component
multiple times until it best mimics real data collected
from infected areas. This means they must run the
simulations many thousands of times, eating up thousands
of hours of computing time. The team has already carried
out a pilot project using 40 computers, and the results
will be published next month. They found from clinical
trials that the malaria vaccine being tested
(GlaxoSmithKline's RTS,S jab) would be around one-third as
effective in real life as it was in the controlled
conditions of a clinical trial. But gathering more data
about patterns of malaria exposure and infection will also
be crucial, otherwise it won't be possible to tell whether
these extensive models are accurate. Now the team wants to
compare different models and include in their simulations
the number of mosquitoes that each person attracts. They
also want to find out how the natural immunity triggered
by an infection, which decays over time, affects their
predictions. All these things lead to major computing
loads. Around 2,800 people have already enlisted for
MalariaControl.net and the team hopes to recruit about
10,000 in total. Smith says that the results should emerge
within a few months and will eventually be put into an
open-access database. The project is the first to be
launched as part of a broader scheme called Africa@home,
which aims to find distributed computing projects that
both help and involve Africans. The participants are
already talking with other researchers about starting
similar schemes to carry out epidemiological modelling of
tuberculosis and HIV. Distributed computing might prove
particularly valuable for very fast, real-time
calculations of an infectious-disease outbreak such as
avian flu, when there isn't time to run leisurely models
before something needs to be done.
Web resources :
cross-reacting non pathogenetic species
(cross-immunization / heterotypic vaccine /
heterovaccine) : a vaccine that confers
protective immunity against a pathogen not present in the
vaccine, because it contains microorganisms that possess
cross-reacting antigens which they share in common with that
pathogen
anti-Mycobacterium
tuberculosis vaccine (see
also attenuated
vaccine and DNA
vaccine) : developed by Calmette and Guérin in
1921, from a Mycobacterium
bovis strain (Bacille
Calmette-Guérin (BCG)) attenuated after > 230
transfers on glycerinated potato enriched in beef
bile. It is administered by intradermal
injection or scarification to tuberculin-negative
individuals for prevention of tuberculosis. Intramuscular injection (usually in
deltoid muscle) induces formation of granuloma on skin
(easy to detect marker of effective vaccination). It
is the most widely used immunisation in the world,
with 4-5 billion doses having been given over the past
decadesref.
The vaccine fails to protect against pulmonary
tuberculosis in adults (0÷80% effectiveness in
South=>North gradient) : this is partly due to
variability from the original strain (nowadays most
widely used strains are Tokyo, Laos, Copenhagen,
Pasteur, Moscow and Troudeau
ones) and difficulties in right preservation, as well as
exposure in some patients to atypical mycobacteria
infection with resultant cross-immunity, thereby
nullifying the protective effects of BCG vaccinationref.
This effect seemed to be important in those vaccine
trials in tropical or subtropical regionsref.
For the prevention of severe childhood tuberculosis
(tuberculous meningitis and miliary tuberculosis),
BCG vaccination is a highly cost-effective intervention,
and should be retained in those countries with high
rates of tuberculosis. Meta-analyses of prospective
trials have shown that BCG vaccination has an overall
protective efficacy of 51%, and protective efficacy
against severe forms of childhood tuberculosis of about
75%ref1,
ref2,
ref3.
However, even this protection is only relative, and
might be overcome in the presence of severe
malnutrition, exposure to a large infecting dose of
tubercle bacilli from a household contact, and also
after waning immunity, many years after vaccinationref1,
ref2.
Despite these concerns, the prevention of 40 000 cases
of severe childhood tuberculosis a year worldwide is a
cause for celebration. Every year about 100 million
doses of BCG vaccine are given to children worldwide,
which results in the prevention of about 30,000 cases of
tuberculous meningitis and 11,000 cases of miliary
tuberculosis before these children reach their fifth
birthday. This estimation translates into roughly one
case of severe childhood tuberculosis prevented for
every 2500 inoculations. BCG vaccination is thought to
be nearly as cost effective as short-course chemotherapy
for active disease, which is considered good value for
money. Regionally, the highest numbers of cases
prevented were in southeast Asia (46%), followed by
sub-Saharan Africa (27%), and the western Pacific (15%).
These are areas where tuberculosis infection rates and
BCG coverage are highest. Cost-effectiveness of the
vaccine decreases in those richer countries where the
risk of tuberculosis infection is low (B Bourdin Trunz,
PEM Fine and C Dye, Effect of BCG vaccination on
childhood tuberculous meningitis and miliary
tuberculosis worldwide: a meta-analysis and assessment
of cost-effectiveness, Lancet 367 (2006), pp.
1173–1180). BCG should be withdrawn from routine use in
these countries, and reserved for high-risk individuals
: this is currently the situation in the UK, where
routine BCG vaccination of schoolchildren has now been
stopped, and the emphasis is on targeting high-risk
infants and childrenref.
Contrary to the prevailing theory that BCG vaccination
protects only against tuberculosis disease, some results
suggest that the vaccine also protects against
tuberculosis infection : amount of tuberculosis
exposure within the household and age (a marker of
tuberculosis exposure outside the household) were
strongly associated with likelihood of infection as
measured by both TST and ELISpot. ELISpot also
identified absence of BCG scar as an independent risk
factor for infection in tuberculosis-exposed children;
BCG-vaccinated children had an odds ratio of 0.60 for
tuberculosis infection, compared with unvaccinated
childrenref.
So, it is not true that the entire population would have
to be vaccinated if the vaccine was to be considered
efficacious. The vaccine cannot circumvent disease
reactivation in previously exposed individuals.
Vaccination may complicate the way the tuberculin skin
test (TST) is read in this country. In places that do
not vaccinate, the skin test may be used to monitor the
effectiveness of antibiotic therapy. Oral vaccine is
abandoned because it would require increased bacterial
charges to allow survival in gastric juices => Th2 polarization
=> TNF-a => damage in
host tissue (an ideal vaccine should contain only Th1 epitopes).
Anyway oral route is under clinical trial for subunit
vaccine boosters. Main model organisms for designing a
novel vaccine are long-life species : Rhesus monkey (Macaca
mulatta), cynomolgus (Macaca
fasicularis) and deer.It is used for routine
vaccination of children only in regions where there is a
high incidence of tuberculosis. In the USA it is
recommended only for immunization of high-risk
individuals.
Side effects : rare virulent
strains cause lymphadenitis
and osteomyelitis
as side effects. Disseminated infection in individuals
with IL-12Rb1 deficiency.
In 1927 a lot of vaccine contaminated by Mycobacterium
tuberculosis caused Lubeck massacre : among
251 vaccinated newborns, 127 developed TB and 77 died
overexpressing antigen 85 (in guinea pig trials,
the vaccine yielded 10-to 100-fold better protection
than BCG itself)
complemented with the complete region of
deletion-1 (RD1) locus from Mycobacterium
tuberculosis, which contains at
least 11 genes, including esxA and esxBgenes,
which encode the T-cell antigens 6-kDa early
secretory antigenic target (ESAT-6) and 10-kDa
culture filtrate protein (CFP-10) respectively,
as well as a variable number of flanking genes
encoding a secretory apparatus. Mice and guinea pigs
vaccinated with the recombinant strain BCG:RD1-2F9
were better protected against challenge with M.
tuberculosis, showing less severe pathology and
reduced dissemination of the pathogen, as compared
with control animals immunized with BCG alone.
rBCG30 with the pMTB30 plasmid encoding the
secreted 30-kDa major secretory protein of Mycobacterium
tuberculosis, the primary causative agent of TB,
affords greater survival after challenge than parental
BCG in the highly demanding guinea pig model of
pulmonary TB. The parental and recombinant vaccine
strains are comparably avirulent in guinea pigs, as
they display a similar pattern of growth and clearance
in the lung, spleen, and regional lymph nodes. The
plasmid is neither self-transmissible nor mobilizable
to other bacteria, including mycobacteria : it can be
stably maintained in Escherichia coli but is
expressed only in mycobacteria. The recombinant and
parental strains are sensitive to the same
antimycobacterial antibioticsref
fusion-protein vaccine
The vaccines may work well in combination : modified BCG
vaccines could be given at birth and then followed up with
the fusion-protein vaccine. Different delivery methods
could also help to improve the vaccines' efficacy : at
present, the BCG vaccine is injected under the skin, but
it could be introduced more directly to the lungs by
delivering it by mouth or nose.
BCG vaccine is also used in cancer immunotherapy,
particularly in malignant
melanoma
and bladder
carcinoma;
it is thought to act as a nonspecific stimulator of
cell-mediated immunity.
From autumn 2005 the long running routine programme to
vaccinate schoolchildren against tuberculosis with BCG
vaccine will stop. This follows a decision by the chief
medical, nursing, and pharmaceutical officers in July that
there should be selective vaccination of high risk infants
and other groups rather than routine vaccination of
adolescents negative on tuberculin testingref.
This decision comes after several years of discussion
within the Joint Committee on Vaccination and
Immunisation, and it closes an important chapter in the
complex history of BCG vaccination. It comes as
notifications of tuberculosis in England and Wales are at
their highest level since 1983. The decision is well
justified. This BCG programme has been unique from its
start in the mid-1950s, when a Danish vaccine (later
produced by Glaxo) was introduced on the basis of efficacy
shown in a trial carried out by the UK Medical Research
Councilref.
The trial had been carried out in approximately 30 000
adolescents for pragmatic reasons—in order to recruit
participants who were still tuberculin negative, but who
were about to enter a period of high risk of disease. That
trial remains the most rigorous trial of BCG vaccination
carried out anywhere and is an important monument in the
history of research in tuberculosis. At the same time
trials were carried out by the US Public Health Service
(USPHS) in Georgia, Alabama, and Puerto Rico which found
that the Tice BCG vaccines used there had little or no
effectref.
Faced with these results, each nation did the locally
responsible thing—the USPHS decided not to introduce BCG
vaccination because they had no evidence that it worked
among their populations, whereas the UK authorities did
introduce it, as they had good evidence of its value. This
touched off a controversy over the magnitude and
determinants of the efficacy of BCG, which still
continues. Many explanations have been proposed. Perhaps
the most popular is that different populations are exposed
to different environmental mycobacteria, which can provide
as much immunity as BCG or otherwise interfere with it,
and that the US trials happen to have been conducted in
areas where such environmental exposure is highly
prevalentref.
Whatever the explanation for those initial trial results,
they determined the policy of vaccinating adolescents in
the UK, and the efficacy of the vaccines so given has
since been confirmed repeatedly in observational studiesref1,
ref2.
The epidemiology of tuberculosis in the UK has changed
greatly over the years since the BCG programme began. The
annual risk of infection has declined from about 2% a year
in 1950 to < 1 per 1000 today, and the disease has
become increasingly restricted to identifiable segments of
the population, in particular immigrant communities: two
thirds of cases in 2003 were in people born outside the
United Kingdomref.
Recent increases in the incidence of tuberculosis in the
UK thus reflect patterns and trends in the movements of
populations and in the epidemiology of tuberculosis
worldwide. That non-indigenous groups were at higher risk
was first recognised in the 1960s and led to a national
policy encouraging health authorities to consider
supplementary BCG programmes for neonates or for people in
contact with tuberculosis in these communities. The Joint
Committee on Vaccination and Immunisation repeatedly
examined the cost effectiveness of the routine programme
in schools as an increasing proportion of the population
at high risk received the vaccine in infancy and as the
risk of disease in the general population fell. The number
of cases in people born in the United Kingdom reached an
all time low in 2003.6 Although the criteria set by the International Union
against Tuberculosis and Lung Disease for moving
away from routine BCG vaccination were achieved in the
1990sref,
policy makers were reluctant to stop the programme in
schools because of lingering concerns that increases in
the prevalence of HIV and in tuberculosis internationally
might increase the risk of tuberculosis in the UK general
population. This has not occurred, and it is clear that
the risk of tuberculosis among immigrant communities
declines over time once they have settled in the United
Kingdom and that the imported disease has not led to
increases in the risk of disease for the indigenous
population. Under the new policy, BCG vaccination will be
offered to infants in communities with an average
incidence of tuberculosis of at least 40 per 100 000 and
to unvaccinated individuals who come from, or whose
parents or grandparents come from, countries where the
incidence exceeds 40 per 100 000. Most people born in the
United Kingdom will thus probably never receive BCG
vaccination, and most will not be exposed to mycobacteria.
This means that tuberculin testing will become
increasingly efficient as a means of identifying people
exposed to and latently infected with the tubercle
bacillus, who may be given prophylaxis. The change from
routine to targeted vaccination is accompanied by
technical changes. The Glaxo BCG vaccine has been replaced
by one from the Danish Statens Seruminstitut and the
multipuncture "Heaf" technique for tuberculin testing is
being replaced by the intradermal injection "Mantoux"
technique, which is the standard in the rest of the world.
All of these changes bring the UK's approach to preventing
infection with tuberculosis in line with policies and
practice in many other countries. BCG vaccination will
continue to have an important role in protecting children
in high risk populations from tuberculosis. Coupled with
vigorous efforts to identify and appropriately treat
cases, and to ascertain and offer prophylaxis to people
with latent infection, the new policy should allow more
efficient control of tuberculosis in the entire UK
populationref
Web resources : Aeras Global TB Vaccine
Foundation
intranasal vaccination in mice using OMPs from B.
multivorans plus the mucosal adjuvant
adamantylamide dipeptide (AdDP). Robust mucosal and
systemic immune responses were stimulated by vaccination
of naive animals with OMPs from B.
multivorans and B. cenocepacia plus AdDP.
Using a mouse model of chronic pulmonary infection,
enhanced clearance of B. multivorans was
demonstrated from the lungs of vaccinated animals, which
correlated with OMPs-specific secretory IgA responses.
Furthermore, OMPs-immunized mice showed a rapid
resolution of the pulmonary infection with virtually no
lung pathology after bacterial challenge with B.
multivorans. In addition, administration of B.
multivorans OMPs vaccine conferred protection
against B. cenocepacia challenge in this mouse
infection model, suggesting that OMPs afford
cross-protection ability against B. cepacia complex.
Mucosal immunity to B. multivorans elicited by
intranasal vaccination with OMPs plus AdDP could prevent
early steps of colonization and infection with B.
multivorans and also ameliorate lung tissue
damage, while eliciting cross-protection against B.
cenocepaciaref.
cross-reacting anti-viral
vaccines :
anti-Orthopoxvirus
vaccine [see also variolation
and DNA
vaccine]
: in 1774 Benjamin Jesti, a farmer in Dorset, UK,
inoculated material taken from udders of cows with
cowpox to members of his family. In 1796 Edward
Jenner noticed that milkmaids infected on their
hands with a self-limiting contagious agent (Cowpox virus)
as a result of milking cows were protected subsequently
against smallpox.
Once discovered cross-immunity, Jenner used fluid from a
blister on the hand of the milkmaid Sarah Nelms to confer
immunity to smallpox to the 8-year-old farm boy James
Phipps, whom he subsequently challenged with Variola
virus.
Vaccination (from the Latin vacca = cow) replaced
variolation, outlawed in 1840
in Europe. Because cowpox was a relatively rare disease of
Western Europe and was absent in the Americas, live
vaccine was tranported from Cadiz (Spain) to America
through arm-to-arm transfer by orphan children on
the long voyage across the Atlantic, with increased risk
of transmission of measles
virus
and Treponema
pallidum subsp.pallidum
: growth of the virus on the skin of flank of a calf offered
the prospect for provision of an adequate and safer supply
of vaccine material, but the harvested vaccine remained
viable for only 1 or 2 days at ambient temperature. The
solution was found in 1950 with the introduction of more
stable air-dried or freeze-dried vaccine
(preserved indefinitely at -20°C, or also at -4°C), with
no need for refrigeration or loss of potency. Multiple
infection of cows with Cowpox virus, Vaccinia virus, and Buffalopox
virus, caused Cowpox virus to be replaced by the
following strains of Vaccinia virus
:
New York City Board of Health
(NYCBH) strain ==attenuation by repeated
passing through rabbit testis, chick embryo
explants, and chorioallantoic membranes of
embyonated hens' eggs==>
Rivers strain
CVI-78
highly attenuated modified Vaccinia
virus
(strain Ankara) (MVA) smallpox vaccine
(source : Acambis Plc and Bavarian Nordic A/S) was
generated by > 500 passages of vaccinia virus
in chick embryo fibroblasts, during which it
acquired multiple deletions and mutations and lost
the capacity to replicate efficiently in human and
most other mammalian cellsref1,
ref2,
ref3,
ref4,
ref5,ref6.
The host restriction of MVA occurs during a late
stage of viral morphogenesis, resulting in the
accumulation of immature virions and the formation
of abnormal onesref1,
ref2,
ref3,
ref4.
As a result of extreme attenuation, MVA causes no
adverse effects even when high doses are injected
into immune-deficient non-human primatesref.
Animal studies carried out more than 30 years ago
showed that MVA protected animals against
orthopoxvirus infections, although few immune
responses were measured and those that were
measured appeared lowref1,
ref2.
In a recent study, MVA and the smallpox vaccine
induced a similar variety of immune responses in
miceref.
MVA seemed to be safe in humans and there was a
reduction in the size of skin lesions produced by
a subsequent standard smallpox vaccinationref1,
ref2,
ref3.
MVA protects monkeys infected with monkeypox virus
(the best experimental model for human smallpox)
and caused very few side-effects. After 2 doses of
MVA or one dose of MVA followed by Dryvax,
antibody binding and neutralizing titres and
T-cell responses were equivalent or higher than
those induced by Dryvax alone. After challenge
with monkeypox virus, unimmunized animals
developed > 500 pustular skin lesions and
became gravely ill or died, whereas vaccinated
animals were healthy and asymptomatic, except for
a small number of transient skin lesions in
animals immunized only with MVAref.
Because an initial MVA injection may help lessen
the side effects experienced from Dryvax, MVA may
serve as an important pre-vaccine for large-scale
vaccination efforts in the event of a bioterror
threat involving smallpox. Immune-compromised mice
remained healthy even when given 1000 times the
usual MVA dose.
LC16m8 (source : VaxGen, Inc.) :
derived from the Lister strain of vaccinia, LC16m8
has been licensed in Japan since 1980 and forms
the basis of that country's national vaccine
stockpile. In a phase I/II clinical trial it had a
100% take rate and has been well tolerated.
Intensive monitoring for myopericarditis has not
uncovered any cardiac toxicity in the first 66
volunteers
EM63
Attenuated strains have decreased incidence of
complications but induce lower neutralizing antibody
titers and so lower protection
... with the following additives : fluorocarbon, phenol,
peptone. Currently it is of calf lymph or chick embryo
origin.
Reconstitution of the vaccine
for administration is made by creating a solution of 50% v/v
: after reconstitution the vaccine can be preserved for
> 1 weeks at 41°C. Dilutions at 1/5 or 1/10 could be
used to expand the supply of vaccine.
Administration routes :
1 scarification (without injurying skin
capillaries) : both subcutaneous and intramuscular
vaccinations fail to provoke a pox reaction and do not
effecively incite neutralizing antibodies or
vaccinia-virus-specific cytotoxic T cellsref
5-15 rapid intradermally strokes injurying skin
capillaries using a bifurcated needle to
inject 0.0025 mL vaccine with a titer > 108
PFU / mL (glycerin in McIlvaine solution is used for
reconstitution)
high pressure jet injector (saline solution
for reconstitution)
Succesful primary vaccination in a nonimmune person who
is not immunosuppressed results in virus proliferation
in the basal cells of the dermis => papule with
surrounding erythema (2-5 days) ==(2-3 days)=> vesicle
growing until it reaches its maximum diameter on the 9th
or 10th day=> pustule (accompanied by mild
fever, swelling of the draining lymph nodes, tenderness;
maximum size after 8-12 days) => brown scab =>
separation (14 to 21 days) => scar, a mark by which
previous vaccinees can be recognizedref.
Protective vaccination with vaccinia virus depends on
delivery of the virus to the epidermis by a technique
known as scarification, leading to an epidermal 'pox'
reaction — a cutaneous T-cell-mediated delayed-type
hypersensitivity reaction presumably involving
vaccinia-virus-specific skin-homing T cells. Both
subcutaneous and intramuscular vaccinations fail to
provoke a pox reaction and do not effectively incite
neutralizing antibodies or vaccinia-virus-specific
cytotoxic T cellsref.
Immune response to primary
vaccination :
strong virus-specific CD4+ and CD8+
T lymphocytes response (TNF-a
and IFN-g secretion by
PBMCs), which declines slowly with an average
half-life of 8-15 years.
neutralizing antibodies develop about the 10th
day and remain steady for as long as 75 yearsref
hemagglutinin-inhibiting antibodies develop about
the 10th and last < 6 months
complement-fixing antibodies develop in < 50% of
the vaccinees and last < 6 months
a DTH is detectable after 2 days
Vaccinia-specific B-cell responses are essential for
protection of macaques from monkeypox
virus.
Antibody-mediated depletion of B cells, but not CD4+
or CD8+ T cells, abrogated vaccine-induced
protection from a lethal intravenous challenge with
monkeypox virus. In addition, passive transfer of human
vaccinia-neutralizing antibodies protected nonimmunized
macaques from severe disease. Thus, vaccines able to
induce long-lasting protective antibody responses may
constitute realistic alternatives to the currently
available smallpox vaccineref.
Multiple diagnostic techniques identify previously
vaccinated individuals with protective immunity against
monkeypox : approximately 50% of the US population
received smallpox vaccinations before routine immunization
ceased in 1972 for civilians and in 1990 for military
personnel. Several studies have shown long-term immunity
after smallpox vaccination, but skepticism remains as to
whether this will translate into full protection against
the onset of orthopoxvirus-induced disease. The US
monkeypox outbreak of 2003 provided the opportunity to
examine this issue. Using independent and internally
validated diagnostic approaches with 95% sensitivity and
90% specificity for detecting clinical monkeypox
infection, we identified 3 previously unreported cases of
monkeypox in preimmune individuals at 13, 29 and 48 years
after smallpox vaccination. These individuals were unaware
that they had been infected because they were spared any
recognizable disease symptoms. Together, this shows that
the US monkeypox outbreak was larger than previously
realized and, more importantly, shows that
cross-protective antiviral immunity against West African
monkeypox can potentially be maintained for decades after
smallpox vaccinationref.
These findings are not unexpected in that vaccinia virus
(i.e. smallpox vaccine) and 21 other orthopoxviruses share
the same inventory of 90 essential genes for infection and
multiplication in cellsref.
In individuals exposed at risk, boosting every 3 yrs.
Mistakenly resistance to vaccinia virus proliferation in
the basal cells of the dermis after intradermal
inoculation with vaccinia (showing no major reaction) is
equated with resistance to variola virus acquired by
droplet inhalation : this is note the case, as major
reactions can appear also in those who are immune.
Side effects (and hence contraindications)
in ...
... vaccinated persons : 1 every 1,000 experience
severe adverse effects, 14÷52 every million experience
life-threatening effect and 1÷2 every 1,000,000 dies.
... their unvaccinated contacts : 2÷6 cases
every 100,000 vaccinated subjects (68.5% are < 5
years)
in December 2002, the Department of Defense (DoD)
began vaccinating military personnel as part of the
pre-event vaccination programref.
Because vaccinia virus is present on the skin at the
site of vaccination, it can spread to other parts of
the body (autoinoculation) or to contacts of
vaccinees (contact transfer). To prevent
autoinoculation and contact transfer, DoD gave
vaccinees printed information that focused on
handwashing, covering the vaccination site, and
limiting contact with infantsref1,
ref2.
This report describes cases of contact transfer of
vaccinia virus among vaccinated military personnel
since December 2002; findings indicate that contact
transfer of vaccinia virus is rare. Continued
efforts are needed to educate vaccinees about the
importance of proper vaccination-site care in
preventing contact transmission, especially in
household settings. DoD conducts surveillance for
vaccine-associated adverse events by using automated
immunization registries, military communication
channels, and the Vaccine Adverse Events Reporting
System (VAERS). Contact transfer cases are defined
as those in which vaccinia virus is confirmed by
viral culture or PCR assays. Other cases are
classified as suspected on the basis of lesion
description and reported linkage to a vaccinated
person 3 to 9 days before lesion development. During
the period Dec 2002 to Jan 2004, a total of 578 286
military personnel were vaccinated; 508 546 (88%)
were male, and 407 923 (71%) were primary vaccinees
(received smallpox vaccination for the 1st time).
The median age of vaccinees was 29 years (range: 17
to 76). Among vaccinees, cases of suspected contact
transfer of vaccinia were identified among 30
persons: 12 spouses, 8 adult intimate contacts, 8
adult friends, and 2 children in the same household.
These cases were reported from Colorado (4), North
Carolina (4), Texas (4), Alaska (2), California (2),
one in each of Connecticut, Kansas, New Jersey,
Ohio, South Carolina, Washington state, West
Virginia, and overseas. The sources of suspected
contact transfer were all male service members who
were primary vaccinees. Except for 6 male sports
partners, all infected contacts were female.
Vaccinia virus was confirmed in 18 (60%) of the 30
cases by viral culture or PCR. 16 of the 18
confirmed cases involved uncomplicated infections of
the skin; 2 involved the eyeref.
None resulted in eczema vaccinatum or progressive
vaccinia. 12 of the 18 confirmed cases were among
spouses or adult intimate contacts. The observed
rate of contact transfer was 5.2 per 100,000
vaccinees overall or 7.4 per 100,000 primary
vaccinees. Among 27 700 smallpox-vaccinated DoD
health-care workers, no transmission of vaccinia
from a vaccinated health-care worker to an
unvaccinated patient or from a vaccinated patient to
an unvaccinated health-care worker has been
identified. 2 of the 18 confirmed cases of transfer
of vaccinia virus resulted from tertiary transfer.
One involved a service member, his wife, and their
breast-fed infant; the other involved serial
transmission among male sports partners.
on May 4 2003, a service member received his
primary smallpox vaccination. About 6 to 8 days
after vaccination, he experienced a major reaction
(an event that indicates a successful take; is
characterized by a papule, vesicle, ulcer, or
crusted lesion, surrounded by an area of
induration; and usually results in a scar). The
vaccinee reported no substantial pruritus. He
slept in the same bed as his wife (not been
vaccinated against smallpox) and kept the
vaccination site covered with bandages. After
bathing, he reportedly dried the vaccination site
with tissue, which he discarded into a trash
receptacle. He also used separate towels to dry
himself, rolled them so the area that dried his
arm was inside, and placed them in a laundry
container. His wife handled bed linen, soiled
clothing, and towels; she reported that she did
not see any obvious drainage on clothing or linen
and had no direct contact with the vaccination
site. In mid-May, the wife had vesicular skin
lesions on each breast near the areola but
continued to breastfeed. About 2 weeks later, she
was examined at a local hospital, treated for
mastitis, and continued to breastfeed. The same
day (May 29), the infant daughter developed a
papule/vesicular lesion on the upper lip/philtrum,
followed by another lesion on the left cheekref.
3 days later, the infant was examined by a
pediatrician, when another lesion was noted on her
tongue. Because of possible early atopic
dermatitis lesions on the infant's cheeks, contact
vaccinia infection with increased risk for eczema
vaccinatum was considered. The infant was
transferred to a military referral medical center
for further evaluation. On examination, the infant
had seborrheic dermatitis and no ocular
involvement. Skin lesion specimens from the mother
and infant tested positive for vaccinia by viral
culture and PCR at the Alaska Health Department
Laboratory and at Madigan Army Medical Center.
Because both patients were stable clinically and
the lesions were healing without risk for more
serious complications, vaccinia immune globulin
was not administered. Neither patient had systemic
complications from the infection. After being
monitored in the hospital for 12 days, the child
was discharged. This is the first documented case
of inadvertent contact vaccinia transmission from
a mother to her infant through direct skin-to-skin
and skin-to-mucous membrane contact while
breastfeeding. The mechanism of transfer from the
vaccinee to the spouse is uncertain. This report
demonstrates that breastfeeding infants living in
close contact with smallpox vaccinees are at
potential risk for contact vaccinia, even if the
vaccinee is not the breastfeeding mother, and
highlights the need for special precautions to
prevent secondary transfer to breastfeeding
mothersref.
in July 2003, a service member who had been
vaccinated was wrestling with an unvaccinated
service member at a military recreational function
when the bandages covering the vaccination site
fell off. The unvaccinated service member
subsequently wrestled with another unvaccinated
service member. 6 days later, both unvaccinated
service members had lesions on their forearms,
neck, and face. Skin lesion specimens from both
men tested positive for vaccinia virus by PCR and
viral culture at Tripler Army Medical Center's
microbiology laboratory.
The findings in this report indicate that the primary
risk for secondary transfer of vaccinia was among
persons who shared a bed; 12 of the 18 confirmed cases
were spouses or adult intimate contacts. However, the
majority of vaccinated DoD personnel who shared a bed
did not transfer vaccinia virus to their contacts. The
frequency of contact transfer in the military
vaccination program is comparable to rates observed
during the 1960s, although persons are less likely to
be immune to vaccinia today and thus are more
susceptible to contact transferref.
The 1st case of tertiary transfer described in this
report underscores the need for breastfeeding mothers
with household contact with vaccinees to take
precautions to prevent inadvertent transmission of
vaccinia to their infants. Direct contact is presumed
to be the major mode of transmission, but clothing and
bed linen might act as vectors for secondary
transmission. Tertiary transmission, although rare, is
facilitated when the secondary infection is not
recognized. Programs that educate health care workers,
vaccinees, and contacts should note that new vesicles
or pustules that appear <15 days after the vaccinia
scab falls off from the vaccination site might be
vaccinia infections. Although an infant living in the
home is not a contraindication to vaccination of a
family member in a non-outbreak setting, measures to
prevent transmission include having vaccinees launder
their own linens and towels and change their bandages
away from other household members. During the 1960s,
the rate of unintentional infection with vaccinia in
secondary contacts was 2-6 cases per 100 000 primary
vaccineesref1,
ref2,
ref3.
During that period, 2/3 of reported contact infections
occurred among children, typically siblingsref.
Such spread could manifest as an inadvertent infection
or, in more severe fashion, as eczema vaccinatum or
progressive vaccinia. Infections of the skin
predominated, with rarer ocular involvement posing a
risk for scarring or keratitis. In the current DoD
smallpox vaccination program, no cases of eczema
vaccinatum have occurred, although the population of
atopic dermatitis patients might have increased
substantially since the 1960sref.
During the 1960s, eczema vaccinatum resulted in
deaths, and 2/3 of such cases were related to contact
transfer of vaccinia virus. In the current DoD
smallpox vaccination program, careful screening of DoD
vaccinees and their household contacts for skin
diseases along with targeted education likely
contributed to both screening out vaccine candidates
with personal or close-contact contraindications and
educating vaccinees about proper infection-control
measures
Recommendations for covering the vaccination site
vary. The World Health Organization (WHO) does not
advocate bandagingref.
The US Centers for Disease Control and Prevention (CDC)
recommend a porous gauze dressing in nonhealth care
settings or a gauze dressing covered with a
semipermeable membrane for health care workersref.
The conventional methods of preventing a secondary
transmission event in the household of a smallpox
vaccine recipient include the use of bandages and long
sleeves (OpSite Post-Op dressing (Smith and Nephew,
Massilon, OH, USA) to limit direct contact with the
lesion and immediate hand-washing when contact occursref.
Several recent reports have measured the presence of
vaccinia virus on the dressings or hands of vaccinated
persons; however, the recovery of vaccinia virus in the
environment has not been evaluated after vaccination in
a controlled settingref1,
ref2,
ref3.
In an attempt to recover live vaccinia virus from the
homes of recently vaccinated persons, a sterile
Calgiswab type 2 applicator (Harwood Products Co.,
Guilford, ME, USA), moistened in sterile water, was
rotated over the linen from the study participant's bed
(approximate location of sleeping area), the middle of
his or her bath towel, and the inside area of a shirt
sleeve adjacent to the vaccination bandage (before
laundering). These sampling areas were chosen on the
basis of the likelihood of exposure to the semipermeable
bandage and the potential for another person to come in
contact with the vaccinia virus in these areas. An
additional 129 samples from the palm of the study
participant's hand used to take the environmental
samples were taken to serve as a control mechanism. All
516 environmental samples from designated sampling areas
in the homes of recently vaccinated vaccinia-naive
persons were negative for live virus as determined by
plaque infectivity assay. Only 1 (0.78%) of 129 dressing
samples tested on day 7 had measurable titers of
vaccinia. Contact with live vaccinia virus from the
lesion at the site of vaccination is the underlying
cause of secondary transmission. Common mechanisms for
transmission include contact with contaminated bandages
and intimate sexual contact. Recent studies have
compared a variety of bandages used to cover the
vaccination site to determine which class of bandage
provides the greatest protection against disseminated
virus. Talbot et al. observed that <1% (N = 918) of
dressing samples were positive for vaccinia (an initial
semipermeable OpSite Post-Op dressing and an outer
semipermeable Tegaderm bandage)ref.
In a single-blind randomized trial design, Waibel et al.
compared the presence of vaccinia virus on the external
surface of 3 different types of bandages and noted that
the unfolded 5.1 × 5.1cm gauze (Kendall Clarity
Gauze Sponge) covered by a 5.1 × 7.0 cm semipermeable
membrane (Polyskin II Transparent Dressing; Kendall)
had the smallest proportion of recoverable virus
compared with the groups that used a 1.9 × 7.6cm
self-adhesive bandage (Band-Aid; Johnson & Johnson)
or unfolded 5.1 × 5.1 cm gauze (Kendall Clarity Gauze
Sponge) covered by a 2.5 × 12.7 cm piece of adherent
tape (Transpore surgical tape; 3M). Viral DNA was
measured once on bandage surfaces after 8 h. In
practice, however, recipients might be instructed to change
their dressing every 1-3 days for up to 3 weeks,
coinciding with reduced bandage adhesion or visible
exudates. 3 weeks of dressing changes complicate
compliance, especially if a less convenient, bulkier
dressing is used. This underscores the notion that a
simple plaster adhesive containing absorbent material
might increase compliance, and perhaps reduce the risk
of accidental transmissionref.
Despite the difference in types of bandages from these
studies, the results were remarkably consistent with
regard to the limited dissemination of vaccinia virus
outside the dressing. The semipermeable bandage provided
significant protection from exposure to the virus on the
outside of the bandageref
In a national survey in the United States conducted after
smallpox had been eliminated, there were 66 cases, with no
deaths, among 14.5 million vaccinees.
lymphadenitis persisting for 2÷4 weeks
after blister has healed
feverof over 100°F in ~ 70% of
children and 17% of adults.
mild rash, lasting 2÷4 days
rash on entire body (1 per 4,000)
eczema
vaccinatum / pyoderma varioliforme infantum (a
kind of Kaposi's
varicelliform
eruption (KVE))
in individuals who have active or quiescent atopic
dermatitis
(AD)
(1 per 26,000) results from an inability of the host
to control the spread of virus from the inoculation
site (Th2
polarization prevents Th1-mediated
viral clearance, and increased levels of the Th2-type
cytokine IL-4 can be detected in both affected and
unaffected skinref
: ectromelia virus genetically engineered to produce IL-4
results in a lethal disease in mice that are normally
resistant to unmodifed ectromelia, indicating a role
for this cytokine in restricting immune responses to
pox virusesref).
After
5 days, a vaccinial eruption occurs at sites that are
eczematous or that had previously been so, sometimes
spreading to normal skin => high fever and
generalized lymphadenopathy. Although usually mild and
self-limited, severe or fatal cases have been reported
and are independent of the activity of the underlying
eczema at the time of vaccination : disease may cause
multiple duodenal ulcers and death by acute
peritonitis and is associated with substantial
morbidity and mortalityref1,
ref2.
Production of Th1-type cytokines, such as
IFN-g, and CTL functions
are also impaired in patients with ADref1,
ref2.
T-cell homing might be dysfunctional in these patients
as well. In mice, the generation of Th1-type,
but not Th2-type, cytokines, is associated
with a skin-homing phenotyperef.
The presence of skin-homing Th2 cells in
atopic patients might represent an uncoupling of this
associationref.
Surprisingly, even innate immunity might be impaired
in these patientsref.
The production of IL-18 is increased in AD :
however, serum IL-18 levels tended to correlate
negatively with serum IgE levels in patients with AD
and NC/Nga miceref,
and keratinocytes from patients with AD produce a
different array of cytokines and chemokines than do
keratinocytes from non-atopic individualsref1,
ref2,
ref3
progressive
(or gangrenous) vaccinia / vaccinia necrosum in
individuals with agammaglobulinemia, hypoglobulinemia,
neoplasms affecting the RES, CMI
deficiencies,
or treated with immunosuppressive
drugs
(1 per 625,000). The vaccinia lesion fail to
heal and metastatic lesions sometimes appear.
Methisazone is reported to be partially effective in
treatment, but 33% of such patients die from secondary
visceral involvment.
generalized
vaccinia (1 per 4,000) : spread of the virus in
the bloodstream cause after 6-9 days development of
vesicles and pustules resembling the initial one found
at the inoculation site (but sometimes varied in size)
, sometimes covering the entire body => uneventful
recovery without the need for specific therapy.
Generalized vaccinia is not associated with
immunodeficiency, although it is more severe in
immunocompromised individuals. The rash was usually
self-limiting and thus, little or no therapy was
administered.
accidental autoinoculation to eyelids (vaccinophthalmia),
mouth, nose, genitalia, and rectum. Such lesions
evolve rapidly and heal at the same time as the
primary lesion. VIG can
be used for vaccinophthalmia : however, if vaccinial keratitis is present, VIG is
contraindicated, because it might increase corneal
scaring.
circulatory
encephalopathy 5-10 days after vaccination in
children with age < 2 : hyperemia of the brain,
lymphocytic infiltration of the meninges, widespread
degenerative changes in ganglion cells, and
perivascular hemorrhage => after 6-10 days fever
and convusions => hemiplegia and aphasia =>
death within few days or recovery with some degree of
mental impairment and/or paralysis.
postvaccinial
autoimmune
encephalomyelitis 8-14 days after vaccination
in children with age > 2 (1 per 5,000÷20,000) :
perivenous demyelination and microglial proliferation
=> after 11÷15 days : fever, vomiting, headache,
malaise, anorexia, disorientation, drowsiness,
convulsions, coma => death (10-50%) within a week
of onset, recovery with upper spastic paralysis (25%)
or full recovery within 2 weeks. In the United States,
there were 12 cases, of which one resulted in death,
among the 13 million vaccinees. VIGs are useless.
fetal vaccinia
in pregnant women (< 20 cases recorded)
bacterial overinfections at the vaccination
site in as many as 1 per 667,000
coronary
artery
diseases (CAD),
hypersensitivity
myocarditis
and pericarditis
5 to 17 days after vaccination in recipients with age
from 43 to 55 and previous heart diseases. 8 cases of
cardiac adverse events [5 AMIs and 2 cases of angina,
with 3 deaths] have been reported among 493,000
vaccinees since the beginning of the US smallpox
vaccination program in 2002 to 18 June 2003. As of 20
Jun 2003, a total of 21 cases of myopericarditis were
reported among civilians and another 10 cases
among those in the military. Viruses create a
self-perpetuating, hypercoagulable state by adhering
directly to blood vessel walls. When this occurs,
circulating fibrin is deposited directly onto the
virus creating a protective coating, in an attempt to
isolate the virus from the rest of the body. The
result is the formation of visible bumps along the
inside wall of the blood vessels, increasing the blood
flow turbulence, releasing more thrombin, creating a
perpetual thrombin-fibrin-deposition cycle, leading to
hypercoagulabilty and clot formation. 2 cases of dilated
cardiomyopathy
(DCM)
were diagnosed 3 months after vaccination in persons
with no previous history of cardiomyopathy, coronary
artery disease (CAD), or congestive heart failure.
9 other serious events were reported, including 3
cases of chest pain, one case of gastro-esophageal
reflux
disease,
one case of cholecystitis,
one case of sudden death caused by atherosclerotic coronary
artery diseases (CAD)
69 days postvaccination. 3 neurologic cases were
reported, including a central nervous system tumor
diagnosed 28 days postvaccination, a headache
evaluated for encephalitis, and a cerebral vascular
accident. An additional 111 other nonserious events
also were reported . Among the 610 vaccinees with
reported other nonserious adverse events during 24 Jan
2003--20 Jun 2003, the most common signs and symptoms
were fever (n = 121), rash (n = 114), headache (n =
103), pain (n = 95), and fatigue (n = 85). All of
these commonly reported events are consistent with
mild expected reactions following receipt of smallpox
vaccine. Some vaccinees reported multiple signs and
symptoms.
a total of 14 cases of transmission from military
personnel to civilian contacts have been reported
since the program began.
pustule at 6 to 8 days if residual CMI is low (major
reaction)
antibodies rise within 7 days and reach higher
levels (at least for neutralizing ones)
Repeated vaccinations provide a short-term boost in
immunity but, over time, do not create a sustained higher
level of protection compared to those persons vaccinated
only once
Status of the practice : in
USA and Canada (last Canadian case : 1946) vaccine
administration has been suspended in 1971-1972 for
civilians, in 1976 for healthcare workers, in 1982 for
international travelers, and in 1990 for military
personnel. Part of military and healthcare personnel has
been vaccinated in 2002-2003 : the military
has inoculated 454,856 personnel (70.5 primary vaccinees),
nearly 90% of them before the invasion of Iraq, and is now
vaccinating about 1000 a week. State health departments
have inoculated only 37,608 civilian emergency health
workers in 55 jurisdictions and are adding about 100 more
each week, although the goal was 500 000. VIG was needed
only 3 times. About 125 women who were pregnant or became
pregnant were inadvertently vaccinated, despite screening
: thus far, there has been no vaccinia in fetuses, and
miscarriage rates have been normal, though they are still
being followed. Revaccinate those already vaccinated in
childhood and at a very low risk would be a better
strategy than risking the side effects on the population
as a whole. When revaccinated with a 1:10 dilution of
smallpox vaccine, previously immunized persons exhibit
fewer side effects and a similar immune response to that
seen in vaccinia-naďve subjects : major reactions were
documented in 95% patients given undiluted vaccine, 90%
given a 1:3.2 dilution, and 81% given a 1:10 dilution.
Only a 1:32 dilution resulted in significantly fewer major
reactions, 52.6% compared with undiluted vaccine (p =
0.003)
Commercialized formulae :
Dryvax® (Wyeth-Ayerst; side
effect : encephalitis) : prepared from lymph collected
from lesions on calves' bellies, making it a
relatively expensive and difficult endeavour. Despite
its efficacy, Dryvax's manufacture is seen as dated.
ACAM1000®ref (OraVax, Inc. => Acambis, Ptl.,
USA) : a vaccinia virus was derived from the
existing Dryvax vaccine by adaptation for growth in
a human diploid cell line, providing a purer
product. 6 cloned and one uncloned vaccine
candidates were produced. The ACAM1000 clone was
chosen for development based on its comparability to
Dryvax when tested in mice, rabbits, and monkeys for
virulence and immunogenicity. By most measures,
ACAM1000 was less virulent than Dryvax (less likely
to cause encephatis) and the vaccines are equivalent
in initial trials in their ability to produce major
cutaneous reactions ('takes') and to induce
neutralizing antibody and cell-mediated immunity
against vaccinia virus
ACAM2000®
(Acambis, Ptl., USA; less likely to cause
encephalitis). With the US on high terrorist
alert, Acambis fast-tracked orders for 209 million
doses of the vaccine from it before it had been fully
tested. On 14 April 2004, intense monitoring of
who participated in the phase III trials has
discovered that 3 suffered myopericarditis and the
trial has been suspended. The drug has not been given
to anybody outside the trials. It remains to be
established whether the cell culture-derived and
-produced vaccine is inferior to Dryvax, or whether
the stringency of the phase III trials procedure has
been increased in the light of more clinical
assessment of the performance of the Dryvax vaccine
La Variole® (?, France)
Lancy Vaxina® (Swiss Serum and
Vaccine Institute)
Liovax® (Sclavo)
Liovaxs® (Biocine)
? (VaxGen, USA + Kaketsuken,
USA)
Ospa® (?, Poland)
Pocken® (?, Germany)
Pocken-Impfstoff® (?, Germany)
Vaccinia® (?)
Vaiolo® (?, Italy)
Vaksin Cacar® (?, Indonesia)
Varicela el® (?, Spain)
Varie® (Institute of Sera and
Vaccine) : lyophilized
Viruela® (?, Spain)
Vaccine production in USA has been discontinued in 1982
and reinitiated in 2002.
Web resources :
subunit
vaccines / acellular vaccines are cell-free
vaccine prepared from purified antigenic components of
pathogenic microorganisms, thus carrying less risk of adverse
reactions than whole-cell preparations.
conventional vaccinology : biochemical,
serological and microbiological methods have been used to
dissect pathogens and identify the components useful for
vaccine development. Although successful in many cases, this
approach is time-consuming and fails when the pathogens
cannot be cultivated in vitro, or when the most abundant
antigens are variable in sequence.
reverse vaccinologyref
: genomic approaches allow prediction of all antigens,
independent of their abundance and immunogenicity during
infection, without the need to grow the pathogen in
vitro. Candidate peptide
vaccine components representing T cell epitopes
might be predicted from the various microbial genome
projects, tumor vaccine candidates from mRNA expression
profiling of tumors ("transcriptomes") and auto-antigens
from the human genome. Promising antigens are then
mass-produced in Escherichia coli, purified, and
used to immunize mice. Anyway the possibility of
splicing at the protein level certainly adds to the
complexity of the possible repertoire of peptides displayed
to T lymphocytes : e.g. C2 CTLs, cloned from human CTLs
infiltrating a renal cell carcinoma, recognize HLA-A3 MHC
class I molecules presenting a 9-residue FGF-5 peptide
generated by protein splicing of residues 172–176 and
199–220. This process, previously described strictly in
plants (involving reverse proteolysis) and unicellular
organisms (regulated by “inteins”), entails
post-translational excision of a polypeptide segment
followed by ligation of the newly liberated carboxy-terminal
and amino-terminal residuesref.
Within 18 months of the beginning of the sequencing of Neisseria
meningitidis
serogroup B (Men B), over 600 potential vaccine candidates
had been predicted by computer analysis of the genome, and
350 of them were expressed in Escherichia coli,
purified, and used to immunize miceref1,
ref2.
Today, the genome-based approach is routine in vaccine
development and is being applied to streptococci,
Chlamydiae, staphylococci, Plasmodium falciparum,
and bioterrorism-associated agents such as Yersinia
pestis.
candidate peptide vaccine
components representing B cell epitopes are typically
identified by their ability to bind Abs from subjects
exposed to the relevant pathogen, which we call direct
Abs. To be useful as a vaccine component, a peptide
must be not only antigenic but also immunogenically fit :
when used as an immunogen, the indirect Abs it
elicits must cross-react with native intact pathogen. Immunogenic
fitness is gauged by the fraction of indirect
anti-peptide Abs that cross-react with the pathogen : it
is a property of epitope structure and the response
charactetrstics of immune cells, and does not depend on
idiosyncratic details of pathogenesis. It is distinct from
immunogenicity, which is gauged by the total anti-peptide
titer of those indirect Abs, including Abs that do not
cross-react with pathogen. Peptides with excellent
antigenicity and immunogenicity frequently lack adequate
immunogenic fitness and therefore fail as potential
vaccine components. A common explanation for this poor
immunogenic fitness is the conformational flexibility
of most short peptides. A flexible peptide may bind
well to direct Ab and thus have good antigenicity; indeed,
flexibility may sometimes enhance antigenicity by allowing
the peptide to bind by an induced fit mechanism. Likewise,
a flexible peptide may be highly immunogenic, eliciting
substantial Ab titers. However, if the peptide has a large
repertoire of conformations, a preponderance of those Abs
may fail to recognize the corresponding native epitope on
the intact pathogen. Antigenic peptides can be obtained
through a strategy called epitope discovery, in which
direct Ab is used to affinity select Ags from very large phage-displayed
libraries of peptides. The property that enables a peptide
to prevail during selection - high affinity for a
prevalent subspecificity in the selecting direct Ab
population - augurs well for success as a candidate
peptide vaccine component, even though its correlation
with immunogenic fitness is imperfect. Selections can be
made from 2 types of libraries :
random peptide libraries
(RPLs), in which the phage-displayed peptides are
encoded by synthetic random degenerate oligonucleotide
inserts
natural peptide libraries
(NPL), in which the phage particles display
fragments of natural pathogen proteins, encoded by short
DNA fragments of the pathogen genome
Ligands affinity selected from RPLs and
NPLs will be called random antigenic peptides (RAPs)
and natural antigenic peptides (NAPs), respectively.
While RAPs have only marginal immunogenic fitness, a large
fraction of NAPs have excellent immunogenic fitness.
Finding efficient ways to get an antigen presented to the
immune system : pH-sensitive microspheres that seem to
enhance antigen uptake and presentation significantly. Capsules
made with Eudragit 100 (E100), a methacrylate-based
polymer, remain largely stable at neutral pH, only slowly
releasing their contents over the course of several weeks. After
their injection, however, dendritic cells (DCs) readily
phagocytose these capsules, which quickly dissolve in the acidic
pH of the phagosome, releasing their contents into the vesicle.
Thus released antigens enter directly into the MHC class I
pathway for presentation. Encouragingly, these capsules seem to
have minimal detrimental effect on DCs. The uptake of
encapsulated antigen is considerably greater than that of
unencapsulated antigen, and uptake of antigen-laden E100
particles significantly increases the capacity of DCs to
activate T cell response relative to antigen alone or antigen
encapsulated in a non-pH-sensitive methacrylate polymer. In
vivo, splenocytes from mice injected with E100 capsules
containing an influenza-derived peptide antigen proved capable
of stimulating more robust cytotoxic activity than cells from
mice treated with soluble antigen alone. Data indicate that
these microparticles do not induce DC maturation by themselves.
It is possible that the inflammatory reaction to the particles
may be involved in enhancing the T cell response in vivoref
To counter highly mutable pathogens, a number of vaccines are
being developed to deliver multiple mutant forms of antigens to
provoke multivalent CTL. However it is uncertain whether such
multiple mutant epitope vaccines will generate the diverse CTL
responses desired or will instead create immune
interference.
At least some immune intereferences can be avoided by delivering
mutant Ags to the immune system simultaneously.
homologous
Ags
transfer factors (TF) : a
dialyzable extract obtained from lysates of peripheral
blood lymphocytes that is capable of transferring
antigen-specific cell-mediated immunity (delayed-type
hypersensitivity) from donor to recipient and also has
nonspecific immunostimulatory activity. TF is nonantigenic
and does not transfer humoral immunity. It has been used
in the treatment of a variety of immunodeficiency
diseases. It comes from ...
dried cow colostrum
(Transfer Factor®, Transfer Factor Plus®, Transfer
Factor
XF®)
concentrated 30 times, devoid of allergens.
Transfer factor contains :
RNA
protein : a mix of >
200 different peptides with 4 < molecular weight
< 10 kDa, about 44-amino acids long, from
which antibodies have been eliminated (probably
because they could interfere with induction of
adaptive immune response), and
hence containing mainly :
cytokine are normally produced from all
species with an adaptive immune system (i.e.
Vertebrates). These cytokines can be administered
even by oral route as natural(i.e. in mammary gland
or eggs) hyperglycosylation allows them to resist gastric pH and digestive
proteases.
antigens are present thanks
to (multiple) vaccination (with adjuvants) of the experimental
animal
It doesn't contain :
DNA
viable cells can't account for
the protective role of transfer factor as it can be effectively administered
even in powdered or freeze-dried
forms.
Transfer factors are said to be able
to elicit a secondary immune response
just because they also already contain those cytokines
that require some days in
humans to be produced after primary exposure : hence we
should more properly say transfer
factors induce a fastened primary immune response, as for
most vaccinations (in this case
transfer are just like subunit vaccines and cytokines are the adjuvants).
Even if transfer factors can pass
protective immunity to mice (patent
data support this, hoping they're serious), this doesn't
mean they can pass
protective immunity to humans. Cytokines effects depends
on their ability to bind receptors on immune system cells
: the greater the
phylogenetic distance between the producer species and
humans (hen > cow > human), the
higher the likelihood that these cytokines can't bind
human receptors. Human cytokines have a molecular weight
between 6 and 60 kDa : 4-5 kDa could be the weight of
intact avian / bovine cytokines, otherwise if they were
the result of a proteolytic cleavage these peptides would
have reduced likelihood of retaining an active
receptor-binding domain.
Not all human diseases are
zooanthoroponoses (e.g. human herpesviruses are
human-restricted). Anyway when
an antigen from an heterologous infectious organism is
injectedtogether with adjuvant, the unusual host can
develop an adaptive immune
response against it. Anyway for antigens to be found in
yolk orcolostrum they have to reach a significant
concentration in blood and this
seems quite difficult if they can't replicate in such
unusual host, unless high amount of
antigens are directly injected intothe bloodstream of the
producer species : this let scientists doubtful about
the effectiveness of the anti-EBV
patented transfer factor, even because eggs are collected 175 days after
immunization, where antigens have been reasonably cleared.
microorganism Ags
Some examples :
broad-spectrum antibacterial vaccine :
injection of low-dose LPS
to mice prior to induction of GVHD
with allogeneic spleen cells saved > 40% of the
recipients, whereas all mice in the untreated control
group died. The survival of recipients of spleen cells
from immunized donors rose to 54% and clinical signs of
GVHD were attenuated as compared to control mice
inoculated with spleen cells obtained from unimmunized
donors. This immunization protocol suggests that
immunization of the donor or the recipient against LPS
prior to transplantation may be protective against
gram-negative bacteriaref
protein antigens
anti-viral subunit vaccines /
subvirion vaccines
anti-human
papillomaviruses (HPV) vaccines (see also DNA
vaccine): virus-like particles (VLP)
consist of the capsid proteins L1 or L1 and L2.
Chimeric VLP, which have the E7 protein fused to
either L1 or L2, are being developed for
immunotherapeutic vaccine strategies against
cervical cancer. The constitutive expression of
high-risk HPV E6 and E7 proteins, which bind and
inactivate tumor suppressors p53 and pRb,
respectively, in cervical cancer cells, makes them
attractive targets for immunotherapy. A 2002
double-blind study on 768 women of ages 16-23 who
received 3 doses of an HPV16 VLP vaccine has shown
100% effectiveness against infection and preinvasive
cervical cancer. Both women taking and not taking oral
contraceptives develop detectable titres of
anti-HPV16L1 VLP immunoglobulins in their cervical
secretions after immunization : anyway these titres
were fairly constant in the contraceptive group
throughout the mentrual cycle, but titres of both
vaccine-specific and total IgG decreased by about
9-fold during ovulation in the no contraceptive
group, then rose again in the luteal phase of the
cycle. Sex hormones might have a role in regulating
antibody concentration in the cervix, and the
decrease in antibody concentration at ovulation
might be a protective mechanism to reduce the level
of antisperm antibodies in the genital tract at a
time when conception is most likely : it is unclear
whether the decrease in antibody production will
affect the ability of this vaccine to protect
against cervical cancer.
no objective clinical response
open-label uncontrolled trial
bivalent HPV-16/18 (that have been linked to 70% of
cervical cancers) L1 VLP (Cervarix®) (not
yet been submitted for regulatory approvals)
a study of 1,113 women aged 15 to 25 years old in North
America and Brazil has found it is 100% effective at
preventing the persistent infections that cause cervical
cancer. It was 91.6% effective at reducing incident or new
infections for as long as 2 years among 366 women (65% of
the total 1,113 patients) who received all 3 doses according
to schedule. In the intention-to-treat analyses, vaccine
efficacy was 95.1% against persistent cervical infection
with HPV-16/18 and 92.9% against cytological abnormalities
associated with HPV-16/18 infectionref.
A Glaxo-financed phase III trial, conducted in Europe and
Russia showed that 158 healthy girls aged 10 to 14 who
received the vaccine had immune responses twice as strong as
458 women 15-25 years old given the vaccine
HPV 16 and 18, cause about 70% of cervical cancer cases,
while HPV 6 and 11 cause about 90% of genital warts cases (Gardasil®,
Merck & Co.) (already awaiting approval from U.S. and
European regulators)
over 2 1/2 years of follow-up, the vaccine blocked about
90% of infections with the 4 HPV types. None of the vaccine
recipients developed cervical cancer, precancerous lesions
or genital warts related to those HPV types
The goal would be to give the vaccine to girls before
they are sexually active. The vaccine prompts the body
to produce high numbers of antibodies to fight the HPV
infection and the only side effects were some redness
and irritation at the vaccine site. Although the
vaccine won't prevent all cervical cancers because it
doesn't protect against all cancer-producing strains,
a quadrivalent vaccine that also protects against
types 6 and 11 is already under study. Merck presented
results that showed its vaccine, which targets just
the HPV16 form of virus, continued to protect against
the disease for 4 years. Merck is testing a more
advanced vaccine that targets 4 forms of the virus in
a study of 25,000 women. Although teenagers and adults
took part in the trials, in practice the vaccine is
likely to be administered to girls as young as 10 to
13. Because HPV is transmitted through sexual
intercourse, older sexually active girls are more
likely to be infected. Some critics have argued that
treating young girls with the vaccine might encourage
under-age sex
The FDA allowed Merck to use a potentially reactive
aluminum containing placebo as a control for most
trial participants, rather than a non-reactive saline
solution placebo. A reactive placebo can artificially
increase the appearance of safety of an experimental
drug or vaccine in a clinical trial. Gardasil contains
225 mg of aluminum and,
although aluminum adjuvants have been used in vaccines
for decades, they were never tested for safety in
clinical trials. Merck and the FDA did not disclose
how much aluminum was in the placebo. Animal and human
studies have shown that aluminum adjuvants can cause
brain cell death and that vaccine aluminum adjuvants
can allow aluminum to enter the brain, as well as
cause inflammation at the injection site leading to
chronic joint and muscle pain and fatigue. Nearly 90%
of all Gardasil recipients and 85% of aluminum placebo
recipients reported one or more adverse events within
15 days of vaccination, particularly at the injection
site. Pain and swelling at injection site and fever
occurred in approximately 83% of Gardasil and 73% of
aluminum placebo recipients. About 60% of those who
got Gardasil or the aluminum placebo had systemic
adverse events including headache, fever, nausea,
dizziness, vomiting, diarrhea, myalgia. Gardasil
recipients had more serious adverse events such as
headache, gastroenteritis, appendicitis, pelvic
inflammatory disease, asthma, bronchospasm and
arthritis. Merck and the FDA do not reveal in public
documents exactly how many 9 to 15 year old girls were
in the clinical trials, how many of them received
hepatitis B vaccine and Gardasil simultaneously, and
how many of them had serious adverse events after
being injected with Gardasil or the aluminum placebo.
For example, if there were fewer than 1,000 little
girls actually injected with three doses of Gardasil,
it is important to know how many had serious adverse
events and how long they were followed for chronic
health problems, such as juvenile arthritis. According
to the Merck product manufacturer insert, there was 1
case of juvenile arthritis, 2 cases of rheumatoid
arthritis, 5 cases of arthritis, and 1 case of
reactive arthritis in 11,813 Gardasil recipients plus
1 case of lupus and 2 cases of arthritis out of 9,701
participants primarily receiving an aluminum
containing placebo. Clinical trial investigators
dismissed most of the 102 Gardasil and placebo
associated serious adverse events, including 17
deaths, that occurred in the clinical trials as
unrelated.
anti-HAV vaccines (see also killed vaccine) :
2 intramuscular injections separated by 6-12 months
Avaxim® (Aventis Pasteur)
160 U in 0.5 mL
80 U in 0.5 mL or 800 U / 5 mL (for pediatric
use)
Apaxal® : 0.5 mL
Epaxal® (Swiss Serum and
Vaccine Institute) : the first product based on
the virosome technology developed and patented by
Berna Biotech. The innovative carrier system
provides rapid, long lasting protection and
exhibits good tolerability.
There is no worldwide consensus on how long protection
will last or whether there will be a need for HAV
booster vaccinations in the future. In most countries,
booster-vaccination policy is guided by manufacturers'
recommendations, national authorities, or both. In
June, 2002, a panel of international experts met to
review the long-term immunogenicity and protection
conferred by HAV vaccine in different population
groups. Data have shown that after a full primary
vaccination course, protective antibody amounts
persist beyond 10 years in healthy individuals, and
underlying immune memory provides protection far
beyond the duration of anti-HAV antibodies. The group
concluded that there is no evidence to lend support to
HAV booster vaccination after a full primary
vaccination course in a healthy individual. However,
further investigations are needed before deciding if
boosters can be omitted in special patient-groupsref
anti-HBV vaccine (HBV) (see also DNA
vaccine) for immunization of persons at
high risk, e.g., medical and dental personnel,
immunocompromised patients and patients requiring
hemodialysis or frequent transfusions, residents and
staff of closed institutions, contacts of carriers,
and male homosexuals : it protects also from HDV. 4 intramuscular injections (not
on gluteus !) at months 0, 1, 2, and 8-14; effective
([Ab] > 10 mU/mL) for 3-5 yrs in 90-99%. 1-2
boosters may be required only after age 60. If titer
has never been measured after vaccination, practice
a booster : if titer rises sharply the patient was
already protected, otherwise patient is classified
as non-responder (rather he/she has an undetectable
but still protective titer). The HBV vaccine market
outside of the USA is approximately $500 million
formalin-treated HBsAg isolated from plasma
of human carriers of hepatitis B
H-B-Vax®
(MSD-Behringwerke) : serum
Heptavax B® (Merck) :
plasma derived, no longer in use
Biken-HB® (Research
Foundation for Microbial Disease)
Bimmugen®
(Chemo-Sero-Therapeutic Research Institute)
a new HBV vaccine (source : Dynavax)
combines immunostimulatory
(ISS)
oligodeoxynucleotides (ODN) / TLR9 agonists with rHBsAg induced more
rapid immunogenicity and more durable protective
response compared to Engerix-B in healthy young
adults 4 weeks after administration of the third
dose in a phase II/III trial
Engerix-B®
(RIT/GlaxoSmithKline Inc., Dong Shin
Pharmaceuticals Co.) : 20 mg
/ mL for adults, 10 mg
/ mL for babies. 12.5 mg
mercury per dose (0.005% thimerosal).
Strong
immunological memory persists more than 10 years
after immunisation of infants and adolescents
with a primary course of vaccination. Protective
anti-HBs concentrations were retained in 64% of
children and 89% of recruits. Antibody amounts
< 10 IU/L were recorded in 36% of children
and 11% of recruits. 1 child and 4 recruits were
positive for anti-HBc, but negative for HBsAg
and hepatitis B viral DNA. Antibody
concentrations were higher in recruits than in
children. 97% of children and 96% of recruits
who received a booster showed an anamnestic
response, whereas 3% of children and 4% of
recruits remained negative for anti-HBs or had
antibody concentrations of less than 10 IU/L.
Prebooster and postbooster antibody titres were
strongly correlated with each other in both
groups. All individuals given 2 additional
vaccine doses showed anti-HBs amounts > 10
IU/L at 1 month after vaccination. Booster doses
of vaccine do not seem necessary to ensure
long-term protectionref
Hepacare® (Medeva) :
recombinant, 20 mg
S, pre-S1 and pre-S2 Ags in 1 mL
Hepavax-Gene® is a DNA
recombinant HBV vaccine with a proven safety and
efficacy record. The vaccine is produced using
the highly-efficient proprietary Hansenula
polymorpha technology.
Heprecomb® (Berna) : yeast
derived
Hepatitis tipo B® (?,
Spain)
Recombivax
HB® (Merck & Co.;
royalties : Chiron) : preservative-free; LIQ(5 mg / 0.5 mL) IM (10 mg for adults, 5 mg for babies). No
mercury added.
rHBsAg cloned in mammalian cell
GenHevac B® (Aventis
Pasteur)
R-HB Vaccine® (Mitsubishi
Chemical Corp.) : precipitated, CHO derived
Hepagene® (Medeva) :
multiple antigens
Bilive®
(Sinovac, China) : combined anti-HAV and anti-HBV
vaccine
anti-influenzaviruses
A
and B vaccine (see also kllled vaccine, attenuated vaccine
and DNA
vaccine) : 2 intramuscular injections.
Current vaccines are highly effective for 4-6 months
in children and adults (70%–90%), although not in
those >65 years of age (30%–50%)ref
: booster every year. Counterindicated in
individuals allergic to egg proteins.
universal
influenza vaccineref
based on invariant proteins that confer heterotypic
or heterosubtypic immunity. Incorporation of
several conserved targets in a universal vaccine
may decrease the likelihood and rate of emergence
of escape mutants and increase the strength of
protection. They have been studied extensively in
animals and found to be mediated predominantly by
virus-specific memory T cellsref1,
ref2,
antibodiesref1,
ref2,
ref3,
or a combination of bothref1,
ref2
(Gerhard W, Mozdzanowska K, Furchner M. The nature
of hetero-subtypic immunity. In: Brown LE, Hampson
AW, Webster RG, editors. Options for the control
of influenza III. Amsterdam: Elsevier Science;
1996. p. 235–43). The reason for these differences
in the relative strength of T-cell and
antibody-mediated protection is not clear but
could be attributable to differences in
vaccination procedures, virus challenge, and read
out (how protection was measured) between the
various studies. A large number of memory T cells
may also result in immunopathologic manifestationsref1,ref2,
which tend to be associated with excessive
inflammatory responses in acute infections :
antibody-mediated protection is the accessibility
of the viral antigen to antibody on infectious
virus particles, intact infected cells, or both.
This accessibility restricts the potential targets
to conserved structures of the ectodomains of
viral transmembrane proteins HA, NA, and M2, in
the case of influenza A viruses, and HA, NA, NB,
and BM2, in the case of influenza B viruses. In
the elderly, another high-risk population, a
universal vaccine may be particularly advantageous
because the protective antibodies are generated by
memory B cells that tend to be maintained into old
age and can be recalled by booster vaccination. In
contrast, the efficacy of current inactivated
vaccines depends greatly on the ability to mount a
strong response to novel (strain-specific)
determinants generated through antigenic drift and
shift on HA and NA. This response requires naive
B cells, whose frequency tends to decrease with
increasing age. When all factors are taken into
account, protection against influenza virus
infection likely can be improved by a universal
vaccine.
intersubunit region of hemagglutinin
: The protective potential of antibodies
directed to this region of HA0 has
been explored in 2 studies by immunization of
mice with synthetic peptides spanning the
cleavage siteref1,
ref2.
Both studies found that mice vaccinated with a
peptide spanning the HA1/HA2
joining region exhibited less illness and fewer
deaths on virus challengeref1,
ref2.
Most importantly, HA1/HA2
joint-specific antibodies were undetectable in
virus-immune human seraref.
These findings make the HA1/HA2
joining region another promising candidate for
inclusion in a universal vaccine. Indeed, the
authors of 1 study, some of whom had been
involved in an M2e-vaccine study, commented that
joint-specific immunity in the mouse model was
more robust than M2e-specific immunityref.
Although the HA1/HA2-joining
region is the most broadly conserved HA
sequence, other determinants on HA2 are shared
between a restricted number of subtypes. For
instance, a MAb that reduced illness and death
in passively immunized mice against viruses of
the H1, H2, and H5
subtypes has been describedref1,
ref2.
This MAb was shown to recognize a conformational
epitope of HA2ref,
but no immunogen that could selectively induce
this response has been described. A search for
determinants shared by a more restricted number
of closely related subtypes such as H2
and H5, which display 85% sequence
homology in HA2, or shared by members
of the same subtype, which typically display
>95% sequence homology in HA2ref,
would be worthwhile, particularly since the HA2-specific
antibody response appears to be induced less
effectively than the HA1-specific
response by infection in humansref.
That many HA2-specific antibodies do
not display substantial antiviral activities in
vitro does not preclude protective
activity in vivo because the mere binding of
antibody to native HA expressed on infected
cells and infectious virus could mediate
protective activity by targeting FcR expressing
cells or complement deposition to these
structures
ectodomain of matrix protein 2 (M2e)
: M2e-specific antibodies, while they did not
prevent infection, restricted subsequent virus
replication and reduced illness and proportion
of deathsref1,
ref2,
ref3,
ref4,
ref5.
This antibody response was only poorly induced
by infection, both in miceref
and humansref1,
ref2.
A likely reason for the poor M2e-specific
antibody response is extensive antigenic
competition with HA- and NA-specific responsesref.
Thus, in view of the >10-fold difference in
ectodomain size, the frequency of M2e-specific
precursor B cells must be orders of magnitude
lower than the frequencies of HA- and
NA-specific precursor B cells. Assuming that
most immunogenic entities generated in the
course of infection contain a mixture of all 3
transmembrane proteins, most M2e may be taken up
by HA- and NA-specific B cells, leaving little
or none for B-cell receptor–mediated uptake and
processing by M2e-specific precursor B cells.
Note that the same phenomenon results also in a
suppression of the NA-specific antibody response
by immunodominant HA-specific B cellsref.
Such competition can be avoided by presenting
individual antigens on physically distinct
immunogenic entities to the immune systemref.
The substantial M2e-specific antibody responses
seen in mice after vaccination with dedicated
M2e vaccines (20–24) supports the above
explanation. In view of the poor or absent
M2e-specific antibody response in humans,
confirming the genetic stability of M2e was
essential when the virus was propagated in an
immune environment. Replication of A/PR/8/34(H1N1)
(PR8) virus for >3 weeks in severe combined
immunodeficient (SCID) mice that were
chronically treated with M2e-specific monoclonal
antibodies (MAbs) resulted in the emergence of
M2e-escape mutantsref.
However, only 2 distinct escape mutants emerged,
1 with a replacement of Pro at position 10 by
Leu (P10L) and the other with a replacement of
the same Pro by His (P10H)ref.
Each of these mutants was isolated repetitively
from many distinct mice treated with distinct
M2e-specific MAbs, which indicates that they
represented essentially the entire range of
escape mutants capable of arising from the PR8
wild-type virus under the given experimental
conditions. No escape mutants emerged after 11
consecutive passages of PR8 in BALB/c mice that
had been actively vaccinated with M2e. In
addition, incorporating determinants of
potential escape mutants into a polyvalent
universal M2e vaccine would likely further
impede emergence of escape mutants. Indeed,
preliminary studies have shown that no escape
mutants emerged in SCID mice treated with a
combination of MAbs specific for M2e of
wild-type PR8 and the P10H and P10L escape
mutants. Thus, although M2e is not totally
invariant, it is remarkably stable, even under
immune pressure. Several vaccination strategies
have been evaluated in mouse and ferret models,
including M2-expressing recombinant viruses, M2
recombinant proteinsref1,
ref2,
M2-encoding plasmid DNAref,
and synthetic M2e peptides that were chemically
linked to carrier proteins or synthetically
linked to defined helper T-cell determinantsref1,
ref2,
ref3.
In most studies in which induction of an
antibody response was confirmed, M2e-specific
immunity reduced illness, but did not entirely
prevent it. The best protection was reported for
mice vaccinated by the intranasal route with an
M2e-hepatitis B core fusion protein construct
and detoxified heat-labile Escherichia coli
enterotoxin adjuvant; almost none of these mice
died after a virus challenge that killed 90% of
control miceref.
However, in contrast to the significant
protection seen in most mouse models, pigs
vaccinated with recombinant M2e-hepatitis B core
protein or plasmid DNA encoding an
M2e-nucleoprotein fusion protein showed no
protection or even had higher death rates,
respectively, after virus challengeref.
This finding needs to be confirmed, and the
explanation for it remains unknown. At this
time, it serves as a reminder that immune
phenomena are complex and that observations made
in 1 species may not apply to another. By the
same token, good protection in an animal model
does not guarantee protection in humans. Taken
together, the observations that M2e shows
minimal antigenic variability, even under
antibody-mediated pressure in vivo, that
M2e-specific antibodies typically restrict virus
replication in vivo, and that humans exhibit low
or undetectable M2e-specific antibody titers
provide a strong rationale for further
exploration of an M2e-based vaccine.
i.n. synthetic multiple antigen peptide
(MAP) constructs that contain covalently
linked M2e and Th-determinant
peptides. M2e are highly conserved amongst
human influenza type A viruses and the new
vaccine may obviate repetitive immunizations
with updated strains to maintain protectionref
BM2 of influenza B virus, the homolog
of M2, has only a 6-aa-long ectodomainref.
This ectodomain is most likely too small for
formation of a BM2-specific epitope because
protein epitopes have usually been found to
comprise 12–17 contact residues. NB of influenza
B virus also shows structural similarities with
M2 of influenza A virus, including ion channel
activityref,
and has an 18-aa-long ectodomain. However, NB2
has 2 attached carbohydrate chains that can be
expected to mask the protein core from
recognition by antibody. NA, however, is a good
and not sufficiently explored target for
cross-protective antibodies. Like HA, it
displays a large ectodomain of 420 aa. Nine
subtypes are recognized among influenza A
viruses, while influenza B virus contains 1
subtype. The C-terminal of the polypeptide (380
aa) forms a globular head that is anchored to
the viral membrane by a flexible stalk. The
globular domain contains the enzyme-active site
and all known antigenic sites.
Although no cross-protective NA-specific
antibody population has been identified,
indirect evidence supports the existence of
cross-reactive determinants on N1 and
N2, the subtypes found in classic
human strains. Thus, mice vaccinated first with
a mixture of purified N1 and N2
proteins and subsequently boosted with the
individual antigens showed a small memory
response also against the heterologous subtyperef.
Given the ample expression and accessibility of
NA on infectious virus and infected host cells,
a search for determinants shared between or
within subtypes would be worthwhile.
Fluvirin®
FluBlŘk™ (source : Protein
Sciences) consists of 3 rHA proteins
corresponding to the flu strains selected by the
WHO and the CDC for each year's vaccine. These
proteins are produced in serum free insect cells
and formulated in PBS without preservatives or
adjuvants. Clinical trials have shown safety and
efficacy in healthy adults and the elderly
population:
several Phase I and II trials conducted by
the NIAID involving over 600 subjects
demonstrated safety and efficacy as reported in
four published studies in the Journal of
Infectious Diseases. A significantly higher
percentage of elderly subjects receiving a
higher dose of our vaccine develop protective
antibody titers compared to the licensed
vaccine.
a Phase II(b) trial conducted by NIAID in 399
elderly subjects was completed in November,
2003. The trial involved 3 different doses of
FluBlŘk™ (containing 15, 45 and 135µg,
respectively, of each antigen) compared to the
licensed inactivated vaccine (15µg of each
antigen).
a pivotal Phase III efficacy study of
FluBlŘk™ is scheduled to take place in the fall
of 2004. The vaccine initially includes 45µg of
each antigen.
an rHA cloned from a highly pathogenic avian
H5 strain has also been tested as a vaccine for
the potential "bird flu" threat. The rHA vaccine
provided complete protection against a lethal
viral challenge in chickens (PDF file). In a
human clinical trial of our vaccine 52% of the
subjects had a 4-fold increase in serum titers.
(Treanor et al., 2002, PDF file). Significantly
improved results can be anticipated with the use
of an adjuvant, and such studies are being
scheduled.
recombinant neuraminidase (rNA) has
potential for use as an efficacy-enhancing
additive to influenza vaccines. rNA has completed
Phase II(b) challenge studies conducted by NIAID.
Clinical data demonstrated safety and, when
combined with the current vaccine, a significant
increase in the level of antibodies and, for
vaccinated people who become ill, less viral
shedding, less severe and shorter duration of
illness compared to the licensed vaccine alone.
FSME Immun® (FSME is the
German abbreviation of "Early Summer
Meningo-Encephalitis", a name that in fact is
misleading, since there is another peak in the
fall) by Baxter, Austrai
The conventional vaccination schedule consists of 3
doses at day 0, 1-3 months
and 9-12 months after the 2nd dose. After 30 years of
development, both vaccines are now available in adult
and paediatric formulations that cause few adverse
side effects. Encepur is licensed for rapid
immunisation at days 0, 7 and 21, and this provides
protection 2 weeks after the 2nd dose of vaccine. The
FSME-IMMUN rapid schedule involves 2 vaccine doses
given 2 or 3 weeks apart. This 2-dose rapid schedule
is only recommended for immunisation protection over
the summer months because, unlike the Encepur
schedule, its protection is only optimal for 6 months.
The difference of the products is found in the
frequency of adverse side effects only. The Japanese
strain was sequenced, and vaccination trials in
Japanese volunteers showed no difference in the
neutralization test using different antigensref.
Neutralizing antibodies between different strains have
a Spearman rank correlation was between 0.6 and 0.76,
comparing the neutralizing antibodies against 3
different strains, namely, NDF # 04/94, which is the
strain used for FSME Immun®, 12 Loop.ill
and N 132 2BMP. Encepur® should have the
same efficacy against the Russian and Far Eastern
strain as the above-mentioned vaccine. Encepur is used
in Germany, in former Eastern countries (now new
members of the EU), and in Austria. Patients can be
immunized, or boostered, with one or the other
vaccine.
anti-HTLV-1 vaccine : Although HTLV-1
Tax is the most dominant antigen for HTLV-1-specific
CD8+ CTLs in HTLV-1-infected individuals,
few epitopes recognized by CD4+ Th
lymphocytes in HTLV-1 Tax protein have been
described. The aim of the present study was to study
Th-cell responses to HTLV-1 Tax and to
identify naturally processed MHC class II-restricted
epitopes that could be used for vaccine development.
An MHC class II binding peptide algorithm was used
to predict potential Th cell epitope
peptides from HTLV-1 Tax. The ability of the
corresponding peptides to elicit helper T-cell
responses was assessed by in vitro vaccination of
purified CD4+ T lymphocytes. Peptides Tax191-205
and Tax305-319 were effective in
inducing Th-cell responses. Although Tax191-205
was restricted by the HLA-DR1 and DR9 alleles,
responses to Tax305-319 were restricted
by either DR15 or DQ9. Both these epitopes were
found to be naturally processed by HTLV-1+
T-cell lymphoma cells and by autologous
antigen-presenting cells that were pulsed with
HTLV-1 Tax+ tumor lysates. Notably, the
two newly identified helper T-cell epitopes are
found to lie proximal to known CTL epitopes, which
will facilitate the development of prophylactic
peptide-based vaccine capable of inducing
simultaneous CTL and T-helper responses. HTLV-1 Tax
protein could serve as TAA for CD4+
helper T cells and that the present epitopes might
be used for T-cell-based immunotherapy against
tumors expressing HTLV-1ref.
Since 1987, researchers have studied about 60
potential HIV vaccines to help stem the AIDS epidemic.
So far, no vaccine has won FDA approval as safe and
effective. The rapid antigenic variation of HIV virus
is frequently presented as the main scientific
obstacle for developing vaccine. To be true, such
opinions quite frequently are followed by honest
remarking that a number of effective vaccines are
already available against other viruses who also
display high rates of antigenic variation (poliovirus
is usually mentioned). Therefore, the actual problem
is to understand how existing vaccines overcome
antigenic variation. Drug users are attractive for
trials because incidence is so high and because they'd
benefit from a vaccine but it may be more difficult to
protect people who've been infected by injection than
those infected sexually, in which the first challenge
is mucosal.
recombinant Tat IIIB toxoid vaccine :
with or without an adjuvant it induces high
avidity anti-Tat antibodies with neutralizing
activity. Because of the toxic effects of the Tat
protein, an inactivated recombinant Tat IIIB
protein is used.
IR103, which combines the company's
patented HIV-1 immunogen with Amplivax®,
an immunostimulatory oligonucleotide adjuvant,
with or without incomplete
Freund's
adjuvant (IFA)
gp120-based vaccines :
AIDSVax®
(source : VaxGen)
designed to produce antibodies : clinical trials
in 5,400 men and women considered at high risk
in the USA and Netherlands reported in February
have shown that the vaccine only reduces the
rate of HIV-1 infection by 3.8%, while
Blacks and Asians had a 67% lower rate of
infection. It failed to prevent HIV infection or
even slow the development of disease in its
second phase III clinical trial, conducted in
Thailand and reported on November 2003 : the
results were even worse than those from the
first trial. Antibody induced by this vaccine
against gp120 is not protective : now there are
already several groups working on second
generation gp120, or other envelope vaccines,
using deglycosylation or tinkering with
deletions, making trimers as in the natural
protein and so on. One option is to develop more
immunogenic antibody vaccines, possibly vaccines
that induce antibodies that neutralize primary
or clinical isolates of HIV, which the VaxGen
candidate couldn't do. Lab isolates of the virus
have been adapted to grow in tissue culture and
tend to bind to CXCR4 (X4) coreceptors rather
than CCR5 (R5), which are used by clinical
isolates : initially, most of the gp120 vaccines
were based on X4 strains. Bob Gallo has some
hybrid constructs, a chimeric protein of gp120
and CD4, that can induce antibodies that seem to
be able to neutralize primary isolates and
different subtypes. This is probably because gp
120 complexed with CD4 opens up and exposes
cryptic regions
another approach is to induce cytotoxic T
lymphocytes (CTLs). A number of candidates use a
prime-boost combination, for example DNA
followed by modified Vaccinia Ankara virus
(MVA). Other CTL candidates are in the pipeline
using prime boost with adenovirus, or boosting
with Semliki forest virus or Venezuelan equine
encephalitis replicons. Other groups, like Merck
and Aventis, are now working together to combine
vaccines.
prime-boost regimen using Merck's
replication-defective adenovirus type 5 vector
(Ad5) vaccine candidate first, followed by the
canarypox virus vector (ALVAC vCP1452 on weeks
0, 4, 8 and 12 + daily low-dose IL-2) vaccine candidate from
Aventis Pasteur
Epitopes of the HIV-1 envelope
glycoproteins that induce neutralizing antibodies:
cluster I of gp41 (clone 3, 246-D) : highly
immunogenic epitope, but clone 3 is the only one
of many mAb specific for this epitope that has
neutralizing activityref1,
ref2,
ref3
transmembrane-proximal region of gp41 (2F5,
4E10, Z13) : poorly immunogenic, but antibodies to
this region are broadly neutralizingref1,
ref2,
ref3
CD4-binding domain of gp120 (IgG1b12, 559/64D,
15e) : highly immunogenic, but IgG1b12 is the only
mAb of many specific for this epitope that has
broad neutralizing activityref1,
ref2,
ref3
CD4-induced epitope of gp120 (17b, 48D) : only
antigen-binding fragments of antibodies specific
for this epitope are neutralizing. Intact IgG
molecules specific for this epitope do not
neutralize primary isolatesref1,
ref2,
ref3
a1=>2 mannose
residues of gp120 (2G12) : poorly immunogenic, but
at least one mAb to this region is broadly
neutralizingref1,
ref2
V2 loop of gp120 (697-D) : highly immunogenic,
but antibodies to these epitopes are isolate
specificref1,
ref2
V3 loop of gp120 (447/52-D, 19b, 2182) : highly
immunogenic, but antibody specificity broadens
only after extended antigenic stimulationref1,
ref2,
ref3
Lessons for HIV-1 vaccine design
:
it might be useul to target the antibody
response to neutralizing epitopes rather than to
immunize with native molecules or constructs based
on whole molecules bearing many neutralizing and
non-neutralizing epitopes
most, if not all, neutralizing epitopes are
conformation sensitive, indicating that the
peptide immunogens might not present the optimal
"shapes" to the immune system.
the V3 loop should be considered as a
"semi-conserved region" due to its structural and
conformational conservation, and might therefore
be as valuable a target for vaccines as envelope
constant regions for the induction of neutralizing
antibodies
an increased emphasis should be placed on the
design of immunogens that will induce antibodies
specific for the various constant and variable
domains that interact with chemokine receptors
an increased emphasis should be placed on
inducing antibodies that interfere with the
required conformational changs in gp41
virus diversity poses a challenge to vaccine
development. This might be addressed by
recognizing the need for a polyvalent HIV-1
vaccine, by identifying representative viruses to
include in such a vaccine, and by recognizing
that, despite virus diversity, there are constnt
features on the virus envelope that are required
for interaction with its receptor and co-receptors
induction and maintenance of antibody and T
cell responses will be critical for developing a
successful vaccine against HIV. A rational
approach for generating such responses is to
design vaccines or adjuvants that have the
capacity to activate specific antigen-presenting
cells. In this regard, DCs are the most potent
antigen-presenting cells for generating primary T
cell responses. TLR agonists and ligands that
activate DCs in vitro influence the magnitude and
quality of the cellular immune response in
nonhuman primates (NHPs) when administered with
HIV Gag protein. NHPs immunized with HIV Gag
protein and a TLR7/8 agonist or a TLR9 ligand had
significantly increased Gag-specific Th1
and antibody responses, compared with animals
immunized with HIV Gag protein alone. Importantly,
conjugating the HIV Gag protein to the TLR7/8
agonist (Gag-TLR7/8 conjugate) dramatically
enhanced the magnitude and altered the quality of
the Th1 response, compared with animals
immunized with HIV Gag protein and the TLR7/8
agonist or CpG ODN. Furthermore, immunization with
the Gag-TLR7/8 conjugate vaccine elicited
Gag-specific CD8+ T responses.
Collectively, our results show that conjugating
HIV Gag protein to a TLR7/8 agonist is an
effective way to elicit broad-based adaptive
immunity in NHPs. This type of vaccine formulation
should have utility in preventive or therapeutic
vaccines in which humoral and cellular immunity is
requiredref
A vaccine delivered to maturing dendritic cells in
lymphoid tissue by engineering protein antigen into an
antibody to DEC-205, a receptor for antigen
presentation. The CD4+ T cell immune
response to HIV gag was characterized and efficacy
compared with other vaccine strategies in a single
dose. DEC-205-targeted HIV gag p24 or p41 induces
stronger CD4+ T cell immunity relative to
high doses of gag protein, HIV gag plasmid DNA, or
recombinant adenovirus-gag. High frequencies of IFN-g- and IL-2-producing CD4+
T cells are elicited, including double
cytokine-producing cells. In addition, the response is
broad because the primed mice respond to an array of
peptides in different MHC haplotypes. Long-lived T
cell memory is observed. After subcutaneous
vaccination, CD4+ and IFN-g-dependent protection develops
to a challenge with recombinant vaccinia-gag virus at
a mucosal surface, the airway. A DEC-targeted vaccine,
in part because of an unusually strong and protective
CD4+ T cell response, will improve vaccine
efficacy as a stand-alone approach or with other
modalitiesref.
Web resources :
BHPIV3 is being
developed for intranasal paediatric immunisation
against HPIV3 infection and diseaseref1,
ref2.
BHPIV3 was derived from bovine (B)PIVref1,
ref2,
ref3
a closely-related bovine counterpart of HPIV3 that
is attenuated in primates because of a natural
host range-restriction. It has also been shown to
be attenuated and immunogenic in humans, and is a
candidate vaccine against HPIVref1,
ref2,
ref3.
BPIV3 was modified previously with recombinant DNA
methods to replace its F and HN protective surface
antigen genes with their HPIV3 counterparts,
yielding BHPIVref1,
ref2.
BHPIV3 was an improved HPIV3 vaccine, since it
bears protective antigens that exactly match HPIV3ref
Protein
Sciences was awarded a $2.7M grant by NIAID
to produce 2,000 doses of a recombinant S-protein
sub-unit vaccine. The product has shown to induce
virus neutralizing antibodies in preliminary mouse
studies. Expanded animal studies are underway and
the Company expects to test the material in human
clinical trials in late 2004 or early 2005.
6 rhesus macaques (Macaca mulatta)
immunised i.m. with a combination of 3 Ad5
vectors (early regions 1 and 3 had been deleted
by use of Cre-lox recombination; 1x1011
viral particles each) expressing codon-optimised
SARS-CoV strain Urbani structural antigens (spike
protein S1 fragment, membrane protein, and
nucleocapsid protein) and given a booster
vaccination on day 28 all had strong
neutralising antibody responses against spike
protein S1 fragment and T-cell responses against
the nucleocapsid proteinref.
There is no date set for clinical trials
poxvirus vectors
the American vectored mucosal vaccine was made
by inserting the Urbani strain spike (S)
protein into a recombinant live attenuated
BHPIV3 (a hybrid between bovine parainfluenza
virus 3 and human
parainfluenza
virus 3 (HPIV3). It was sprayed i.n. (the nose
is where the infection attacks) once each of 4
African green monkeys (Cercopithecus aethiops)
that, 4 weeks later, were deliberately exposed to
the coronavirus that causes SARS. The monkeys
showed no sign of the disease in their respiratory
tracts, and blood tests showed that they had
developed a type of protein known as neutralizing
antibodies that best correlate with protection of
disease, while SARS virus replicated in all 4
monkeys in a control group that receive the
BHPIV3/Ctrl. The current form would presumably be
most effective in young children because most
adults have suffered respiratory infections caused
by the parainfluenza virus. So the researchers are
seeking to develop a different vaccine by using
another virus into which the S protein could be
insertedref.
Leishmune® vaccine is the
first licensed vaccine against canine visceral
leishmaniasis. It contains the
Fucose–Mannose-ligand (FML) antigen of Leishmania
donovani. The potential Leishmune®
vaccine effect on the interruption of the
transmission of the disease, was assayed by
monitoring, in untreated (n = 40) and vaccinated
dogs (n = 32) of a Brazilian epidemic area: the
kala-azar clinical signs, the FML-seropositivity
and the Leishmania parasite evidence by
IHC of skin and PCR for Leishmanial DNA of lymph
node and blood samples. On month 11 after
vaccination, untreated controls showed: 25% of
symptomatic cases, 50% of FML-seropositivity,
56.7% of lymph node PCR, 15.7% of blood PCR and
25% of immunohistochemical positive reactions. The
Leishmune®-vaccinated dogs showed 100%
of seropositivity to FML and a complete absence of
clinical signs and of parasites (0%) in skin,
lymph node and blood PCR samples (p <
0.01). The positivity in FML-ELISA in untreated
dogs significantly correlates with the PCR in
lymph node samples (p < 0.001) and with
the increase in number of symptoms (p = 0.006)
being strong markers of infectiousness. The
absence of symptoms and of evidence of Leishmania
DNA and parasites in Leishmune®-vaccinated
animals indicates the non-infectious condition of
the Leishmune®-vaccinated dogsref
anti-Plasmodium
spp. vaccine : it is unlikely
that a vaccine directed against a single antigen
will be protective, so multivalent vaccines
that combine antigens expressed at different stages
of the parasite life cycle have been developed. Most
of these jabs create conditions in which, although
the parasites can still infect people, the immune
system slows their multiplication so they do not
cause disease. Parasites that moved from one
vaccinated animal to another evolved into nastier
strains than those grown in non-vaccinated animals :
the vaccinated animals stayed healthy, but when the
parasite they carried was transferred into other
mice, it killed more red blood cells and made them
lose more weight than the original malaria strain.
Researchers might also avoid types of vaccine that
allow the parasite to survive at low levels, he
suggests. Instead, they could focus on classes of
vaccine that hobble the parasite before it infects
red blood cells or which cripple it in the mosquito
and so stop it passing from one person to another.
Many of the vaccines under trial already take the
latter approach. In fact experts predict that an
effective malaria vaccine will probably trigger the
immune system into attacking the parasite at several
different stages of its life cycleref.
The cultured ELISPOT assay, in which cells are
restimulated and clonally expanded in vitro
prior to measuring IFN-g
production, might measure the central-memory T-cell
population, which was recently proposed to be more
important in protective immunity to malaria than the
short-lived effector-memory cell population measured
in standard ex vivo ELISPOTref.
APT2683®
is based on a malaria parasite protein called MSP1.19,
which stimulates a very weak immune reaction.
Adprotech is working on genetically modified
versions of MSP1.19 which elicit a greater immune
reaction and it is further enhancing the
immunogenicity of MSP1.19 by binding to C3d. Ab to MSP1.19 prevent the
processing of MSP1.42 and stop the merozoite
invading the RBC.
pre-erythrocytic vaccines directed
against Plasmodium falciparum circumsporozoite
(CS) protein. Their effectiveness can be
studied in rodents thanks to hybrid parasites
generated by targeting a CS-deficient form of the
rodent malaria parasite Plasmodium
berghei with a plasmid encoding Plasmodium
falciparumCS repeat regions (CS(Pf)).
RTS,S/AS02A
vaccine specifically targets the
pre-erythrocytic stage of Plasmodium
falciparum and confers protection against
infection by P falciparum sporozoites
delivered via laboratory-reared infected
mosquitoes in malaria-naive adult volunteers and
against natural exposure in semi-immune adultsref1,
ref2,ref3,
ref4.
RTS,S consists of a hybrid molecule
recombinantly expressed in yeast, in which the
circumsporozoite proteinref,
central tandem repeat, and carboxyl-terminal
regions are fused to the N terminal of the S
antigen of hepatitis B virus (HBsAg) in a
particle that also includes the unfused S
antigen. A full adult dose of RTS,S/AS02A (GSK
Biologicals, Rixensart, Belgium) contains 50 µg
of lyophilised RTS,S antigen reconstituted in
500 µL of AS02A adjuvant (proprietary oil in
water emulsion with the immunostimulants
monophosphoryl lipid A and QS21). The adult dose is a 250 µL
dose containing 25 µg of RTS,S antigen in 250 µL
AS02A adjuvant. It is administered
intramuscularly in the deltoid region of
alternating arms according to a 0, 1, 2 month
vaccination schedule. A trial in 2000 children
in Mozambique showed it reduced the risk of
infection by only 37% compared with a control
vaccine (11.9% vs 18.9%) - far better than any
previous result. Even more impressive is that
the vaccine reduced the risk that the children -
aged 1-4 - would develop the most severe and
lethal form of malaria by 57.7%. Better still,
the risk of severe disease in recipients aged
< 2 saw a 77% reductionref.
But it might take until 2010 to get the vaccine
cleared and ready for use. And the price
-estimated at $10 to $20 per vaccination - may
be too much for some poorer nations unless
richer countries help foot the bill.
SPf66 peptide
CD4+ T cells specific for a
circumsporozoite-protein-derived peptide were
found to be strongly associated with protection
against naturally acquired infection and disease :
individuals in the unvaccinated group who showed
similar responses to this peptide (resulting from
previous natural exposure) are also found to be
protectedref.
oral immunization : oral feeding of a
malaria protein induced serum antibody levels
similar to those induces by intraperitoneal
immunization with Freund's adjuvant. Further,
responses to conformational epitopes are induced.
In the rodent challenge system, significant levels
of protection to lethal challenge with malaria are
induced in mice. The protective efficacy is highly
correlated with antibody levels, which depend on
the antigen dosage and require cholera toxin
subunit B as an oral adjuvantref
anti-bacterial protein
vaccines : a proteomic approach has
been described for identifying bacterial
surface-exposed proteins quickly and reliably for
their use as vaccine candidates. Whole cells are
treated with proteases to selectively digest
protruding proteins that are subsequently identified
by mass spectrometry analysis of the released
peptides. When applied to the sequenced M1_SF370 group
A Streptococcus strain, 68 PSORT-predicted
surface-associated proteins were identified, including
most of the protective antigens described in the
literature. The number of surface-exposed proteins
varied from strain to strain, most likely as a
consequence of different capsule content. The
surface-exposed proteins of the highly virulent
M23_DSM2071 strain included 17 proteins, 15 in common
with M1_SF370. When 14 of the 17 proteins were
expressed in E. coli and tested in the mouse for their
capacity to confer protection against a lethal dose of
M23_DSM2071, one new protective antigen (Spy0416)
was identified. This strategy overcomes the
difficulties so far encountered in surface protein
characterization and has great potential in vaccine
discoveryref.
alum-precipitatedPA recovered
from the culture of the avirulent, nonencapsulated
Sterne strain of Bacillus anthracis,
rendered sterile by filtration and containing
0.005%W/v thimerosal
as preservative. Kept at temperatures between 2°C
and 8°C. Freezing must be avoided. According to
FDA the licensed anthrax vaccine is safe and
effective for preventing all forms of anthrax
regardless of the route of exposure (including
inhalational anthrax), thereby undermining the
rationale of a recent court injunction that halted
the Pentagon's anthrax vaccination program.
Protocol : 4 doses of
0.5 mL each in the deltoid muscle (there is a
greater risk of local reactions when the vaccine is
given subcutaneously) : the first 3 doses should be
given at intervals of 3 weeks, followed by a 4th
dose at an interval of 6 months (other protocol : 6
doses over 18 months). Reinforcing doses of 0.5 mL
i.m. should be given annually.
Contraindications : the
vaccine should only be administered to healthy
individuals from 18 to 65 years of age, since
investigations to date have been conducted
exclusively in that population. It is not known
whether the anthrax vaccine can cause fetal harm,
and pregnant women should not be vaccinated.
tenderness, mild erythema or swelling lasting
for ~ 2 days may occur at the site of
inoculation or even at the site of a previous
injection of the vaccine. Large-magnitude
swelling occurs in 1-2% of recipients
urticaria
headache
malaise
regional lymphadenopathy
mild fever
women vaccinated against anthrax conceive and
give birth to healthy children at the same rate
as unvaccinated women. Of a total of 4092 women,
3136 received at least 1 dose of the anthrax
vaccine. There was a total of 513 pregnancies,
with 385 following
at least 1 dose of anthrax vaccine. The pregnancy
rate ratio (before and after adjustment for
marital status, race, and age) comparing
vaccinated with unvaccinated women was 0.94 (95%
confidence interval [CI], 0.8-1.2; P =.60). There
were 353 live births and 25 pregnancies lost to
follow-up. The birth odds ratio after anthrax
vaccination (before and after adjustment for
marital status and age) was 0.9 (95 percent CI,
0.5-1.4; P =.55). After adjusting for age, the
odds ratio for adverse birth outcome after
receiving at least 1 dose of anthrax vaccination
was 0.9 (95% CI, 0.4-2.4; P =.88). However, this
study does not have adequate statistical power to
rule out a small effect of vaccination on adverse
birth outcomes, given the low incidence of adverse
outcomes. A post hoc power analysis showed the
study only had a 12% power to detect a 20%
increase in abnormal birth outcomes, based on
potential effects on likelihood of pregnancyref.
Men vaccinated against anthrax have sperm of
comparable quality and quantity as unvaccinated
men (Catherino et al. Fertility & Sterility
2002;78(Suppl 1);O-285). We await a final report
from a collaborative project between the U.S.
Naval Health Research Center (NHRC) and the
Centers for Disease Control & Prevention (CDC)
regarding birth defects and anthrax vaccine that
involves chart review. That collaborative project
responds to preliminary data from a computer-based
analysis that raised a tentative signal that there
may be an association with an increased rate of
birth defects if anthrax vaccine was given during
pregnancy; the same analysis showed no elevation
in risk for vaccination before pregnancy. This
signal is being investigated thoroughly, to
determine which of several explanations for the
signal is most likely.
[ Some UK soldiers who served in Iraq have
expressed fears for their unborn babies after
claiming there have been 2 miscarriages, 3
premature births, one still-birth, and a medical
termination associated with one Hampshire unit so
far in 2004 in families in which at least one of
the parents had received the anthrax jab in each
case. A total of 105 soldiers from the Gosport
based 33 Field Hospital were stationed on the
Kuwaiti-Iraqi border and then Basra at the
beginning of 2003. The unit includes medics,
chefs, Royal Engineers, drivers, clerks, and
quartermasters. Among the cases is Lance Corporal
Andy Saupe's son, who was born 10 weeks premature
with growth problems and limb defects. Baby Kye
survived only 5 weeks before his life support
machine was switched off. L/Cpl Saupe, a
23-year-old Army chef, had 2 anthrax injections
before being deployed to the Gulf. His wife Alex,
25, became pregnant weeks later but the foetus did
not develop properly. It follows claims that women
in the first Gulf War were advised by the Army not
to conceive children for at least one year after
they or their partner received the vaccine. A
number of studiesref1,
ref2,
ref3
showed a higher rate of congenital disabilities
(including Goldenhar syndromeref)
of children conceived after the war by 1991
Persian Gulf War veterans (GWVs) and born in
medical treatment facilities (MTFs) than of
children born to military personnel who were not
deployed to the Gulf War (NDVs) (despite some
opposed findingsref1,
ref2,
ref3),
but
these were not connected to vaccination programmes
: the authors concluded they were unable to
determine whether the higher rate was due to
inherited, or environmental factors or due to
chanceref
]
U.S. District Judge Emmet G. Sullivan ruled on a
suit filed in March 2003 by 6 service members and
civilians who argued that the FDA never properly
reviewed the vaccine's ability to protect against
inhalation anthrax. The suit contended that the drug
was never shown to be effective, and that some
vaccinated troops experienced extreme fatigue, joint
pain and temporary memory loss after being
vaccinated. Sullivan first ordered a halt to the
mandatory vaccinations on 22 Dec 2003, saying the
vaccine was being used for an unapproved purpose. 8
days later, the FDA issued an order intended to give
the vaccine final approval for use to prevent
inhaled anthrax. Sullivan said the FDA had met
his requirements and lifted the ban, except
for the 6 plaintiffs. The soldiers then asked
Sullivan to reinstate the prohibition. He agreed,
rejecting the government's claim that the FDA had
considered arguments against the vaccine, on Wed 27
Oct 2004 : the FDA's approval was invalid because it
did not meet the required review standards and the
agency failed to seek the necessary public comment.
There was some public comment when the approval was
first sought in 1986, but the 2003 decision was
based on research conducted later and never
subjected to public comment. The FDA argued that
comments had been submitted as part of a 2001
citizens' petition questioning proposals to begin
the vaccinations, but Sullivan found them
insufficient. It was unclear whether soldiers who
already have started the series will be able to
finish it. Research has shown that the vaccine is
effective after 2 or 3 shots. The vaccine has a
2-year shelf life, so the Pentagon can store some
supplies for later use if the vaccine program is
restarted. Root said the shelf life of the vaccine
likely will be extended to 3 years this winter.
Because the anthrax agent is so deadly, it has been
difficult to test a vaccine that might protect
against it. The best data have come from a study in
the 1950s of workers at a factory that processed
animal hides and furs, which can transmit naturally
occurring anthrax. That study found that the vaccine
now used by the military was effective in reducing
the incidence of anthrax spread by contact, but the
research involved only a tiny sample of people who
might have inhaled the bacteria. Mark Zaid, an
attorney for the 6 who has also defended more than a
dozen service members court-martialed for refusing
the vaccination, said one of his clients is a
breast-feeding mother who does not think the vaccine
is safe for her child. Sullivan's ban on involuntary
vaccination will remain in place until the FDA
reviews the anthrax vaccine properly or until
President Bush determines that the normal process
must be waived because of emergency circumstances.
Anthrax vaccine was used in a limited way in the
1991 Persian Gulf War. A more expansive effort began
in 1998. The American anthrax vaccine has been given
to about 1.1 million people since 1998; the British
anthrax vaccine somewhat fewer. Difficulties in
manufacturing the vaccine stopped the program in
2000 and 2001, but the vaccination effort was
resumed and greatly expanded in 2002. The Defense
Department has required many troops serving in Iraq
and Afghanistan to be vaccinated, and it has
punished and sometimes court-martialed those who
refused. The Pentagon expanded its anthrax and
smallpox vaccination programs in July 2004 to
include troops stationed in South Korea and other
areas in Asia and Africa, despite complaints from
some service members that the anthrax vaccine made
them sick. BioPort
Co. spokeswoman Kim Brennen Root said the
company is continuing to produce and ship the
anthrax vaccine under its $245 million contract with
the Pentagon, which runs through 2006. The entire
Australian anthrax vaccination program for the
military deployment to Afghanistan was secretly
suspended for 2 months after 38-75% of the 1500
Afghan deployment in 2002, including elite special
forces who were to engage in fierce fighting with
the Taliban, fell ill in November 2001ref1,
ref2,
ref3
anthrax
spore vaccine : a live vaccine consisting of
Bacillus anthracis spores in saponified
diluent, used for vaccination of domestic farm
animals against anthrax
dually
active anthrax vaccine (DAAV) created by
conjugating the capsular poly-g-D-glutamic
acid (PGA) to protective antigen (PA).
This converted the weakly immunogenic PGA to a
potent immunogen and synergistically enhanced the
humoral response to PA. It prevent or stop the
disease by eliminating bacteria by means of
anti-capsular antibodies early in the sequence of
anthrax infection, well before severe bacteremia
and toxemia take place. In addition, antibodies to
PA provide a parallel line of defense against
residual toxins. DAAVs embody the paradigm of
combining both antibacterial (i.e., prophylactic)
and antitoxic (i.e., therapeutic) components into
a single vaccine
anti-Borrelia burgdorferi
(sensu strictu) vaccine : lipidated
recombinant lipoprotein outer surface protein A
(OspA) adsorbed onto aluminum adjuvant
LYMErix®
(withdrawn from the market on February 26, 2002);
Glaxo SmithKline Inc.: LIQ(30 mg
/ 0.5 mL)IM). It is indicated for use in persons
aged 15-70 years. 3 doses of the vaccine are
administered by intramuscular injection. The
initial dose is followed by a second dose 1 month
later and a third dose 12 months after the first.
Vaccine administration should be timed so the
second dose and the third dose are given several
weeks before the beginning of the transmission
season which usually begins in April. The duration
of immunity following the three-dose vaccination
series is unknown, and the need for booster doses
has not been determined. The vaccine doesn't work
in individuals (5%) that have low expression of TLR1.
? (Pasteur Merieux Connaught)
anti-Helicobacter
pylori vaccine :
(ureA+ureB or cagA+vacA) inducing a Th2-polarized immune response. Helicobacter
pylori is in steep decline in many parts of
the world, thanks to improved sanitation and the
widespread use of antibiotics, and some biologists
are beginning to wonder whether its disappearance is
really for the best. Challenge model for Helicobacter
pylori infection in human volunteers (40 mg of
famotidine at bedtime and 104-1010
cfu of H pylori in beef broth the next
morning)ref1,
ref2.
The mechanism(s) by which immunisation of mice can
affect helicobacter colonisation of mice remains a
mystery, but may be related to immune mediated
environmental changes. In particular, it is proposed
that severe gastritis and T-cell mediated changes in
mucin production can significantly impact upon H.
pylori colonisation : an appropriate antibody
response has not yet been accomplishedref
J8 fragment from GAS M-protein
conjugated to diphtheria toxin (DT)
pneumococcal surface protein A (PspA)
induces protection against pneumococcal bacteremiaref1,
ref2.
PspA is composed of 5 domains : a signal peptide,
an a-helical domain, a
proline-rich region, a choline binding domain and
a C-terminal tailref.
Antigenic variability is mapped to the highly
charged a-helical
N-terminal region of PspAref.
A classification of PspA based on the amino acid
sequence divergence located just before the
proline-rich region, defined as clade-defining
region (CDR), divides strains into 3 familiesref
:
family 1, composed of clades 1 and 2
family 2, composed of clades 3, 4, and 5
family 3, rarely isolated and composed of
clade 6
Since cross-reactivity between families is
restricted, these authors have proposed that PspA
fragments from families 1 and 2 should be included
in a vaccine formulation.
toxoids / anatoxins (toxins which have lost
their biological activity but retain
their antigenicity and their immunizing capacity) :
the use of toxoids began in 1923 at the Pasteur
Institute, when Demontre and Ramon found that
diphtheria toxin treated with formalin and heat was
transformed into a nontoxic but immunogenic moiety
that could be used to immunize against
diphtheria. Initially called anatoxines by
Ramon, these compounds are now known as toxoids. They protects against many of the
disease symptoms but not against the infection !
More toxoids are often associated in vaccine
formulations.
purified toxoids that have been inactivated
by
chemical means (0,3%
formaldehyde/formol for 48 hrs at 37 °C,
glutaraldehyde, iodine, pepsin, ascorbic
acid, ketones, etc.) : LPS cannot be converted to
toxoid. The mixture is maintained at 37 °C at pH
6÷9 for several weeks
genetic means
live attenuated strains of the causative
agent that produce a genetically derived toxoid
anti-Bordetella pertussisvaccine
: combinations of pertussis toxoid, FHA, pertactin,
and the 2 types of fimbriae. The new vaccine, known
as acellular pertussis (aP) has fewer side
effects than the whole cell vaccine.). In the United
States, it is licensed for use only in children at
least 15 months of age. The acellular pertussis
vaccine was protective among adolescents and adults,
and its routine use might reduce the overall disease
burden and transmission to childrenref.
3 x 0.50 mL subcutaneous injections at the level of
the supra- or sub-spinal fossa at month 3, 4 and 5 :
booster after 1 year.
Acelluvax® (Biocine => Chiron, Italy)
Celluvax® (SCL)
Coguelucheux Vaccine®
(Merieux)
Cocquelucheux® or Coquelucheux®
(PMC) : adsorbed
Dur Brzuszny® (?, Poland)
Hinkuys karokoe® (National
Public Health Institute) : adsorbed
Kikhoste-Vaksine® (Statens
Institut for Forkehelse)
Krztuscowi® (?, Poland)
Ksztu Siec® (?, Poland)
Pertosse® (?, Italy)
Serobacterin® (Merck) : no
longer in use (1945 to 1954)
Tos Ferina® (?, Spain)
Vaxicoq® (Aventis Pasteur) :
adsorbed (0.50 mL syringe-ampoule contains Bordetella
pertussis in phase 1 - 15 billion, Al(OH)3
0.001 g)
Vax-Tet® (Finlay Vaccunas y Sueros
Centro de Investigacion)
Zatevax® (Institute of Immunology -
Croatia)
3 intramuscular injections (1
mL) at months 3, 4÷5 and 6÷12. First booster at age
5÷6, following boosters every 10 yrs. Uneffective in
2÷5%. If an injury occurs between 5 and 10 years
since last boosting, a novel booster is recommended
if the wound is highly contaminated and/or necrotic.
anti-Corynebacterium
diphteriae vaccine (Ramon's vaccine) : the
schedule for immunization against diphtheria in
children <7 years old requires a 4-dose primary
series of intra muscular injections (0,5÷1 mL
each) of diphtheria toxoid (at 2, 4, 6, and 12 to
18 months of age) and a booster at 4 to 6 years of
age. The minimum interval between the 1st and 2nd
doses and between the 2nd and 3rd doses is 4
weeks; between the 3rd and 4th dose, the minimum
is 6 months. Infants and children <7 years old
are usually given diphtheria
and
tetanus toxoids and pertussis vaccine (DTP);
children > 15 months may be given diphtheria
and
tetanus toxoids and acellular pertussis vaccine
(DTaP) for the 4th and 5th doses of the
series. Diphtheria and tetanus toxoids for
pediatric use (DT) should be substituted for DTP
in children for whom pertussis vaccine is
contraindicated. Infants traveling to areas where
diphtheria is endemic or epidemic should receive 3
doses of DTP or DT before travel. The first dose
should be given at 6 to 8 weeks of age and the
next 2 doses after intervals of 4 to 8 weeks. The
primary schedule for persons >7 years of age
who have never been vaccinated requires 3 doses of
tetanus and diphtheria toxoids for adult use (Td)
(the 2nd dose is given 4 to 8 weeks after the
first; the 3rd dose is given 6 to 12 months after
the 2nd). 2 doses of Td received after an interval
of at least 4 weeks may provide some protection; a
single dose is of little benefit. Td booster doses
should be given at 11 to 16 years of age and
whenever 10 or more years have elapsed since
completion of a primary series or the last booster
dose containing diphtheria toxoid. For persons
whose primary schedule was interrupted, the series
should be completed by using a vaccine appropriate
for age. For example, an adult who received (as a
child) 2 doses of a vaccine containing diphtheria
toxoid requires only 1 more dose of Td to complete
the primary series and additional Td boosters
every 10 years thereafter. It protects for 10 yrs.
As the vaccine prevents also colonization, natural
boostings are rapidly decreasing nowadays : so
artificial boostings every 10 years are likely to
be introduced, expecially in the elderly. Very
rare complication : postvaccinial
autoimmune
encephalomyelitis
10-14 days after vaccination.
carbohydrate antigens.
Historically, conjugate vaccines have been shown to
induce boostable memory responses and longer-lasting
immune responses than polysaccharide vaccines => glycoconjugate vaccines :
the high level of success attained by Hib glycoconjugate
vaccinerefhas
been
quickly followed by similar approaches to meningococcal
group Cref
and Streptococcus pneumoniaeref.
Many candidate vaccines against other pathogens using
the same principles are currently at different stages of
research.
anti-bacterial vaccines
anti-Haemophilus
influenzae serotype B (Hib) polysaccharide vaccine (HbPV)
: capsular polysaccharide : the fragment of the Hib
capsular polysaccharide used in some of the licensed
vaccines can be as short as 5
ribosylribitol-phosphate repeating unitsref.
Extensive use of the polysaccharides as vaccines has
offered a useful way to protect adults and older
childrenref1,
ref2,
and further improvement in generating long-lasting
immunity, especially in infants, has been achieved
by covalently coupling the polysaccharide to carrier
proteinsref.
=> stimulates an immune response in B lymphocytes
only. 1 subcutaneous skin injection. It protects for
1.5÷3 yrs. Used as an immunizing agent in children
between the ages of 18 months and 5 years who belong
to certain high-risk groups : uneffective before age 2
as polysaccharides are T-independent
Ags
and the marginal zone is not fully developed yet.
AMC® (?, Cuba)
B-CAPSA® (Mead Johnson) : no
longer in use (1987 to 1989)
anti-Haemophilus
influenzae serotype B (Hib) conjugated synthetic
capsular polysaccharide : the ability of
synthetic carbohydrate chemistry to mimic such
fragments has been demonstrated in several
laboratories with the use of stepwise multistep
preparationref1,
ref2,ref3;
the resulting synthetic antigens have served as
components of candidate vaccines that have proven
efficient in generating immunity in animalsref1,
ref2.
It was evaluated in clinical trials in Cuba and
showed long-term protective antibody titers that
compared favorably to licensed products prepared
with the Hib polysaccharide extracted from bacteriaref.
A phase I trial was initiated with 139 2-month-old
infants who received three vaccine doses scheduled
at 2, 4, and 6 months, as recommended for other
conjugate anti-Hib vaccines. The test vaccine
induced a strong and bactericidal antibody response
against Hib in infants that fell to values ranging
from 5 to 7 µg/mL at 18 months of age but remained
at least 5 times that required for long-term
protection. A booster dose with sPRP-TT applied to
all groups increased the antibody against Hib titers
by 10-fold. Thus, the capacity of sPRP-TT to prime
an effective immune response against Hib was
demonstrated. In a second phase II trial, a total of
1141 infants distributed in three groups received
three doses of either sPRP-TT conjugate, sPRP-TT
mixed with aluminum phosphate, or the control
vaccine (Vaxem-Hib®). Of the test
infants, 99.7% reached antibody titers above 1
µg/mL, which is considered appropriate for
long-lived protection against Hibref1,
ref2.
The mean IgG anti-PRP titer was 27.4 µg/mL for all
infants vaccinated with the sPRP-TT, which is
consistent with previously reported clinical trials
(between 7.67 and 35 µg/mL) for anti-Hib vaccines
without adjuvantref1,
ref2
... to make it a thymus-dependent
Ag.
Used as an immunizing agent in children between the
ages of 18 months and 5 years who belong to certain
high-risk groups.
Mencevax
ACWY® or ACWYVax®
(GlaxoSmithKline Inc.; cost per dose : US$ 1) :
Haj pilgrims at December are at a high risk of
contracting a meningococcal infection due to
overcrowding. As a precautionary measure, Saudi
Arabia has made it mandatory for foreign
pilgrims to be vaccinated before entering the
country
Menomune®
(Aventis Pasteur) protects for approximately 3-5
years
B and C serotypes
VA-Mengoc-BC®
(Finlay Vaccunas y Sieros Centro de
Investigation)
B serotype : the New
Zealand accine is a strain-specific outer membrane
vesicle product not available in the USA as yet.
Such a biologic, when combined with the newly
licensed (in the USA) protein-conjugated
quadrivalent capsular meningococcal vaccine (for
types A, C, Y, and W-135), would be a large nail
in the coffin for invasive meningococcal disease
B serotype capsular polysaccharides are poorly
immunogenic, conjugated or not.
Immunogenicity of polysaccharides may be improved by conjugation
with a proteic carrier (e.g. ...
group A meningococcal polysaccharide
tetanus toxoid (GAMP-TT) conjugate vaccine
(PsA-TT, MenAfriVac)
(source : Serum
Institute of India (SII) and SynCo
BioPartners) : high-efficiency
conjugation technology using hydrazine (cost
per dose : 40 US cents, affordable in Africa
where serotype A is endemic)ref1,
ref2.
Meningitis cases have dropped to near zero in
every country where MenAfriVac has been
introduced since 2010. group C meningococcal polysaccharide
tetanus toxoid (GCMP-TT) conjugate vaccine
: Neisvac-C® (Shire
Biologics), SUS(10 mg
/ 0.5 mL, 20 mg /
0.5 mL)IM
B conjugate C meningococcal vaccine
(source : Bio-Manguinhos
in Rio)
Menactra®
(Sanofi Pasteur; licensed in USA on 14 Jan
2005) MCV4 is a tetravalent vaccine; each
0.5-mL dose contains 4 mg
each of capsular polysaccharide from Neisseria
meningitidis serogroups A, C, Y, and
W-135 conjugated to 48 mg
of diphtheria toxoid. MCV4 offers protection
for 7-8 years against invasive meningococcal
disease : another vaccine that was previously
available conferred immunity that lasted only
3-5 years : both vaccines are about 85%
effective, however. Only a single shot is
necessary. It typically costs patients about
$100 (Ł55; €81), but because it is being
recommended by the Centers for Disease Control
and Prevention and the American Academy of
Pediatrics, its cost is likely to be covered
by most health insurance plansref.
In February 2005, the Advisory Committee on
Immunization Practices (ACIP)
recommended routine vaccination for 3 groups of
young peopleref
:
children between 11 and 12 years old at
routine doctor checkups
15 year olds or those students entering
high school, because they’re becoming more
socially active and exposed to more germs
new students at college who will be
living in student accommodation, because
disease spreads easily among people at close
quarters for other persons at
increased risk (Military recruits, travelers
to areas in which meningococcal disease is
hyperendemic or epidemic, microbiologists
who are routinely exposed to isolates of N.
meningitidis, patients with anatomic
or functional asplenia, and patients with
terminal complement deficiency)
5 persons aged 17-18 years in New York, Ohio,
New Jersey and Pennsylvania (2) experienced Guillain-Barre
Syndrome
(GBS) 14-31 days after MCV4
vaccination, occurred during 10 Jun - 25 Jul
2005,
after > 2.5 million doses of vaccine have
been distributed. Data from the Vaccine
Safety
Datalink (VSD), a collaborative project
between CDC and 8 managed care organizations
in the USAref,
and the Health Care Utilization Project on GBS
incidence in persons aged 11-19 years indicate
a background annual incidence of 1-2 cases per
100 000 person-years (CDC; Healthcare
Utilization Project Nationwide Inpatient
Sample; Agency for Healthcare Research and
Quality, unpublished data, 1989-2001). This
finding suggests that the rate of GBS based on
the number of cases reported within 6 weeks of
administration of MCV4 is similar to what
might have been expected to occur by chance
alone. However, the timing of the onset of
neurologic symptoms (i.e., within 2-5 weeks of
vaccination) is of concern. In addition, the
extent of underreporting of GBS to VAERS is
unknown; therefore, additional cases might be
unreportedref1,
ref2.
Pre-licensure studies conducted by Sanofi
Pasteur of approximately 7000 recipients of
MCV4 revealed no GBS casesref.
CDC has conducted a rapid survey by using
available VSD and other health care
organization databases. No cases of GBS have
been detected among nearly 110 000 MCV4
recipients represented in these databases.
Data from 2 VSD sites indicated that 86-97
percent of vaccine recipients had 6 weeks of
follow-up via automated data collection. These
data do not rule out an association between
MCV4 and GBS. During 1999-2005, a total of 30
million doses of 3 different meningococcal C
conjugate vaccines (MenC), with either
diphtheria CRM (nontoxic variant of diphtheria
toxin) or tetanus toxoid as carrier proteins,
have been used in the United Kingdom (UK) for
persons aged less than 18 years. 5 cases of
GBS were reported in the UK after
administration of MenC vaccines (UK Department
of Health, unpublished data, 2005). This
reported number of cases is lower than would
have been expected to occur by chance in a
population this age. To date, evidence is
insufficient to conclude that MCV4 causes GBS.
An ongoing known risk for serious
meningococcal disease exists. Therefore, CDC
is recommending continuation of current
vaccination strategies. Whether receipt of
MCV4 vaccine might increase the risk for
recurrence of GBS is unknown; avoiding
vaccinating persons who are not at high risk
for meningococcal disease and who are known to
have experienced GBS previously is prudent.
FDA and CDC are alerting health-care providers
to this preliminary information and are
actively investigating the situation because
of its potentially serious nature. The
manufacturer has sent letters to health-care
providers and is updating the package insert
to reflect that GBS has been reported in
association with the vaccine. CDC recommends
that adolescents and their caregivers be
informed of this ongoing investigation as part
of the consent process for vaccination with
Menactra. FDA and CDC are requesting that
providers or other persons with knowledge of
possible cases of GBS (or other clinically
significant adverse events) occurring after
vaccination with MCV4 report them to VAERS.
Reports of GBS should be submitted to VAERSref
or by telephone at 800-822-7967. CDC further
requests that health-care providers report
other cases of GBS that occur among persons
aged 11-19 years to state health departments
in accordance with state or local
disease-reporting guidelines. CDC suggests
that state health departments consider
enhancing surveillance for GBS in adolescents
to assist in answering these critical
questions. Cases of meningococcal disease
should be reported to state health departments
and, if available, information on vaccination
status should be provided; isolates should be
saved and sent to state health departments for
serogroup identificationref.
It
is curious that only one of the 5 cases
described above had a seemingly "clean"
medical history with no prior episodes or
illnesses or possible exposures that might
predispose for GBS (one of the cases had a
history of 2 prior episodes of GBS following
receipt of other vaccines in early childhood,
another had a mother with a history of GBS,
another had a sore throat which may have been
due to an infectious etiology 6 days after
receipt of the vaccine, and another was on
multiple psychotropic agents).
1 subcutaneous injection (100 mg
in babies, 50 mg in
adults; booster at month 7 in newborns). Boosters
every 3-5 years. The vaccine is administered to
persons over 2 years of age at risk in event of an
epidemic of meningococcal disease caused by these
serotypes and routinely only to military recruits.
Web resources : Meningitis Vaccine
Project (MVP) by WHO and PATH
anti-Salmonella
typhiintramuscular
vaccine : purified Vi
polysaccharide from the strain Ty2, used
for immunization against typhoid fever in persons
at risk for exposure due to travel or household
contact
23 serotypes (1, 2, 3, 4, 5, 8, 9, 12, 14, 17,
19, 20, 22, 23, 26, 34, 43, 51, 54, 56, 57, 68,
and 70, which are responsible for about 90% of
pneumococcal disease in the USA) (23PS)
1 subcutaneous injection (0.5 mL) protects
from week 2÷3 after injection up to 5-6 yrs.
Polysaccharides are T-independent
Ags
and so they do not induce neither memory B-cell nor
class switch. Anyway this pathway allows vaccination
being effective also in individuals affected by CMI
deficiencies,
but not in babies before age 2, when marginal zone is
not fully developed yet. Used for immunization of
persons over 2 years of age having chronic cardiac,
pulmonary, hepatic, or renal disease, AIDS,
Hodgkin's
disease,
diabetes
mellitus,
SCA,
or anatomic or functional asplenia,
and persons in nursing homes or other institutions
where there is high risk of pneumococcal disease or
with age > 65. Immunogenicity of
polysaccharides may be improved by conjugation with a
proteic carrier :
PCV7 : capsular antigen saccharides
from S. pneumoniae serotypes 4, 6B, 9V,
14, 18C, 19F and 23F (heptavalent) conjugated to
diphtheria CRM197 protein (Prevnar®;
Wyeth Lederle) ; administered at ages 2 months, 4
months and 6 months, with a final dose between the
ages of 12 months and 15 months; SUS(2 mg / 0.5 mL, 4 mg / 0.5 mL, 2 mg / 0.5 mL, 2 mg / 0.5 mL, 2 mg / 0.5 mL, 2 mg / 0.5 mL, 2 mg / 0.5 mL)IM, 20 mg / 0.5 mL)IM. It helps
prevent routine fevers, headaches, and earaches in
young children—as well as rarer, invasive
infections with bacterial pneumonia or
meningitis—caused by the 7 most widespread
varieties of 90 types of pneumococcus bacteria.
Kids and adults routinely carry all 90 strains in
their noses and throats, even when they are not
sick. Prevnar vaccinations have been recommended
for all American babies since mid-2000. Between
1999 and 2001, "invasive" pneumococcal infections,
the most serious category, dropped 68% in babies
under age 2. Prevnar also lowered pneumococcal
infection rates in older people who had never
received the vaccine : over the same 2 years,
invasive pneumococcal infections in the USAdropped
29% in adults aged 20 to 39 and 17% in people over
65 thanks to the fact that vaccinated babies no
longer carry the 7 most prominent strains in their
noses and throats, so they can't infect parents or
grandparents. Between 1999 and 2001, another study
in the Pittsburgh area found the percentage of
pneumococcal acute
otitis
media (AOM) caused by strains that Prevnar
doesn't protect against more than doubled, from 16
to 37%. This shift in prevalence from one kind of
infection to another is due to a "replacement"
effect because Prevnar effectively replaces
infections by the 7 targeted strains of
pneumococci with similar infections by the other
83 strains. Prevnar vaccination also enables a
slight increase in middle ear infections caused by
2 unrelated bacteria. These infections spread more
easily because the vaccine wipes out their 7
former competitors. If vaccines would target
something that's in all pneumococci, then you
won't have this problem. 6 adult volunteers
received a booster dose of Pnc7 12-18 months after
primary immunization. CD27hiCD38hiCD20+/-
IgG antibody-forming cells were detected in
peripheral blood with maximum frequency at days
6-7 after immunization. This was accompanied by a
more prolonged rise in memory B cells that
required in vitro stimulation with Staphylococcus
aureus Cowan strain and IL-2 to induce
antibody secretion. These data provide evidence
for at least 2 subsets of antibody-forming cells
involved in the secondary humoral response to a
glycoconjugate vaccine in primed individuals. A
briefly circulating subset of B cells that
spontaneously secrete IgG may be responsible for
early defence against re-encountered encapsulated
bacteria. However, the kinetics of the appearance
of these cells may indicate that the humoral
immune response is too slow in defence against an
organism that invades within days of acquisition.
The more sustained presence of a memory population
may provide persistence of antipolysaccharide
antibody after a booster dose of vaccine and may
also include re-circulatory populations
responsible for further anamnestic responsesref
a novel nonavalent conjugated vaccine reduces
invasive pneumococcal disease by more than 65% in
children with HIV and 83% in HIV-free children. It
slashes overall mortality by 5% among all
children, and by 6% among those with HIV. The
vaccine also significantly reduces the incidence
of invasive pneumococcal disease caused by
antibiotic-resistant strains by up to 67%.
anti-human pathogenic fungi vaccine :
laminarin (Lam), a well-characterized but
poorly immunogenic b-glucan
preparation from the brown alga Laminaria
digitata, with the diphtheria toxoid CRM197,
a carrier protein used in some glyco-conjugate
bacterial vaccines. This Lam-CRM conjugate proved to
be immunogenic and protective as immunoprophylactic
vaccine against both systemic and mucosal (vaginal)
infections by Candida
albicans. Protection probably was
mediated by anti-b-glucan
antibodies as demonstrated by passive transfer of
protection to naive mice by the whole immune
serum, the immune vaginal fluid, and the
affinity-purified anti-b-glucan
IgG fractions, as well as by administration of a b-glucan-directed IgG2b mAb.
Passive protection was prevented by adsorption of
antibodies on Candida cells or b-glucan particles before
transfer. Anti-b-glucan
antibodies bound to C. albicans hyphae and
inhibited their growth in vitro in the
absence of immune-effector cells. Remarkably,
Lam-CRM-vaccinated mice also were protected from a
lethal challenge with conidia of Aspergillus
fumigatus, and their serum also bound
to and markedly inhibited the growth of A.
fumigatus hyphae. Thus, this novel conjugate
vaccine can efficiently immunize and protect against 2
major fungal pathogens by mechanisms that may include
direct antifungal properties of anti-b-glucan antibodiesref
preventive cancer vaccines should
be ideally directed against dysplasia antigens rather than
tumor antigens : many of the potentially insurmountable problems
that
diminish the effects of therapeutic cancer vaccines,
would not need to be considered in the setting of cancer
prevention (see also immunooncology). Shared tumor
antigens can be produced as synthetic or recombinant
proteins and are, therefore, ideally suited for
prophylactic vaccination of individuals who do not have a
tumour, but are at high risk of developing a tumour.
Having vaccines that could prevent the progression of
these esions to cancer would make the cancer screening
efforts much more useful than they are now and set the
stage for a more general use of prophylactic cancer
vaccines in the near future.
vaccines against tumour causing infectious
microorganisms
young
women with hereditary risk of breast
carcinomas
and ovarian
carcinoma
due to mutations in the gene encoding BRCA1
or BRCA2
: in the most extreme case of cross-reactivity,
autoimmune destruction of normal breast or ovarian
tissue should have no more serious consequences than
their surgical removal
colorectal
carcinomas
: colon-tumour antigen mucin 1 is not expressed by
normal colon, but is expressed by adenomatous polyps
in the tumour-associated O-underglycosylated
form
anti-ricin vaccines
: a harmless fragment of the ricin molecule, RTA
1-33/44-198, given to mice either as a liquid
dropped directly onto the skin or as a patch impregnated
with the chemical protects mice from a respiratory
challenge with ricin toxin in 100% and 709% of cases,
respectively. Patches will be more practical than skin
drops for treating humans as the correct dose can easily
be delivered. Vaccination using ricin toxoid or its A
chain (RTA) is protective in animals but both vaccines
have two potential toxicities, ribosome inactivating
protein (RIP) and vascular
leak
syndrome (VLS).
3 recombinant RTA constructs from which both toxicities
were eliminated by site-specific mutations have been
described : one mutant, V76M/Y80A (RiVax), has
now been further characterized for immunogenicity and
toxicity in animals. RiVax is safe at doses of at least
8 mg in mice, 800-fold higher than the protective dose,
and induces neutralizing antibodies in both mice and
rabbitsref.
RiVax is a recombinant RTA with 2 amino acid
substitutions that disrupt its ribotoxic site (Y80A) and
its VLS-inducing site (V76M). This mutant recombinant
RTA was expressed and produced in Escherichia coli and
purified. When RiVax was injected i.m. into mice it
protected them against a ricin challenge of 10 LD50s.
Preclinical studies in both mice and rabbits
demonstrated that RiVax was safe. Based on these
results, a pilot clinical trial was conducteed in humans
under an IND application submitted to the FDA. In this
study, 3 groups of 5 normal volunteers were injected 3
times at monthly intervals with 10, 33, or 100 µg of
RiVax. The vaccine was safe and elicited
ricin-neutralizing Abs in 20% of individuals in the
low-dose group, 80% in the intermediate-dose group, and
100% (5 of 5) in the high-dose group. These results
justify further development of the vaccineref
Dermatophagoides
pteronyssinusis a major trigger of allergy
and atopic asthma world-wide, and thus, a good vaccine
candidate for allergy prevention.
i.m. injection of a gene construct (pCMVD)
containing an Der p 5 results in the
induction of Der p 5-specific IgG antibodies, but
not IgE antibody. The effect of transduced allergen
gene on the expression of specific IgE response in
mice after i.p. challenge with recombinant Der p 5
(rDer p 5). Both vector (mock) control- and
pCMVD-treated mice were i.p. sensitized with rDer p
5 at 3 weeks after injection of gene construct.
Results showed that there is a 90% reduction in the
level of specific IgE in pCMVD-treated mice when
compared with mock-treated mice. Furthermore, the
suppression of specific IgE response can be
adoptively transferred with CD8+ T cells
from pCMVD-treated mice and such inhibition is in an
antigen-specific manner, since the level of specific
IgE to an irrelevant allergen, Der p 1, remained
unchanged in comparison to that of the mock-treated
group. In addition, Der p 5-specific CD8+
T cells could produce high levels of IFN-g which probably inhibit
allergen-specific IgE responsesref.
since Der p 1 is a cysteine protease, the
catalytic effects of Der p 1 vaccination may be
unpredictable. One approach to reduce this risk is
to vaccinate with DNA encoding enzymatically
inactive forms of Der p 1 : Der p 1 DNA without its
native pre-pro sequences potently induces Der p
1-specific antibodies, as long as its pre-sequence
is substituted by another leader sequence. Without
any pre-pro sequence, the same DNA fragment is well
expressed but fails to induce significant level of
anti-Der p 1 antibodies, without further boosting by
proteinref.
I.m. immunisation with full length Der p 1
cDNA induces significant humoral response to the
left domain (approximately corresponding to amino
acids 1-116) but not to the right domain
(approximately corresponding to amino acids 117-222)
of Der p 1 allergen. DNA constructs pDer p 1 (1-222)
and pDer p 1 (114-222) complexed with chitosan and
delivered orally followed by an i.m.
injection of pDer p 1 (1-222) 13 weeks later
successfully primes Th1-skewed immune
responses against both domains of Der p 1ref.
anti-venom vaccines :
anti-Bothrops
asper vaccine : the region
comprising amino acid residues 115-129 of myotoxin
II, a Lys49 phospholipase A2 from the venom of Bothrops
asper, was previously shown to constitute a
heparin binding site, and to be associated with its
toxic activities. The corresponding synthetic
peptide, KKYRYYLKPLCKK, was coupled to diphtheria
toxoid as a carrier, and utilized as an immunogen in
mice, to explore the possible protection from the
myotoxic activity induced by myotoxin II in vivo.
Mice receiving peptide-carrier injections produced
antibodies to peptide 115-129, which cross-reacted
to myotoxin II, as determined by enzyme-immunoassay.
In contrast, no antibodies against peptide 115-129
were detected in mice immunized with myotoxin II,
despite the strong antibody response to the whole
antigen. Thus, region 115-129 of myotoxin II is not
an immunodominant B-cell epitope in the mouse. After
immunization with conjugated peptide or myotoxin II,
mice were challenged with myotoxin II, and the
extent of myonecrosis was estimated by determining
their plasma creatine kinase activity, in comparison
to non-immunized mice. After the challenge, both the
group immunized with myotoxin II, and the group
immunized with peptide 115-129, had a significant
reduction of myonecrosis. These results demonstrate
that region 115-129 of myotoxin II constitutes a
neutralizing epitope, and provide further evidence
for the relevance of this region in its myotoxic
effect in vivoref
anti-Bothrops
colombiensis (Central and South
American snake) : a new technique is described for
the preparation of Bothrops venom and their
different fractions toxoid. This method preserves a
high degree of immunogenicity but eliminates lethal
effects. All the animals vaccinated with Bothrops
crude venom toxoid survived when they were injected
with crude venomref.
anti-Crotalus
durissus
cumanensis vaccine : a new technique
is described for the preparation of Crotalus
venom toxoid. This method preserves the
immunogenicity but eliminates the toxic effects. All
the animals vaccinated with Crotalus venom toxoid
survived when they were injected with raw venomref
anti-Naja
atra vaccine : potency of 60
antitoxic unit was reached after 2 immunizations in
2-week intervals of rabbits and horses with 10-25 mg
venom which was detoxified by 0.125% glutaraldehyde.
Now this procedure has become a routine
antivenine-producing method by which snake bivalent
neurotropic antivenine is produced. The stability
test showed that Taiwan cobra toxoid kept at 37
degrees C for 40 days, the antigenicity increased by
24% and toxicity decreased by 10% as compared to the
toxoid maintained at 4°Cref
anti-Naja
nigricollis vaccine : a free peptide
capable of eliciting antibodies that neutralize
toxin a, a protein that
binds specifically to the acetylcholine nicotinic
receptor, has been synthetised. Of the 5 tested
fragments that encompassed the whole toxin sequence,
only fragment 24-41 stimulated T cells from BALB/c
mice primed with the whole toxin and conversely,
only T cells from mice primed with fragment 24-41
could be stimulated by both the toxin and priming
peptide. No other peptides had such properties,
indicating that only fragment 24-41 possessed T
determinant(s) in BALB/c mice (H-2d haplotype). In
agreement with the current view that B cell
proliferation requires specific T cell stimulation,
only fragment 24-41 elicited an antibody response.
However, the antipeptide antisera failed to bind to
the native toxin and thereby to neutralize it.
Instead, it recognized an unfolded form of the
toxin. The peptide 24-41 was then made cyclic. A
circular dichroism analysis revealed that, in
organic solvent, this peptide had a tendency to
adopt a beta-sheet structure, as in the folded
toxin, whereas the linear peptide adopted an helical
structure. The cyclic peptide not only remained T
stimulating but elicited antisera that recognized
and neutralized the native toxin. Furthermore, the
antisera cross-reacted with several toxin variants.
Our data show, therefore, that it is possible to
give an appropriate B cell specificity directly to a
T cell-stimulating peptide, an approach that may be
of value for the design of synthetic vaccinesref.
Action of formaldehyde on the a
toxinref
anti-Trimeresurus
flavoviridis vaccine : in order to
clarify the effect of Habu Toxoid, serum sampling
was performed with from July 1990 to February 1991,
on 503 vaccinated subjects living in Amami Islands
by staff of Naze health center. Sera were analyzed
by Enzyme Linked Immunosorbent Assay (ELISA) for
levels of serum antitoxin to venom, both
anti-Hemorrhagic Factor 1 (anti-HR1) and
anti-Hemorrhagic Factor 2 (anti-HR2). Information on
vaccinated subjects-age, sex, occupation,
vaccination date, frequency, period and interval of
vaccinations, years after final vaccination and past
history of Habu bites-was obtained and analyzed with
relation to serum antitoxin levels. The following
results were obtained: 1) Serum antitoxin levels,
both anti-HR1 and anti-HR2, of the Habu bitten group
(N = 47) were significantly higher than that of the
unbitten group (N = 456). This finding suggests that
crude Habu venom injected by bites elevated the
levels. Regardless of past history of Habu bites,
levels of antibody to HR2 was significantly lower
than that to HR1. 2) Among the unbitten group,
detection of antitoxin was related to subjects'
attributes. Production of antitoxin was related to
being male, high frequency of vaccinations, long
period of vaccinations and short period after final
vaccination. 3) Among the unbitten group, anti-HR2
was found in high levels with the following factors:
high frequency of vaccinations and short period
after final vaccination. However among the
well-vaccinated group (N = 153), differences in
antitoxin levels by vaccination frequency were not
recognizedref.
Immunization of human beingsref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8,
ref9,
ref10,
ref11,
ref12,
ref13,
ref14,
ref15,
ref16,
ref17,
ref18
autoantibodies to external domains of the sperm
plasma membrane : the body must make enough
antibody to cripple all of the hundreds of millions of
sperm in each ejaculate
affect the movement of normal motile spermatozoa.
Serum antibodies increase amplitude of lateral head
displacement (ALH) and decreased velocity of
progression (VSL) whereas sperm eluted antibodies
decrease ALH and increase VSL.
investigational sperm vaccine against 4 proteins
associated with the acrosomal reaction (safe and
immunogenic in female baboons)
7 out of 9 (78%) male Macaca radiata
monkeys injected every 3 weeks with human epididymal
protease
inhibitor (Eppin) / serine protease
inhibitor-like, with Kunitz and WAP domains 1
(SPINLW1) (an androgen-regulated,
sperm-binding protein containing protease-inhibitory
motifs, is expressed specifically in the testis and
epididymis) manufactured copious antibodies against
the Eppin protein, and all of these monkeys proved
infertile when mated with females. 66% of a group
injected with a placebo vaccine went on to father
offspring. Only 5 out of 7 (71%) monkeys recovered
their fertility once the injections were stopped.
One problem is that antibodies against sperm
proteins can affect other cells in the testes and
cause orchitis. In the new study it is thought that
the antibody is latching on to sperm further down
the male reproductive tract, leaving the testes
unharmedref.
testis specific protein fP13 is a 97-kDa
protein homologous to the FSP2 and CABYR
proteins described by Flinkinger. The pVAX-fSP13
vector is to be used as DNA vaccine using the fox as
an experimental model. To ensure the functionality
of the pVAX1-fSP13 vector, researchers have
transfected MDCK cells using lipofectamine, and
using RT-PCR and western-blot we have observed the
subsequent expression of the fSP13 protein. In their
assays they use foxes as canine model to study the
humoral and cellular immune responses after
immunisation by intra-muscular route with
pVAX1-fSP13. Further work using alternative
immunisation routes should be tested to measure the
effect on canine reproduction.
LHRH-based
vaccines in humans, although theoretically
possible, are unlikely, because profound behavioural
modification can occur as a consequence of inhibiting
the production of testosteronein males.
However, a avery active area of research is the use of
LHRH-based
vaccines
in the control of hormone-dependent cancers, including
breast and prostate cancers. Because the sequence of
LHRH is conserved in all mammals, LHRH-based
immunocontraceptives are candidates for use in the
companion animal livestock and livestock arenas. Here
the concerns of behavioral modification are not of
such overriding importance and the use of
immunocontraception as an alternative to surgical
castration has attracted a great deal of attention.
female immunocontraceptive
vaccines :
a phase I clinical trial of the immunogenicity and
safety of a vaccine against the C-terminal region of
the b subunit of human chorionic
gonadotropin (hCG-B)
demonstrated a dose-related immune response. The
antigen was a synthetic peptide of the C 109-145
region of hCG-B, conjugated to diphtheria toxoid, and
administered in a water-soluble synthetic adjuvant in
a saline-oil emulsion. This vaccine had been
previously tested for toxicity in laboratory animals
and for immunogenicity, safety and contraceptive
effectiveness in baboons. 30 previously sterilized
women were given 2 injections 6 weeks apart, ranging
from 50 to 1000 mg of the
antigen. Each woman tested free of HLA B27 antigen and
reacted negative to the diphtheria toxoid skin test.
Based on calculated contraceptive antibody binding
level of 0.52 nmol/l, all subjects mounted an
effective antibody response for at least 6 months. 2
subjects in the group given 1000 mg
who were followed for 9 and 10 months maintained this
level of antibody. 12 women showed an anamnestic
response to diphtheria toxoid, while 8 did not. The
only adverse reactions were mild, transient pain at
the injection site. Several women who received
unstable adjuvant experienced more severe myalgia.
Menstrual changes appeared in 5 subjects: early
menopause in 1, spotting in 3 and menorrhagia in 1
woman. Only transient positive findings were seen in
some sera screened for autoantibodies. This
preliminary trial indicates that anti-hCG vaccine is a
hopeful reversible contraceptiveref.
to examine the immunogenicity of the plasmid DNA
encoding human
sperm
associated antigen 9 (hSPAG9), the cDNA
corresponding to hSPAG9 was cloned in mammalian
expression vector pcDNA 3.1 down stream of
cytomegalovirus promoter. Immunization of female
BALB/cJ mice with pcDNA-hSPAG9 plasmid DNA in saline
by intramuscular (i.m.), by adsorbing onto gold
microcarriers (delivered by gene gun) and by
recombinant hSPAG9 (r-hSPAG9) protein generated
antibody response against Escherichia coli
expressed r-hSPAG9 protein and native SPAG9 in human
sperm. Although mice immunized with r-hSPAG9 protein
exhibited highest antibodies titres (P<0.001), the
difference in the antibody titres seen by the 2 modes
of plasmid DNA delivery were not significant
(P>0.05). A dominant IgG1 isotype
response was observed in mice immunized with
pcDNA-hSPAG9 plasmid DNA delivered by gene gun as
compared to a mixed IgG1-IgG2a
isotype response in mice immunized with r-hSPAG9
protein and pcDNA-hSPAG9 plasmid DNA delivered by i.m.
Further, antibodies generated by pcDNA-hSPAG9 plasmid
DNA localized acrosomal compartment of human sperm and
inhibited sperm adherence to or penetration in
zona-free hamster egg penetration test. These studies
for the first time, demonstrate the feasibility of
generating an immune response to sperm specific hSPAG9
protein by DNA vaccine and that antibodies thus
generated recognize native SPAG9 in human spermref.
with a seasonally polyestrus breeding structure,
the unwanted domestic cat population has proven
difficult to control. Various lethal methods have been
used in an attempt to lower this population of cats.
Recently, humane attempts to control "pest species,"
such as the feral cat, have focused on
immunocontraception. Female cats were immunized once
(n = 3 cats per group). SpayVac® (source :
ImmunoVaccine
Technologies (IVT)) is a vaccine that uses
antibodies raised against porcine (ZP) antigens to
prevent fertilization of the ovum. SpayVac®,
delivered in a single dose, has been evaluated in
fallow deer and several species of seals with >90%
reduction in fertility and no adverse reactions. A
study evaluated the effectiveness of SpayVac in
reducing fertility in domestic kittens. 30 female
kittens were treated with SpayVac containing either
Freund's complete adjuvant (FCA) or alum, or with a
control vehicle. Kittens were monitored for side
effects, estrus cycling at maturity, and fecundity.
Anti-porcine ZP antibodies were quantified by ELISA.
Immunohistochemical assays measured the species
specificity of the antibodies produced and IgG binding
in vivo. Despite high anti-porcine ZP antibody
titers, neither formulation of SpayVac®
prevented estrus cycling at maturity or reduced
fecundity. IHC assays indicated that antibodies
produced by cats treated with SpayVac®
recognized porcine ZP, but not feline ZPref.
A panel of native zona pellucida (ZP) antigens
isolated from 5 mammalian species was screened for
immunocontraceptive activity in the cat (Felis
catus). Native soluble-isolated ZP (SIZP) was
prepared from the ovaries of cows (bZP), cats (fZP),
ferrets (feZP), dogs (cZP), and mink (mZP). Vaccines
were constructed using SIZP from each of the above
species encapsulated in liposomes suspended in saline
and emulsified with Freund's complete adjuvant. Serum
was collected for determination of antibody titers
against SIZP and for binding of antibodies to feline
ovaries. All cats responded to immunization by
producing anti-SIZP antibodies. The most immunogenic
SIZP in cats was from mink, followed by feZP, cZP, and
fZP in descending order. Antibodies had low reactivity
for fZP, and no reactivity against feline ovaries was
detected by immunohistochemistry. A breeding trial was
commenced 20 weeks after immunization. All cats became
pregnant, averaging 4.1 +/- 0.7 viable kittens per
litter. Porcine SIZP is not an effective antigen for
immunocontraception of cats. SIZP from 5 other
mammalian species were immunogenic in the cat, but ZP
antibodies failed to bind to fZP in situ, and
fertility was not impededref
heterologous
Ags (heterotypic vaccine / heterovaccine) : a
vaccine that confers protective immunity against a pathogen
not present in the vaccine, because it contains
cross-reacting antigens which they share in common with that
pathogen
heterophilic Ags
Some examples :
anti-Corynebacterium
diphteriae vaccine : non-toxic protein CRM197
from a genovar induces cross-reactive Abs against
diphteria toxin.
anti-Mycobacterium
tuberculosis vaccine : priming with a prototype recombinant
Mycobacterium smegmatis expressing HIV-1 gp120
elicited CD4+ T lymphocytes with a
functional profile of helper cells as well as a CD8+
T lymphocyte population. These CD8+ T
lymphocytes rapidly differentiated to memory cells,
defined on the basis of their cytokine profile and
expression of CD62L and CD27. Moreover, these
recombinant mycobacteria-induced T lymphocytes rapidly
expanded following boosting with a recombinant
adenovirus expressing HIV-1 env to gp120-specific CD8+
T lymphocytesref
Better antigens can be created by directed molecular
evolution : nature would never select for many of the
products that directed evolution allows you to create as they
wouldn't help the cell. The initial step in DNA shufflingref
(Genetic ReAssortment by MisMatch Resolution (GRAMMR) DNA
shuffling) is to isolate several slightly different genes that
code for the same product. Enzymes chop the genes into random
fragments, and a primer-less PCR recombines fragments from
various genes. Finally, recombined fragments are reassembled
into unique, full-length chimeric genes. Maxygen products created
with this technology include :
chimeric dengue antigens that produce antibodies working
against all 4 strains of dengue
virus:
this could have important advantages as low levels of
antibodies can actually enhance the ability of the virus to
cause hemorrhagic fever.
chimeric HBsAg that led to as much as 12-fold greater
antibody response than the most potent wild-type vaccine.
mouse DCs are efficiently infected with influenza virus
but do not release infectious progeny virus. Ex vivo-infected
DCs secrete IL-12 and
induce a potent Th1-like immune
response when injected into mice (virus-specific antibody
response is primarily of the IgG2a isotype)ref
preservatives and tissue fixatives, which
are supposed to halt any further chemical reactions and
putrefaction (decomposition or multiplication) of the live or
attenuated (or killed) biological constituents of the vaccine.
nanoscopic vaccine delivery system based on the
biodegradable and natural polymer gelatin, to deliver
therapeutic protein antigens along with adjuvants into dendritic
cells (DCs). In this study, gelatin nanoparticles were tested
for qualitative and quantitative uptake in murine DCs in vitro.
A second aim of this study was to prove that the carrier system
is able to deliver tetramethylrhodamine conjugated dextran
(TMR-dextran), as a model drug into the DCs. The TMR-dextran was
incorporated during the preparation of the gelatin
nanoparticles. DCs were generated from murine bone marrow cells
by an established ex vivo technique. Flow cytometry showed that
88% of the cells positive for the specific murine DC marker
CD11c took up TMR-dextran loaded gelatin nanoparticles, whereas
only 4% of the soluble form of TMR-dextran was taken up. Double
color confocal laser scanning microscopy (CLSM) showed that
gelatin nanoparticles were phagocytosed by DCs and the triple
color CLSM showed that the TMR-dextran was localized mainly in
lysosomes as expected, but partly also outside the lysosomes,
presumably in the cytoplasm. An in vitro release study of
TMR-dextran from gelatin nanoparticles demonstrated that there
was hardly any release in phosphate buffered saline (PBS), but
by trypsin-assisted degradation of gelatin nanoparticles
resulted in the release of about 80% of the TMR-dextran from the
particlesref.
Lirubel® (Dow Pittman Moore) : no longer
in use (2/65-6/78)
M-R II® (MSD)
M-R-Vax® (Merck) : no longer in use
(7/71 to ?)
M-R Vax II® (Merck)
Morubel® (Biocine => Chiron, Italy)
Mo-Ru Viraten® (Swiss Serum and Vaccine
Institute)
Rudi-Rouvax® (Aventis Pasteur)
Zamruvax® (Institute of Immunology)
measles,mumps
and rubella (MMR) vaccine :
its use was once linked to autismref1
[retracted],
ref2
and bowel disease, but no real evidences has been found. Given
at age 12 months, and a booster at 3 to 5 years. The Institute
of Medicine (IOM) of the US National Academies after reviewing
recent studies concluded on May 2004 that there is no link
between autism and vaccines containing the mercury-based
preservative thimerosal
: their report also rules out a link between autism and the MMR
vaccineref.
Anyway a genetic susceptibility might make some individuals more
vulnerable to toxic effects of the ethylmercury-containing
vaccine preservative, thimerosal, given alone or in 4 common
vaccines given to children : autoimmune disease-sensitive SJL/J
mice showed growth delay; reduced locomotion; exaggerated
response to novelty; and densely packed, hyperchromic
hippocampal neurons with altered glutamate receptors and
transporters (resembling autism). Strains resistant to
autoimmunity, C57BL/6J and BALB/cJ, were not susceptibleref.
The researchers based their experimental design on the
observation that some children with autism have a family history
of autoimmune disease.
Imovax ROR® (Institut Merieux)
LM-3 RIT® or RIT-LM-3®
(Dong Shin Pharmaceuticals)
M-M-RVax (Chiron, Germany only)
M-M-R
II® (Merck & Co) : PWSO (1000 U /
0.5 mL, 5000 U / 0.5 mL, 1000 U / 0.5 mL) SC
Measles, Mumps, Rubella® (Dow Chemical)
MMR (generic) (Dow Chemical) : no longer in use
(1974 to 1975)
MMR® (MSD)
MMR II® (MSD)
Morupar® (Biocine => Chiron, Italy,
Asia, Latin America) was recalled on March 2006 and withdrawn
because of an increased rate of post-immunization adverse
effects
Children who are allergic to eggs are at no greater risk of a
severe allergic reaction to the MMR vaccine, which is cultured in
chick embryo cells. The real culprit in allergic reactions to MMR
could be gelatin. Overall, any severe adverse effect is almost
certain to occur within half an hour of the vaccination.
Investigations into these prior events
have concluded that the deaths following administration of the
measles vaccine were related to toxic shock syndrome resulting
from the use of non-sterile syringes and the use of the
reconstituted vaccine out of the time range specified for
administration, resulting in contamination of the administered
vaccine. The measles vaccine comes in a lyophilized form
(freeze-dried) that is reconstituted with diluent on the day of
use. Standard practice is to have vials of diluent distributed and
stored with the vaccine vials so that appropriate diluent and
amounts are used routinely for vaccination activities. Current
recommendations are to discard any unused vaccine from
reconstituted vials at the end of a vaccination session. In the
case of the deaths reported in November 2001 in Algeria, the event
was traced to the use of solvent rather than diluent for the
reconstitution of the vaccine at the local health facility where
the events occurred. In the May 2002 case of Cuba, the preliminary
report on the investigation identified "Gram-positive aerobic
bacilli" in remaining vaccine vials in the affected health
facility, suggesting there were breaches in sterilization
practices at the local area. In the 2004 event in Brazil, it
appears as though the severe adverse events were widespread,
occurring in multiple states within Brazil (one newswire mentions
15 states and the other mentions 7 states and the Federal
District) : 5 children suffered from anaphylactic shock, with
breathing difficulties and falling blood pressure, and 115 others
presented with allergic symptoms to the measles vaccine
manufactured by Chiron, Italy, used on Saturday Aug 22 on the 1st
day of the national vaccination campaign against the disease. If
the event is not localized, it suggests a problem with the product
that was distributed to multiple locations, rather than a
localized event such as breaks in safe vaccination procedures or
use of incorrect diluent for reconstitution of the vaccine. The
description of the adverse events as anaphylactic shock and other
allergic related reactions suggests the presence of a highly
allergenic contaminant in one of the 2 products used for the
vaccination process, either the vaccine itself or the diluent used
to reconstitute the vaccine. One of the questions that come to
mind is the providence of the diluent used to reconstitute the
vaccine, as we have not heard of similar events in other countries
that may be using the same vaccine. Was the diluent produced
locally (in Brazil) or was it imported together with the
lyophilized vaccine?
Web resources :
diphteria, tetanus and pneumococcal
vaccine : 4 doses at ages 6, 10, and 14 weeks, and 9
months elicits high concentrations of functional antibodies
against all but one pneumococcal serotype included the vaccine.
Moreover, "most serum samples contained antibodies with
measurable opsonophagocytic activity," ranging from 43% to 98%,
after three doses, they report. The functional activity of
anti-pneumococcal antibodies after the fourth dose was
significantly higher than after the third dose, as demonstrated
by the opsonophagocytic titer. After the fourth dose, the
opsonophagocytic activity was measurable in 75% to 100% of
samples, depending on serotype.
diphteria, tetanus toxoid and pertussis (DTwP or
DPT) vaccine. 5 doses at 2, 4, 6, 12-18 months and 4-6
years of age it is a very stable compound that
withstands temperature and humidity fluctuations.
ADCM® (?, Russia)
Adifteper® (Ism)
AFDC® (?, Russia)
AKDS® (?, USSR)
AKOC® (?, Russia)
Alditerpera® (Sevac) : adsorbed
Anatoxal Di Te Per® or Di Te Per
Anatoxal® (Swiss Serum and Vaccine
Institute)
Diferti Trippel® (?, Sweden)
Dif-Per-Tet-All® (Biocine)
DIFTAVAX® (Sclavo, Inc.)
DSDPT® (Dong Shin Pharmaceutical Co.) :
adsorbed
DT Coq® (Aventis Pasteur)
DTP® or DTwP®
(Aventis Pasteur, Wyeth Lederle, Glaxo SmithKline)
DTC® (for diphteria, tetanus and
coquellode; ?)
Dual Antigen® (Serum Institute of India)
: pediatric
Dual Antigen SII® (Serum Institute of
India) : adsorbed
Funed-CEME® (Belo Horizonte, FunED)
Kilkhosta Trippel® (?, Sweden)
Krztuscowi, Blonicy, Tezcowi® (?,
Poland)
rhorephn, kokjihowa, ctoroohrha® (?,
Russia)
Sii Triple Antigen® (Serum Institute of
India)
Stelkramp® (?, Sweden)
Tri-Immunol® (Lederle Laboratory) : 3/48
to present
Trinivac® (Merck) : no longer in use
(1952 to 1964)
Adacel™ (Sanofi Pasteur)
is a tetanus toxoid (T), reduced diphtheria toxoid (d) and
acellular pertussis vaccine (ap), adsorbed (Tdap) in adolescents
and adults aged 11-64 years. It contains the same
components as DTaP vaccine indicated for infants and children,
but the diphtheria toxoid and one of the pertussis components
are in reduced quantities. Approved by FDA on 10 Jun 2005. The
antibody responses of the adolescents and adults who received
a single dose of this vaccine were at least as good as those
observed in the infants following 3 doses of the pediatric
vaccine. For diphtheria and tetanus, the antibody responses
following this vaccine were comparable to those following
immunization with a USA-licensed Td vaccine. In clinical
trials, the safety of this vaccine was compared to a
USA-licensed Td vaccine. Among adolescent recipients of this
vaccine, injection site pain and low-grade fever were observed
more frequently than among those who received Td vaccine.
Rates of adverse reactions were similar in adults receiving
this vaccine or receiving Td vaccineref
Boostrix®
(GlaxoSmithKline) is a tetanus toxoid (T), reduced diphtheria
toxoid (d) and acellular pertussis vaccine (ap), adsorbed (Tdap).
Although booster vaccines for adolescents 10-18 years of
age containing T and d are currently licensed and
marketed for use in this age group, none contains a pertussis
component. Boostrix has the same components as Infanrix, a
DTaP vaccine for infants and young children, but with lower
amounts of both diphtheria and pertussis components. Boostrix
is indicated for use as a single booster dose to adolescents
10-18 years of age. The efficacy of the vaccine was measured
by looking at the immune response to the vaccine, as measured
by antibody concentrations. The response to the T and d
components was at least as good as the response to a licensed
Td vaccine. Boostrix also induced an antibody response to the
pertussis component of the vaccine. The response to the
pertussis component was compared to the response induced by a
3-dose series of Infanrix given to infants in a previous
study. The response of adolescents to Boostrix was considered
adequate. It is not known how long immunity to pertussis will
last. Adolescents who received Boostrix experienced pain,
redness, and swelling at the injection site. The frequency of
redness and swelling after Boostrix was similar to what is
expected following the administration of a Td vaccine.
However, pain reactions at the injection site were more
frequent with those who received Boostrix. Other side effects
included headaches, fever and fatigue for a short period of
time after the injection. Vaccination in adolescence should
prolong immunity, but an additional booster will probably be
needed later in life. The current vaccine is effective and
does protect for a certain amount of time, up to the age of 7
EEEV,
WEEV, VEEV, West Nile virus, and tetanus (VEWT-WN) vaccine
: the 2 or 3 vaccination routine is good protection against a
preventable disease for horses.
Induction of CTL
responses
Vaccines based on killed or inactivated pathogens, recombinant or
purified proteins, are generally effective in inducing Th lymphocytes
and
Ab responses, but are generally ineffective at induction of CTL
responses. The apparent reason for this limitation is likely to
hinge on the basic biology of Ag processing : CTL are efficiently
induced when Ag is endogenously synthesized and presented in the
context of nascent MHC class I molecules. Th1 polarized responses can be induced
by particular adjuvants (expecially TLR ligands), but the only
possibility for induce CTL with foreign Ags is to induce cross-presentation by administering
synthetic epitopes that can extracellularly bind surface MHC class I
molecules.
Contraindications :
moderate-to-severe acute illness (with or without fever)
fever
moderate otitis media (with or without fever)
immunosuppression in the recipient (family history,
symptomatic or asymptomatic) or in a household contact,
for live vaccines
moderate to severe vomiting and/or diarrhea (with or without
fever) for all vaccines, not only oral vaccines (e.g. OPV)
anaphylactic (life-threatening) reaction to a previous dose
of any vaccine
fever within 48 hours, encephalopathy within 7 days after a
dose for DTP/DTaP
hypersensitivity to 2-phenoxyethanol or alum in HAV vaccine,
baker's yeast in HBV vaccine, gelatin in MMR and varicella,
neomycin in IPV, MMR, and varicella, streptomycin in IPV,
DTP/DTaP within 3 days of previous dose of DTP or DTaP
underlying neurological disorder (including seizure
disorders, cerebral palsy, and developmental delay) for DTP/DTaP
recent or simultaneous IVIg or IMIg administration for MMR
and varicella
Adverse side effects /
adverse events following immunization (AEFI)
The term side effects encompasses all the changes in homeostasis
that don't contribute to progression of immunity against the
intended target. They depend on :
dose
route of administration (ROA)
properties of the preparation itself
genetic factors of the vaccinated.
The immunogenicity of vaccines does not always correlate with their
reactogenicity.
Pathogenesis :
pharmacological effect due to ligands contained in
the vaccine (e.g. LPS)
immunomodulation due to TLR ligands or
contaminant cytokines
autoimmunity : routine childhood
vaccinations do not increase the risk of developing diabetes
mellitus. As
thimerosal was removed from childhood vaccines, the number of
neurodevelopmental disordes has decreased in the USAref.
vaccination
of
the immunocompromised
hostref:
after immunosuppression (e.g. in tranplanted patients) memory
lymphocytes are lost and new immunization schedules are required
to restore immunity
non-leukaemic cancers : children with solid tumours
and lymphoma received 1 or 2 doses of trivalent split virus influenza vaccine, according
to current UK guidelines, in autumn 2001 and/or 2002. Children
were currently receiving chemotherapy or were within 6 months
of completing chemotherapy. Pre and post vaccination sera were
assessed for antibodies to the prevalent influenza strains by
haemagglutination inhibition (HI). 66 children were assessed
prior to 69 episodes of vaccination. In 30% episodes, children
were susceptible to all three circulating influenza viruses
(65% to H1N1, 42% to H3N2
and 90% to B) and only one patient showed protective titres
(HI32) against all three strains. Seroresponse rates (4-fold
rise in HI) for H1N1, H3N2
and B were 52%, 33% and 51% in 65 episodes. Following
immunisation protective titres to all 3 viruses were seen in
25 episodes (38%) and protective responses to 1 or 2 viruses
were seen in a further 12 (19%) episodes. There was no
significant difference in response rates among children on
treatment and off treatment and by intensity of chemotherapy.
Children with solid tumours and lymphoma are highly
susceptible to influenza infection. Influenza vaccine was well
tolerated in this patient group and children showed a
significant response to immunisation. These findings support
the recommendation for annual influenza vaccination in these
childrenref.
leukemia/lymphomas :
cancer patients receiving chemotherapy are prone to develop
infections that might postpone treatment and lead to
complications. In general, adults with cancer are at least at
the same risk of infection with vaccine-preventable diseases
as are healthy populations. Because of their compromised
immune function, many patients who have undergone cancer
treatment are specifically at increased risk of morbidity and
mortality associated with measles and varicella infections.
Asplenic patients with lymphoma are at increased risk of
fulminant bacterial infections. Influenza infection is
associated with significant morbidity in cancer patients.
Although the protection conferred by immunization is lower in
immunosuppressed patients with cancer, immunization with
inactivated vaccines is indicated. Live vaccines should not be
used except in very rare instancesref.
chronic lymphoproliferative disorders (CLPD) and
multiple myeloma (MM) : none of 34 patients had untoward
reactions to the vaccine used. Seroconversion and
seroprotection were up to the standard established by the
European Agency for the Evaluation of Medicinal Products.
Only one patient developed influenza during follow-upref
after 1 vaccination, 25 patients (72%) and 34 controls
(87%) were serologically protected against 2-3 influenza
strains. A higher proportion of patients with solid tumors
(81%) than lymphoma (38%) achieved protection. Age, months
on chemotherapy, and curative versus palliative treatment
did not influence responses to vaccination. In this study
the chemotherapy regimens used were mild or moderately
immunosuppressiveref
in children receiving chemotherapy for malignancyref
:
children with solid tumours and lymphoma are highly
susceptible to influenza infection. Influenza vaccine
(performed both on and after chemotherapy) was well
tolerated in this patient group and children showed a
significant response to immunisationref
9 of 12 children with malignant diseases without
antibodies to A/Victoria/75 before immunization
developed them after the first dose of vaccine. Adverse
reactions after vaccination were minimalref
during the National Influenza Immunization Program in
1976, 147 children with neoplastic diseases received
Wyeth split-product bivalent influenza vaccine: A/New
Jersey/8/76 (HSW1N1),
A/Victoria/3/75 (H3N2). 13 normal
siblings served as controls. 71 patients received 2
doses of the vaccine 4 weeks apart. After the second
injection of A/NJ/8/76, there was a difference between
the response of the patients on chemotherapy and those
off therapy >= 30 days--38% vs. 76%, P < 0.01 for
4-fold rise and 26% vs. 57%, P < 0.05 for the
attainment of protective (>= 32) hemagglutination
inhibition (HI) titers. These differences were observed
in both leukemia-lymphoma and solid tumor patients.
There was a difference in HI titers to A/Vic/75 between
patients on and off chemotherapy after a single
injection, 34% vs. 71%, P < 0.001 for a 4-fold rise.
After the second immunization, only 52% on, and 86% off
therapy (P < 0.05) had a four-fold rise in titers.
32%of the patients on treatment who achieved
"protective" titers did so only after the second
immunization. Immunoglobulin levels and neutropenia did
not correlate with the inability to obtain a 4-fold rise
in titers. Patients on chemotherapy cannot be
effectively vaccinated by a new antigen, and that single
yearly boosters may be insufficient for recall of old
antigens. Patients off chemotherapy >= to 30 days
respond as normal controlsref
among children receiving immunosuppressive therapy
for cancer, possible early loss of specific immunity
acquired from prior vaccination or disease, and likely
diminished responsiveness to initial or booster
vaccination must be considered. In addition, the safety
of vaccine administration requires separate study in
this population. Published evidence demonstrates
preservation of vaccine-induced antibody titers against
tetanus, diphtheria, poliomyelitis and (in children
treated for lymphoma) pneumococcus. In contrast, prior
immunity to varicella, influenza, and hepatitis B (when
naturally acquired), and measles (acquired by
vaccination) is compromised during and/or after
antineoplastic therapy. Studies of immunologic
protection acquired by prior vaccination against
hepatitis B, varicella, and H influenzae have
not been published. The safety of administering toxoids
and inactivated vaccines in this population is well
documented. In contrast, morbidity must be expected if
live attenuated vaccines (oral polio vaccine, attenuated
measles vaccine or attenuated varicella vaccine) are
administered to children receiving anti-cancer therapy.
The risks of using live vaccines should be measured
against demonstrable benefits in any vaccine program.
The response to initial or booster immunizations against
tetanus and diphtheria are similar to those in healthy
children. For all other immunizations reviewed,
responsiveness is diminished during periods of
chemotherapy, more strikingly in children treated for
leukemia than for solid tumors. Antibody responses to
these vaccines range from slightly blunted (in the case
of H influenzae B) to marginal (influenza) or
completely useless (pneumococcus and hepatitis B in
children treated for leukemia)ref
haematological malignanciesref
: 2 doses of influenza vaccine do not improve the antibody
responseref
children with B-cell acute
lymphoblastic leukemia (B-ALL)
developed significant antibody titers to A/Panama /2007/
99 antigen 4 weeks after the second immunization.
Seroconversion rates after 2 doses of vaccine were 57.1
to 84.6% and seroresponse rates were between 24 and 60%
in children with ALL. Compared to children with asthma
in remission, who were regarded as immunocompetent
individuals, the ALL children had less seroconversion
and lower seroresponse rates to A/New Caledonia/20/99 (H1N1).
The
seroconversion and seroresponse rates to
B/Yamanashi/166/98 and A/ Panama/2007/99(H3N2)
antigens were comparable in asthmatic and leukemic
children. On the other hand, the antibody response in
children with ALL who received reinduction chemotherapy
suggests that the therapy did not impair seroresponse
ratesref.
Although post-immunization geometric mean titers
were lower in children with ALL receiving maintenance
chemotherapy compared to healthy children for the H1N1
antigen (P<0.001), the H3N2
antigen (P=0.03), and for the influenza B antigen
(P=0.003), at least 60% of children with ALL had
at least a 4-fold rise in HAI titers to each of the
influenza antigens. Children receiving maintenance
chemotherapy for ALL should receive yearly influenza
vaccineref.
Among 42 susceptible children receiving continuing
chemotherapy immunised with 2 doses of influenza
vaccine, 66% made some protective response to the
vaccine and 55% showed protective antibody titres to all
three viral strains following vaccination. Older age was
associated with increased response to the H1N1
and H3N2 vaccine components, but
total white cell count or neutrophil count at
immunisation, type of cancer, or length of time on
treatment for acute lymphoblastic leukaemia did not
affect responseref.
Studies were performed in 25 patients previously
vaccinated against influenza (Group A) and in 20
children who had never been immunized before (Group B).
In Autumn, 1996, they were vaccinated with subunit
trivalent influenza vaccine containing 15 mg of hemagglutinin of
A/Singapore/6/86, A/Wuhan/359/95 and B/Beijing(184/93.
Anti-HA and anti-NA antibody titers were determined
before immunization and 3 weeks and 6 months after
vaccination by the hemagglutinin inhibition test and the
neuraminidase inhibition test. In Group A mean fold
increase of HA antibodies ranged from 17.2 to 26.7 three
weeks after vaccination and from 22.1 to 38.2 6 months
after vaccination, while in Group B it ranged from 15.7
to 22.6 and from 30.3 to 39.3, respectively. In the case
of neuraminidase, mean fold increases for Group A varied
from 9.2 to 13.2 3 weeks after immunization and from
15.6 to 21.1 6 months after vaccination, whereas for
Group B they varied from 5.5 to 8.3 and from 14.4 to
23.4, respectively. 6 months after vaccination the
proportion of subjects with HA antibodies > or =
1:40, as well as those with at least 4-fold increase of
HI antibody titers, ranged from 68 to 100% in Group A
and from 90 to 100% in Group B. No vaccinated child was
infected with the influenza virus; the vaccine was
well-tolerated and did not cause any adverse reactionsref.
In 44 children receiving maintenance treatment or after
treatment, the GMT increased > 4 times for
hemagglutinins H1N1 and H3N2.
A somewhat lower increase was observed in case of
hemagglutinin HB. The proportion of subjects protected
after vaccination was 35% for hemagglutinin H1N1,
76% for H3N2 and 100% for HB. The
response rate was 33% for hemagglutinin H1N1,
47% for H3N2 and 45% for HB. In
the control group the proportion of subjects protected
and the response rate were very lowref.
In 49 children immunized with a purified subvirion
trivalent influenza vaccine, 6 months after vaccination
GMT for hemagglutinin 1 (H1) was much higher
than previous values. GMT for hemagglutinin 3 (H3) and
hemagglutinin B (HB) was lower than three weeks after
vaccination, but much higher than the original values.
In the control group GMT for H1 was on a low level all
the time and for H3 and HB it was lower when
compared with the original values. The proportion of
vaccines to antibodies > or = 40 ranged between 45%
and 88%. 6 months after vaccination GMT for
neuraminidase 1 (N1) increased when compared
with the second sampling; for neuraminidase 2 (N2)
and neuraminidase B (NB) it was slightly lower. In the
control group GMT for all antigens was on a low level
all the time. The results point to a significant
seroconversion for both components after vaccination
when compared with the control groupref.
The immunosuppressive effects of long-term combination
chemotherapy in children with acute leukemia in
remissionref.
Antibody responses of two doses of a bivalent influenza
vaccine containing A/Victoria/75 (A/Vic/75) and A/New
Jersey/76 (A/NJ/76) viral antigens were studied in 22
children receiving maintenance chemotherapy for acute
lymphoblastic leukemia (ALL), 16 children no longer
receiving therapy for ALL, and 50 sibling controls.
Before immunization, the three groups showed no
difference in titer of antibody to either antigen. After
the first immunization, children off therapy showed
significantly higher titers to A/NJ/76 than did either
sibling controls of children receiving therapy (P <
0.01). After the second immunization, children off
therapy showed significantly higher antibody titers to
both antigens than did children receiving therapy or
controls (P less than 0.01 for both A/NJ/76 and
A/Vic/75). Antibody titers of children receiving therapy
were not significantly different from those of controls.
A year later, there were no significant differences in
antibody titers among the groups. Thus, children with
ALL who are receiving chemotherapy respond normally to 2
doses of influenza vaccine, whereas children off therapy
manifest abnormally high titers of antibody to both
influenza virus antigensref.
Children with acute lymphocytic leukemia and other
malignancies between three and 17 years of age were
immunized with bivalent influenza vaccine containing
A/New Jersey/76 and A/Victoria/75. Folowing a 2-dose
immunization schedule, only 37% (25468) on cancer
chemotherapy seroconverted to a hemagglutination
inhibition titer greater than or equal to 20 for
A/NJ/76; the seroconversion rate in those not on
chemotherapy was 92% (68/74, P < 0.001). The immune
response to the A/Vic/75 antigen was also related to a
history of recent chemotherapy. There was no correlation
between the immune response and the peripheral WBC count
except at counts <= 1,000. The optimum time to
immunize children with malignancies is when they have
been off chemotherapy for 1 month and have peripheral
WBC counts > 1,000ref.
NHL : PET scan hypermetabolism induced by influenza
vaccination in a patientref
patients with lymphoma, who tend to have
hypogammaglobulinemia, responded less well to bivalent
inactivated influenza vaccine containing A/Port
Chalmers/1/73 (H3N2) and B/Hong
Kong/5/72 antigens than did patients with solid tumours.
Among the latter the failure to show a 4-fold or greater
increase in antibody titre correlated with a poorer
18-month survivalref
B-cell
chronic lymphocytic leukemia (B-CLL)
: immune response to influenza vaccination was poor.
Response rates (> 4-fold titre increase) were 5% for
influenza A and 15% for B after the single vaccination
and 15% for A and 30% for B after the booster
vaccination. Protection rates were 0% for influenza A
and 25% for B after the single vaccination; they were 5%
(H1N1) and 10% (H3N2)
for influenza A and 30% for B after the booster. The
MFI+/-S.D. (range) after the booster vaccination was
0.26+/-0.33 (0-1.00), 0.17+/-0.34 (0-1.00) and
0.35+/-0.34 (0-1.20) for H1N1, H3N2and
influenza B, respectively. Thus, single and booster
vaccinations with influenza virus vaccine do not appear
to be of great value to patients with B-cell CLLref.
The Vaxigrip vaccine was administered containing the
antigens A/Ghizhou/54/89, A/Singapore/6/86, and
B/Yamagata/16/88. The side-effects observed were minimal
and well tolerated. Antibody production with titres >
1:20 on day 15 was observed at least for one antigen in
35 patients (81%). In 23 of them (63%) this response was
retained on days 30 and 60. Patients with IgG levels
(< 700 mg/dl) responded less well as compared to
those having normal IgG levels (> 700 mg/dl)ref.
No difference in the response to vaccination against
influenza virus types A and B protein could be detected
in patients treated with ranitidineref.
A correlation between immunological response to
vaccination and both absolute numbers of CD4+/CD45RA+naive T cells and CD5- B cells was foundref.
Hodgkin's
lymphoma
: during and after chemotherapy, both pre- and
postimmunization levels of antibody to Streptococcus
pneumoniae, Hemophilus influenzae type b,
and tetanus toxoid antigens were significantly lower in
patients than in controls. Impairments in the antibody
response were most severe in intensively treated
patients and improved as the interval between treatment
and immunization increased. The primary, but not the
secondary, antibody responses to the hemagglutinins of
the influenza virus A/Victoria/75 and A/New Jersey/76
also were impaired in treated patientsref
There are opinions that patients from high-risk group
are not able to respond to vaccination effectively and
vaccination may contribute to exacerbation of the
chronic disease. The aim was to assess humoral response
to influenza vaccine in 32 patients with non-Hodgkin
malignant lymphoma (mean age 57.2) and 32 healthy
subjects (mean age 44.3). Sixteen patients were treated
with immunosupressive drugs (group A) and 11 were not
subjected to this therapy (group B). Levels of
antihemagglutinin (anti-HA) antibodies were assessed in
sera before vaccination and after 1 month by
hemagglutination inhibition test. Nasal and throat swabs
were collected from persons with influenza symptoms
during the study to detect the etiological agent of the
infection. Post-vaccination anti-HA antibody levels were
significantly higher than pre-vaccination values and
mean fold increases (MFI) ranged from 9.3 to 12.2 in
patients and from 27.6 to 44.3 in healthy subjects. The
percentage of patients with the protective anti-HA
antibody titers > or =1:40 (protection rate) ranged
after vaccination from 59.4% to 68.8%. The percentage of
patients with at least a 4-fold increase of anti-HA
antibody titers (response rate) after vaccination ranged
from 46.9% to 68.8%. There were no significant
differences in antibody levels between patients treated
with immunosuppressive drugs and those not treated. No
respiratory infections were laboratory confirmed. This
study showed that influenza vaccine is less immunogenic
in patients with non-Hodgkin malignant lymphoma, because
it induces antibody production in lower titers in
comparison to the production in healthy people. Despite
this, influenza vaccine should be offered to this group,
considering high MFI values and response rates as well
as the protective effect for individual patientsref
although geometric mean titres of the haematological
lymphoproliferative or myeloproliferative disorders
patients showed lower initial antibody levels, smaller
increments, and lower final titres, after vaccination
83% of this group achieved satisfactory antibody levels
to the A/Pt Chalmers strain, and 57% to the B/Hong Kong
strain. The lowest antibody levels and smallest
responses occurred in patients with NHL, Hodgkin's
disease, and multiple myeloma. 4 of 7 patients who
showed low antibody levels, and no response to the first
injection, responded to a second doseref
mean antibody titer elevations were lower for both
antigens in all disease groups, being significant (p
< 0.05) for A/Victoria in patients with NHL, acute
leukemia and lymphoproliferative diseases, and for A/New
Jersey in patients with HLs and NHLs. In comparison to
controls, significant depression of antibody response to
both antigens was seen in patients on combination
chemotherapy (p < 0.0005), to a lesser extent in
patients on daily single alkylating agent chemotherapy
(p < 0.05), while untreated patients did not differ
significantly. Lymphopenia and depressed immunoglobulin
levels were associated with a higher failure rate in
eliciting "protective" greater than or equal to fourfold
antibody titer increases. The findings suggest that
patients with hematologic malignancies who are receiving
chemotherapy at the time of vaccination are unlikely to
attain seroconversion to protective antibody levels with
influenza vaccineref
Side effects :
atypical lymphoid infiltrations arose within the
influenza inoculation sites of two adult female patients.
One patient developed a low-grade cutaneous marginal zone
B-cell lymphoma (MZL) that was responsive to local
excision and radiation therapy despite spread to a distant
cutaneous site. The second patient's clinical course was
characterized by a locally aggressive, histologically
reactive inflammatory reaction responsive only to
radiation therapy after multiple failed attempts at
surgical resectionref
after vaccination with a 23-valent polysaccharide
vaccine against pneumococci, most patients and controls
achieved protective serum levels of antibodies against the
different serotypes, with the exception that fewer
patients were protected against serotype 4. The responses
in controls were, however, generally stronger to all
serotypes. Tumor type did not influence this vaccination
responseref.
multiple myeloma
(MM)
: resistance to S. pneumoniae and response to
Pneumovax II was poor : prevaccination, 45 patients (93%)
had suboptimal antibody titres and in 26/43 patients (61%)
titres remained low post vaccinationref
Hodgkin's
lymphoma
: before treatment antibody responses to pneumococcal
vaccine was normal regardless of the stage of disease
unless treatment began within 10 days of immunization.
Levels of antibody decreased during therapy in proportion
to the intensity of treatment but remained higher than
levels in comparably treated patients who were not
immunized at diagnosis. Patients should receive
pneumococcal vaccine at diagnosis at least 10 days before
initiation of treatment. Patients who are treated before
immunization may be immunized several months after
treatment, although the response of heavily treated
individuals to vaccination may be marginal. More studies
are needed to determine whether reimmunization of patients
initially immunize at diagnosis is safe and effectiveref
multiple myeloma
(MM)
resistance to Hib and response to vaccination was
comparable with the healthy adult UK populationref.
No increased incidence of leukemia in children vaccinated
with polysaccharide-diptheria toxoid conjugate and
oligosaccharide-CRM197 conjugate Haemophilus
influenzae type b conjugate vaccine formulationsref
B-cell
chronic lymphocytic leukemia (B-CLL)
: patients have decreased capacity to mount relevant
antibody responses upon immunization, and development of
hypogammaglobulinemia is part of the natural history of
the disease. H2 receptor blockade by ranitidine
improves the in vivo antibody production in B-CLL
patients following vaccination. Anti-polysaccharide
antibodies in B-CLL patients, vaccinated with a
tetanus-toxoid conjugated vaccine against Haemophilus
influenzae type-B (Hib), reached long-term
protective levels in > 90% of B-CLL patients randomized
to ranitidine treatment, as compared to 43% of the
untreated patients (P = 0.024). Plasma histamine levels
were 2-fold to 20-fold higher in 23 out of 31 B-CLL
patients, compared to normal controls, and these levels
showed a significant positive correlation to disease
duration. These findings indicate the possibility of
improving in vivo antibody production against a
highly relevant pathogen in B-CLL patients by H2
receptor blockade, and the combined finding of an
immune-stimulatory effect of ranitidine and increased
plasma histamine levels, strongly suggests the involvement
of histamine in the pathogenesis of B-CLL immunodeficiencyref
all anti-diphtheria toxoid (D), tetanus toxoid (T), and Haemophilus
influenzae type b (Hib) antibody levels decreased
during ALL treatment, and protective levels after treatment
were noted for 17% against D, 33% against T, and 100%
against Hib. No high-risk patient had full D or T protection
after treatment. After vaccination all the standard- and
intermediate-risk patients achieved full protection against
D, T, and Hib. The high-risk group showed insufficient
immune response (full protection after vaccination: D 56%, T
22%, Hib 78%). No difference was found between vaccination
at 1 month or 6 months after treatment. The poor antibody
production in the high-risk group correlated to low numbers
of antibody-secreting cells. Nonprotective antibody levels
against D, T, and Hib after childhood ALL are more common
than previously thought. Insufficient immune response was
restricted to the high-risk group and was related to a low
number of memory B cells in this study. Immunizations should
be included in follow-up after childhood ALL, and the policy
should be adapted to treatment intensityref
in
bone marrow transplantationref1,
ref2:
Vaccination of stem cell transplant recipients:
recommendations of the Infectious Diseases Working Party of
the EBMTref.
The conditioning regimen used in marrow graft recipients
ablates normal and abnormal immunohematopoietic elements and
prepares the marrow microenvironment for the donor marrow to
develop. The repopulation of the immune system is dependent on
appropriate nesting, proliferation, maturation and
differentiation of donor cellsref.
Ultimately, the recipients lose immune memory of exposure to
infectious agents and vaccines accumulated throughout their
lives. The loss of protective immunity to agents such as
tetanus, poliovirus, and measles has been consistently
demonstrated in patients submitted to allogeneic and
autologous bone marrow transplantation (BMT), and consequently
a reimmunization program is necessary to ensure immunityref1,
ref2,
ref3,
ref4.
Several surveys regarding reimmunization after BMT have
demonstrated that vaccination protocols vary greatly among BMT
centers, with insufficient data to establish solid
recommendationsref1,
ref2,
ref3,
ref4.
The European Group for Blood and Marrow Transplantation, the
Centers for Disease Control and Prevention, the Infectious
Disease Society of America, and the American Society of Blood
and Marrow Transplantation have recommended that the following
vaccines be included in reimmunization protocols for
autologous, syngeneic and allogeneic BMT recipients:
diphtheria toxoid, tetanus toxoid, pertussis vaccine (children
<7 years old), Haemophilus influenzae type b (Hib)
conjugate, 23-valent pneumococcal polysaccharide, inactivated
influenza vaccine, inactivated polio vaccine and
live-attenuated measles-mumps-rubella vaccineref.
Antibody responses to vaccinations given within the first two
years after transplant are similar between autologous
peripheral blood stem cell and bone marrow transplant
recipientsref.
vaccines currently recommended in reimmunization
protocols :
vaccines
time after BMT
no. of doses
vaccine type
tetanus and diphtheria
after 4 months (evidence recommends an early start)
3 doses
toxoid
Hemophilus influenzae
after 4 months (evidence recommends an early start)
2 doses
conjugate polysaccharide
polio
after 4 months (evidence recommends an early start)
3 doses
inactivated virus
pneumocococcal
after 12 months
1 dose?
polysaccharide
hepatitis B
after 4 months (evidence recommends an early start)
3 doses
recombinant
influenza
yearly
1 dose/year
inactivated virus
MMR
after 2 years
1 dose
attenuated virus
diphtheria
toxoid : immunity to diphtheria wanes over time. Lum
et al.refshowed
that
while 100% of the BMT patients with immune donors had
antibodies to diphtheria within the first 100 days after
transplantation, about 30% of them lost immunity
thereafter. Increasing susceptibility (up to 40%) was
noticed in those with chronic graft-versus-host disease
(GVHD). Other investigators evaluating long-term
diphtheria immunity showed that only 54.5% of the patients
still had antibodies to diphtheria with barely protective
antitoxin levels one year after BMTref.
There is evidence that multiple doses are more effective
than a single dose in allogeneic recipients without
chronic GVHD vaccinated 2 to 6 years after BMTref.
Chronic GVHD seems to interfere with the response to
vaccination 4 months after BMTref.
Although diphtheria vaccination starting one year after
transplantation has been mostly recommended, no definitive
data are available concerning the best time to start
vaccination.
tetanus toxoid
: there is contrasting information concerning the
persistence of tetanus immunity one year after BMT. Some
investigators have observed sustained immunity in
long-term allogeneic BMT survivors irrespective of toxoid
administration pre- or post-transplantationref.
On the other hand, Ljungman et al.ref
observed that only 50% of the patients who were immune
prior to transplantation sustained tetanus immunity for
one year. More recently, Parkkali et al.ref
also observed an increasing reduction in the mean
concentration of anti-tetanus antibodies in this
population. In the cited study, the patients were
randomized to start early (6 months) or late (18 months)
tetanus reimmunization. Before vaccination, 90% of the
patients in the early group were immune to tetanus in
contrast to 70% in the late group. Both schedules were
equally immunogenic. However, in the late group, the
recipient's antibody response after the first and second
vaccine doses was correlated with donor's antibody levels,
suggesting that donor immunity affects recipient response
to tetanus toxoid. Acute GVHD does not seem to interfere
with the response to tetanus vaccinationref.
Some studies on chronic GVHD did not show an effect on the
response to vaccinationref,
while others suggested that chronic GVHD may interfere
with the intensity of the response (below four-fold rises)
or with the duration of tetanus immunity after vaccinationref1,
ref2.
Although most BMT centers start tetanus immunization one
year after transplantation, currently available
information does not justify postponing tetanus
immunization for > 6 months after BMTref.
The correlation of donor antibody levels with the response
to tetanus vaccination indicates that prospective studies
randomly vaccinating the donors before marrow harvesting
should be conducted in this setting to better evaluate the
need for donor vaccination in reimmunization programs.
pneumococcal
polysaccharide : BMT recipients are particularly at
risk to develop life-threatening pneumococcal infections
due to functional hyposplenism as a result of
pre-transplant total body irradiation and chronic GVHD.
The currently available pneumococcal vaccines are the 14-
and 23-valent polysaccharide vaccines and the 7-valent
conjugate vaccine. The polysaccharide vaccines contain
only pure polysaccharides and require mature function of
the immune system for a maximal response. The vaccines are
therefore poorly immunogenic in transplant populations.
Moreover, the polysaccharide vaccine does not cover 20% of
the commonly pathogenic strains and immunized patients
remain susceptible to themref.
Evaluating a 14-valent pneumococcal vaccine in allogeneic
BMT patients, Winston et al.ref
observed that pre- and post-vaccination levels were
significantly lower in BMT recipients compared to normal
control subjects. Multiple regression analysis showed that
vaccination within the early post-transplant period and
corticosteroid therapy of GVHD were the two factors
influencing the antibody response. Other investigators
have also observed decreasing pneumococcal antibody levels
over the first year after BMT and a poor antibody response
to a 23-valent pneumococcal vaccineref1,
ref2,
ref3,ref4.
Little information is available regarding the impact of
GVHD on the response to the pneumococcal vaccine since
even non-GVHD patients are poor responders. Immunization
of the donors before marrow harvesting did not influence
the level of specific antibodies one year or more after
transplantationref1,
ref2.
The data from most of the pneumococcal vaccine studies
suggest that the key factor affecting response is possibly
time to vaccination and consequently vaccination should be
recommended after the second year of transplantation or
even laterref1,
ref2.
However, impaired serum opsonic activity is expected
during the first year after transplantation when
life-threatening pneumococcal infections pose a greater
risk. Thus, the currently available vaccine is not of
substantial additional help in preventing pneumococcal
infection during the first year post-transplant. Long-term
survivors without chronic GVHD are at lower risk for
pneumococcal infection and probably only a few of them
would benefit from vaccination. Among chronic GVHD
patients, the use of corticosteroids affects their
response to vaccination, rendering this strategy at least
questionable. The benefit of the new 7-valent pneumococcal
conjugate vaccine has been recently investigated in
allogeneic hematopoietic cell transplantation. Donors were
randomized to receive or not one dose of the conjugate
vaccine 7 to 10 days before transplantation. The
recipients received three doses of the vaccine at 3, 6 and
12 months after BMT. Protective immunity was achieved
earlier in patients whose donors had been vaccinated, but
after the three doses of the vaccine, protective immunity
was similar in the 2 groupsref.
More studies are needed to better evaluate the
effectiveness of the conjugate vaccine in BMT recipients.
Due to the limited coverage of pneumococcal pathogenic
strains by the 7-valent conjugate vaccine, prolonged
prophylactic oral penicillin should be associated with the
vaccination to prevent pneumococcal infection after BMT.
Opsonophagocytic activity against Streptococcus
pneumoniae type 19F in allogeneic BMT recipients
before and after vaccination with pneumococcal
polysaccharide vaccineref.
Haemophilus
influenzae type b conjugate : polysaccharide
vaccines were not sufficiently immunogenic to the immature
immune system of children and the preliminary results of
Hib vaccination were disappointing. A new generation of
polysaccharide-protein conjugated vaccines was developed
and proved to be more immunogenic in children and also in
BMT patients. The polysaccharide antigen is conjugated to
a protein such as tetanus or diphtheria toxoid or both.
Data from Hib vaccination studies in BMT patients have
demonstrated that at least two doses of the conjugated
vaccine are necessary to ensure protective antibody levelsref1,
ref2.
Comparing multiple Hib vaccination schedules after BMT,
Vance et al.ref
observed that protective levels were achieved after the
third or second dose of Hib vaccine in patients starting
immunization at 3 or 6 months after BMT, respectively.
Parkkali et al.ref,
using a single dose of diphtheria conjugated Hib vaccine
in 45 BMT recipients randomized to start vaccination at 6
or 18 months, observed that both schedules were equally
immunogenic. Since the greatest risk for infection by
encapsulated bacteria occurs during the first 2 years
after BMT, early-start schedules should be preferred in
this setting. Donor and recipient immunization with Hib
vaccine before BMT proved to be more effective than
recipient vaccination after BMT as demonstrated by a
higher antibody concentration in patients as early as 3
months post-transplantationref.
Other investigators showed that between 4 and 18 months
after BMT the response to Hib vaccination did not
correlate with GVHD, use of immunosuppressive drugs or
time to vaccinationref.
The results of these studies indicate that at least 2
doses of Hib-conjugated vaccine can be administered safely
and effectively as early as 4 months after BMT. The impact
of donor immunization before marrow harvesting on the
appearance of protective antibody levels soon after BMT
must be confirmed in larger, prospective, randomized
trials before being widely recommended.
poliovirus vaccine : immunity to polio is progressively
lost after BMT. Immunocompromised patients and their
household contacts should not receive live-attenuated oral
poliovirus vaccine. Thus, inactivated poliovirus vaccine
(IPV) is recommended after transplantation. Ljungman
et al.ref
demonstrated that 50% of the patients lost immunity to all
3 poliovirus types 1 year after BMT. Patients who received
3 IPV doses 12, 13 and 14 months after BMT had
significantly higher specific antibody titers 1 year later
in comparison to patients who received only one dose. GVHD
did not interfere with the response to vaccination when
the 3-dose regimen was adopted. Other investigators have
observed similar findingsref.
More recently, Parkkali et al.ref
compared the response to poliovirus vaccination in 45
patients randomized to receive IPV at 6, 8 and 14 months
(early group) after BMT or at 18, 20 and 26 months (late
group). Both schedules were similarly immunogenic. Acute
GVHD accelerated the decrease of poliovirus antibody
titers before vaccination but did not interfere with the
response to IPV. Chronic GVHD did not influence the
duration of polio immunity or the response to vaccination.
These data suggest that poliovirus immunization also does
not need to be postponed for more than 6 months after BMT.
measles
vaccine : immunity to measles decreases continuously
after BMTref1,
ref2.
Although severe measles is expected to occur in
immunocompromised patients, there are only 2 reports in
the literature of measles following transplantationref1,
ref2.
Probabilities of measles immunity of about 47, 27 and 20%
have been reported 3, 5 and 7 years after BMT,
respectivelyref.
Among non-vaccinated BMT recipients, Machado et al.ref
observed that 36.6% were susceptible to measles between
the first and second year after BMT and this rate
increased to 57.7% after the second year. Type of BMT
(allo or auto), acute or chronic GVHD and the use of
immunosuppressive drugs did not influence the persistence
of immunity in that series. The live-attenuated trivalent
measles-mumps-rubella vaccine has been administered safely
and effectively after the second year of transplantation.
Its use has been recommended only in patients not
receiving immunosuppressive drugsref1,
ref2,
ref3,
ref4.
However, the duration of measles immunity after
vaccination and the need for booster doses deserve further
investigation in this population. Among vaccinated
patients, Machado et al.ref
observed that 70% had lost measles immunity 3 years after
vaccination, suggesting that serological surveillance to
check for immunity should be performed in long-term
survivors. Moreover, the value and the frequency of
booster doses of the vaccine should be better investigated
in patients who lost measles immunity. It is important to
stress that although most of the recommendations for BMT
recipient vaccination are independent of where in the
world the patient lives, there are local variations in the
scenario of infections that must be taken into account and
adjustments in official guidelines are strongly
recommendedref.
For example, in 1997, hundreds of BMT recipients were
exposed to measles when > 20,000 cases of measles were
diagnosed during an outbreak in the city of Săo Paulo,
Brazil. 8 patients acquired measles and early measles
vaccination was the strategy used to avoid the appearance
of new measles cases among the patients who had lost
specific immunityref.
To evaluate the safety and effectiveness of this strategy,
live-attenuated measles-mumps-rubella vaccine was
administered one year after BMT to all patients, even
those receiving immunosuppressive drugs. No moderate or
severe side effect was noted and all susceptible patients
responded to vaccination. The probability of sustained
immunity was 60.2% 2 years after early vaccination
(Machado CM, Sumita LM, Rocha IF, Pannuti CS & Souza
VAUF (2002). Early measles vaccination in BMT recipients.
The 12th International Symposium on Infections in the
Immunocompromised Host. Bergen, Norway, June 23-26, 2002).
Thus, this strategy can be safely used during outbreaks in
countries that have not achieved measles elimination.
Safety of early immunization against measles/mumps/rubella
after bone marrow transplantationref.
Long-term immunity to measles, mumps and rubella after MMR
vaccination among children with bone marrow transplantsref.
During follow-up after allogeneic HSCT, patients
frequently lose their immunity to infectious agents such
as measles. The aim of the study was to analyze the
influence of different factors on measles immunity. In
total, 395 patients with a disease-free survival of at
least 1 year were included. Measles vaccination was given
at 2 years after SCT to children and young adults without
chronic GVHD or ongoing immunosuppression. In all, 264
patients had matched sibling donors and 131 either
mismatched family or unrelated donors. Totally, 318
patients received bone marrow and 77 peripheral blood stem
cells. Overall, 375 patients had undergone myeloablative
and 20 nonmyeloablative conditioning. Out of 395 patients,
133 (34%) were seronegative to measles. In multivariate
models, younger age or being vaccinated to measles, rather
than previous measles disease, before transplantation were
risk factors both for becoming seronegative and to have
doubtfully protective immunity to measles. Acute GVHD
grade II-IV was a risk factor for seronegativity and blood
stem cells a risk factor for doubtfully protective
immunity. Children and young adults previously immunized
to measles have a high risk for becoming vulnerable to a
measles infection. Since measles is again circulating in
many countries and measles is a serious infection after
SCT, vaccination should be consideredref.
Patients received attenuated virus vaccine between 9 and
18 months after BMT. A total of 51 patients were evaluated
and 27 of them (52.9%) were receiving immunosuppressive
drugs. Only mild adverse reactions were noted. Nine
patients (17.6%) were susceptible (IgG< or =100 mIU/ml)
at vaccination, and all seroconverted. In those immune at
vaccination, a four-fold increase in measles IgG titers
was found in one of 34 patients (2.9%) with specific
IgG> or =200 mIU/ml compared to 14 of 17 (82.3%) with
IgG<200 mIU/ml (P< 0.0001). Sustained immunity after
24 months was more likely to occur in patients with
specific IgG levels< or =200 or > or =500 mIU/mL
(83.4 and 100%, respectively) in comparison to patients
with 200<IgG<499 mIU/ml at vaccination (50%
P=0.017). We conclude that even though early measles
vaccination is safe, few patients are susceptible on day
+365 and this strategy should be reserved for epidemic
situations posing significant threat for the patientsref
measles immunity
years after vaccination (P = 0.049 comparing
immune status according to
time after vaccination (chi-square test).)
total
< 3 years
> 3 years
susceptible
6 (27.3)
7 (70)
13
immune
16 (72.7)
3 (30)
19
total
22 (100)
10 (100)
32
influenza vaccine :
few data are available concerning influenza vaccination
after bone marrow transplantation. Engelhard et al.ref
vaccinated 48 patients with 2 doses of influenza vaccine
administered 2 to 82 months after BMT. Vaccination before
the 6th month was totally ineffective and the second dose
did not add substantial benefit in terms of specific
response and its indication is therefore questionable.
Preliminary results of a study evaluating the use of
GM-CSF (2.5 µg/kg) as an immunomodulating factor to
enhance the response to influenza vaccination showed a
limited benefit, mostly in those vaccinated before the
first year after BMT. Since side effects were not
negligible, its use deserves further investigationref.
Idiopathic
thrombocytopenic
purpura
after influenza vaccination in a bone marrow
transplantation recipientref
other vaccines and perspectives
varicella
vaccine : no data are available concerning the
safety and effectiveness of live-attenuated varicella
vaccine before the first year of transplantation, when the
risk of varicella- zoster virus (VZV) reactivation is
higher. Sauerberi et al.ref
did not observe any case of chickenpox or herpes zoster
for up to 2 years after vaccination in 15 patients who
received one dose of VZV vaccine 12 to 23 months after
BMT. These data are difficult to interpret since the
occurrence of zoster is expected around the sixth month
after transplantation and the risk of a second episode is
less than 5% in this population. Thus, few patients would
be really "at risk" after the first year of
transplantation and the benefit of late vaccination would
be minimal. Redman et al.ref
heat-inactivated the live-attenuated vaccine and observed
diminished clinical severity of zoster in patients who
received three doses of the inactivated vaccine 1, 2 and 3
months after BMT. These data suggested that the process of
inactivation did not eliminate the immunogenicity of the
vaccine, which apparently conferred some protection. Based
on this observation, Hata et al.ref
recently demonstrated that 4 doses of the inactivated
varicella vaccine given before hematopoietic cell
transplantation and during the first 90 days thereafter (1
dose at +30, +60 and +90) reduced the risk of zoster in
autologous BMT recipients. The protection was correlated
with the reconstitution of CD4 T cell immunity against
VZV. The safety and effectiveness of the attenuated
varicella vaccine administered to recipients during the
first 6 months after autologous and allogeneic BMT remain
to be demonstrated in controlled trials.
other licensed vaccines have been recommended on an
individual basis.
hepatitis B vaccine has been
recommended after the first year of BMT in countries
where the infection is common and children are routinely
immunized against hepatitis B. In the setting of BMT,
hepatitis B vaccine has been evaluated in different
circumstances: to immunize susceptible patients after
transplantation and also to adoptively transfer
hepatitis B immunity through vaccination of the donors
before marrow harvesting. Surprisingly, few data are
available concerning the effectiveness of hepatitis B
vaccine in BMT recipients and the duration of immunity
after vaccination. Nagler et al.ref
observed seroconversion rates of about 70% within 40
days of transplantation in autologous BMT recipients
receiving a single dose of hepatitis B vaccine
immediately before or after transplantation. Transient
seroconversion was seen in about 35% of the patients.
Ilan et al.ref
demonstrated transfer of hepatitis B immunity in the
first 45 days of transplantation from donors vaccinated
before marrow harvesting. Adopting the classical
vaccination schedule proposed for immunocompetent hosts,
Machado et al. (Machado CM, Rocha IF, Diomede B et al.
(1996). Effectiveness of hepatitis B vaccination and
persistence of immunity after BMT (Abstract). The Ninth
International Symposium on Infections in the
Immunocompromised Host. Assisi, Italy, June 23-26, 1996)
observed 100% seroconversion in 50 patients vaccinated
after the first year of BMT. However, one year after
vaccination nearly 60% of the patients had lost
hepatitis B immunity. Sustained immunity was more likely
to occur in children and in subjects without chronic
GVHD. Interestingly, time to vaccination did not
influence the response to vaccination or the duration of
immunity, suggesting that no benefit is added by
postponing hepatitis B vaccination after the first year
of BMT. Maintenance of immune memory to the hepatitis B
envelope protein following adoptive transfer of immunity
in bone marrow transplant recipientsref.
The EBMT recommends rHBV starting 6-12 months after HCT.
Immunization is optional in the CDC guidelines.
Nevertheless, rHBV is required for re-entry to school
and certain workplaces. To determine the immunogenicity
of rHBV following HCT, the pre and post vaccine titers
of 292 allogeneic transplant recipients who were
immunized with rHBV were analyzed. Immunization was
initiated in patients off immunosuppression who achieved
specific minimal milestones of immune competence.
Overall, 64% of patients seroconverted. In
multivariate analyses, response was adversely
affected by age >18 years (p<0.01) and history
of prior chronic GVHD (p<0.0001) but not by donor
type, use of T cell depletion, adoptive immunotherapy,
or rituximab. By comparison, 89% of rHBV
non-responders mounted a 3 fold rise in polio titers
following 3 doses of inactivated poliovirus. These data
demonstrate that the rate of seroconversion following
rHBV is lower in allogeneic HCT recipients compared with
age matched normal controls. The data emphasize the need
to document pre and post vaccine titers to ensure
response and suggest that immunization guidelines based
on time interval from HCT, irrespective of immune
competence, may not ensure adequate protection against
certain vaccine preventable diseasesref.
there are no data on the use of inactivated hepatitis A
vaccine in transplant recipients. Considering the
efficacy of the vaccine in healthy subjects and the
recommendation of vaccination to travelers to endemic
areasref,
studies evaluating the safety and effectiveness of
hepatitis A vaccine would be of great importance in this
population. Children submitted to BMT and recipients
traveling to such areas would benefit from hepatitis A
vaccination. In a study in Brazil, the prevalence of HAV
antibodies was 92.2% before BMT. As vaccine was not
available in Brazil when the samples were taken, it was
assumed that this prevalence reflects natural infection.
Survival analysis showed that the probability of
becoming seronegative was 4.5% (+/-2.6%), 7.9%
(+/-3.4%), 10.1% (+/-4.0%), 23.4% (+/-9.6%) at
1, 2, 3 and 4 years after transplant,
respectively. The loss of HAV antibodies was
significantly associated with longer follow-up
(P=0.0015), younger age (P=0.049) and aGvHD
(P=0.035). As most reimmunization protocols start around
day +365, in developing countries with similar HAV
endemicity, BMT recipients should have serological
screening before HAV vaccination and the inactivated
vaccine should be advised to those seronegativeref.
"herd immunity" states that when enough people in a
community are immunized, all are protected. For the MMR vaccine,
that proportion is 95%. Anyway, there are many documented
instances showing just the opposite, i.e. fully vaccinated
populations do contract diseases (measles, Hib meningitis, ...)
epidemiological studies : if 100 people are
vaccinated and 5 contract the disease, the vaccine is declared
to be 95% effective. But if only 10 of the 100 were actually
exposed to the disease, then the vaccine was really only 50%
effective. Since no one is willing to directly expose an entire
population to disease--even a fully vaccinated one--vaccine
effectiveness rates may not indicate a vaccine's true
effectiveness.
age : an 8 pound 2 month old child receives the same
dosage as a 40 pound 5 year old : infants with immature,
undeveloped immune systems may receive 5 or more times the
dosage (relative to body weight) as older children !
the number of "units" within doses has been found
upon random testing to range from 1/2 to 3 times what the label
indicates; manufacturing quality controls appear to tolerate a
rather large margin of error. "Hot Lots" (vaccine lots
with disproportionately high death and disability rates) have
been identified repeatedly by the NVIC, but the FDA has never
recalled a vaccine lot due to adverse reactions : some would
call this infanticide.
race, culture, diet, geographic location of recipients
this was perhaps never more dramatically disproved than an
instance a few years ago in Australia's Northern Territory,
where stepped-up immunization campaigns resulted in an
incredible 50% infant mortality rate in the native aborigines.
The aborigine's vitamin C deficient "junk food" diet
(imposed on them by white society) was a critical factor
(vaccination depletes vitamin C reserves; children in shock or
collapse often recovered in a matter of minutes when given
vitamin C injections).
the risk of contracting polio from the vaccine correlates
with injections of antibiotics : a single injection
within one month of vaccination raised the risk of polio 8
times, 2 to 9 injections raised the risk 27-fold, and 10 or
more injections raised the risk 182 times.
Copyright © 2001-2013
Daniele Focosi. All
rights reserved | Terms of use | Legal notices
Cite
this
page! 
