VACCINES (VACCINOLOGY)
(see also therapeutic vaccines)


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Table of contents :
 
  • Active pharmaceutical ingredients (APIs)
  • Adjuvants
  • Summary of common vaccine combinations
  • Induction of CTL responses
  • Adverse effects
  • Warnings
  • vaccination in pregnants
  • vaccination of the immunocompromised hosts
  • hematopoietic stem cell transplant recipients
  • solid organ transplant recipients
  • Bibliography
  • Other web resources

  • In 2002 11 million infants living in under-developed countries died from vaccine-preventable diseases


    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 :

    Recommendations : Regulations : People avoid vaccines for several reasons. The paramount reason, fear (vaccinophobia), knows no geographic or cultural boundaries. But vaccines work : in USA ... Vaccine wishlist :

    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 ...

    Requirements for successful specific immunotherapy : The development of successful vaccines requires the inclusion of a mixture of epitopes for the induction of an effective immune response that 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 :

    Prime-boost is a 2-part process : 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 :

    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.
    delivery system
    antigen
    disease group
    immunogenicity
    clinical outcome
    fusion protein (TA-CIN, Xenova)ref HP16 L2-E6-E7 fusion protein (no adjuvant) healthy volunteers antibody, T-cell proliferation, IFN-g ELISPOT all detected double-blind placebo-controlled trial : no HPV infection
    HSP fusionref (HSP-E7, Stressgen) HPV16 E7 genital warts N.D. regression of warts: 3/14 CRs and 10/14 PRs. Warts not HPV16-. Open-label uncontrolled trial
    encapsulated polynucleotide (ZYC101, Zycos)ref1, ref2 HPV16 E7 peptide anal dysplasia 
    cervical dysplasia
    most individuals ELISPOT positive 
    induction of E2-specific immunity
    HPV16- by selection 
    Open-label uncotntrolled trials 
    Regression of AIN : 3/12 PRs 
    Regression of CIN : 5/15 CRs
    protein/iscomatrix adjuvant (E6E7-IMX, CSL) HPV16 E6-E7 fusion protein CIN antibody, DTH, CTLs HPV-type-specific reduction in HPV infection: 7/14 CRs and 7/14 PRs/no clinical regression 
    Randomized placebo-controlled trial
    vaccinia virus (TA-HPV, Xenova)ref E6-E7 fusion protein cervical cancer CTLs (1/8), antibody (3/8) outcome not documented 
    open-label uncontrolled trial
    vaccinia virus (TA-HPV, Xenova)ref E6-E7 fusion protein vulvar HPV/VIN antibody, CMI (13/18) 50% reduction in disease in 8/18 
    loss of viral load in 12/18
    open-label uncontrolled trial
    vaccina virus (TA-HPV, Xenova)ref E6-E7 fusion protein VIN T helper cell ELISPOT increase (6/10); vaccinia response in all subjects > 50% reduction in disease in 5/12 
    open-label uncontrolled trial
    peptide/oil + water adjuvantref E7 peptides cervical cancer no CTL response HPV16- by selection 
    outcome 2/17 SD 
    open-label uncontrolled trial
    protein/algammulin adjuvant E7-GST fusion protein cervical cancer antibody, DTH no alteration in natural history of disease 
    open-label uncontrolled trial
    peptide + IFAref E7 A0201 peptide VIN/CIN CTLs 10/16, no DTH HPV16- by selection 
    3/18 CRs and 6/18 PRs 
    open-label uncontrolled trial
    VLPs without adjuvantref HPV6b L1 genital warts antibody, DTH regression of warts: 25/33 CRs 
    open-label uncontrolled trial
    dendritic cellsref HPV16 E7 and HPV18 E7 cervical cancer antibody, proliferation, ELISPOT (3/11) 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
    Summary of common vaccine associations : 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 :

    Web resources : Contraindications for Childhood Immunization at CDC

    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 :

    The immunogenicity of vaccines does not always correlate with their reactogenicity.
    Pathogenesis : Symptoms & signs : Warnings  Bibliography : Other web resources :
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