VARIOLA VIRUS (VARV) (from the Latin varius (spotted) or varus (pimple))
Table of contents :

  • Epidemiology
  • Genomics
  • Proteomics
  • Transmission
  • Pathogenesis
  • Symptoms & signs
  • Therapy
  • Experimental animal models
  • Web resources

  • Epidemiology : smallpox originated in Northeastern Africa around 10000 BC (mummified remains of the 18th Egyptian dinasty (1580 to 1350 BC) and of the better known Pharaoh Ramses V (1157 BC)). An epidemic occurred in Athens in 430 BC and is described by Thucydides. In 1096-1291 crusaders bring smallpox back to Europe and between 1400 and 1800 fatalities routinely exceed 500,000 / yr. In 1520 smallpox caused collapse of naive Aztec and Incan Empires after arrival of Spanish conquistadors and in 1763 it was first used as a bioweapon against native American Indians.

    In 1966 the WHO undertake a vaccination campaign to eradicate variola virus by using anti-Orthopoxvirus attenuated vaccine Below is the document signed on December 9, 1979, by members of the WHO Global Commission, certifying that smallpox had been eradicated : the document became public at the World Health Assembly on May 8, 1980.

    Eradication was obtained thanks to : Genomics : Proteomics : Environmental resistance : Transmission : inhalatory (saliva droplets) or percutaneous route (rarely from scabsref due to tightly binding in its fibrin matrix); this is an anthroponosis with no known reservoir
    Pathogenesis : typically enters the host through the oropharynx, invades the mucosal epithelium, and migrates to regional lymph nodes => asymptomatic viremia => multiplication of virus in the spleen, the bone marrow and other lymph nodes, where viral replication occurs => secondary viremiaref. After an incubation period of 12–14 days, virus enters the blood within leukocytes, which seed the skin and produce the characteristic skin lesions (pox), whereas most other tissues are spared. The fact that virus seems to travel in leukocytes that specifically exit blood vessels in the papillary dermis indicates that variola virus preferentially associates with leukocytes that can home to skin; alternatively, it might be that only skin tissues can support the subsequent replication steps that are required for lesion formation.
    Symptoms & signs : ordinary smallpox / Kaffir pox (a.k.a. vaiolo in Italy; poc or pocca = a bag or pouch; as opposed to great pox or syphilis) => 7-17 days incubation => 2-5 days with high fever, malaise, prostration, headache and backache => infected macrophage in small vessels of the dermis migrate into and infect basal layers of the epidermis => necrosis and edema => maculopapular exanthema on mouth and oropharynx (=> ulcer => saliva => contagion source, expecially in the first week of illness, after onset of rash), face, forearms => trunk and legs, all at the same stage of development => vesicular within 48 hrs => round and tense pustule deeply embedded in the dermis => about 8 days after onset of the rash, the pustules dry up and become crusts by day 14 => by the end of the third week crusts detach leaving pigment-free pockmark (a depressed scar). 33% lethality within 2 weeks due to : Blindness was a rare complication, usually occurring in cases where there was malnutrition and/or a secondary bacterial infection. Cases of smallpox among pregnant women often resulted in spontaneous abortion of the fetus or a stillborn infant with evidence of lesions on the skin.
    Whitepox is the name given to 4 isolates alleged to derive from kidneys of African monkeys and Rodentia in the early 1970s, which are distinguishable by Variola virus only for inducing white pocks in chorioallantoic membrane : no taxonomy allocation as been purposed.
    A milder form of disease was seen among those who had partial immunity : Depending on whether the rash is present and its density, this variety is divided into 4 types : Variola virus did not persist in the body after recovery. Upon recovery, neutralizing antibodies were long-lasting, whereas HA-inhibiting antibodies declined to low levels within 5 years, and complement-fixing antibodies rarely persisted for longer than 6 months. Little is known about the development of CMI.
    Probability of infection for unvaccinated close contacts = 40-90%.
    Complications : Therapy : Although the preventive use of smallpox vaccination has been well documented, little is known about its efficacy when used after exposure to the virus. Here we compare the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir or with a related acyclic nucleoside phosphonate analogue (HPMPO–DAPy) after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). MPXV causes a disease similar to human smallpox and this animal model can be used to measure differences in the protective efficacies of classical and new-generation candidate smallpox vaccines. Initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes. These data show that adequate preparedness for a biological threat involving smallpox should include the possibility of treating exposed individuals with antiviral compounds such as cidofovir or other selective anti-poxvirus drugsref

    At a meeting in Geneva on 4-5 Nov 2004, the Advisory Committee on Variola Virus Research voted to recommend approval for genetically altering the smallpox virus with GFP to speed up the screening of anti-smallpox drugs and help to use up the last remaining stocks of the virus. In practice the proposal will first be seen by the WHO executive board and director general before it is considered by the World Health Assembly in May 2005. the marker would accelerate screening by factors of 10 or 100. It would also reduce the amount of time that lab workers would need to be in BSL-4 labs handling live variola virus. The committee's first proviso for its recommendation is that the research must only be done in the 2 laboratories currently handling live variola, at the CDC in the USA and at Novosibirsk in Russia. The second is that the proposal must also be put to the relevant institutional and national safety committees and submitted to the scientific subcommittee of the Advisory Committee on Variola Virus Research. According to WHO, the committee requested more detailed research proposals and a full safety assessment. There is some concern about the stability of the large virus and a small risk of increasing virulence. The committee also made at least 6 other research recommendations that would allow labs around the world to work with fragments of the variola virus as large as 20% of the whole genome : some consider this a problem because different labs with different chunks "would only have to link them together, and it would be a lot easier" to recreate the entire smallpox genome than it would be to synthesize it. They believe a 10–15% threshold would be preferable because the 20% threshold corresponds to about 37,000 bp, a too large a number. The proposals would also permit the 2 smallpox repository labs—one at the CDC and the other at Novosibirsk in Russia—to insert variola genes one at a time into other viruses in the orthopox family, like monkey pox and cowpox, to create a better model for drug screening, as they can be worked on at lower containment levels than the BSL-4 that smallpox requires, but anyway at one higher BSL than each orthopox virus normally requires. 2 other recommendations would allow the Russian and American teams to share their smallpox samples with one another for the first time and to perform experiments on variola and other orthopox viruses simultaneously, provided the work is performed at BSL-4. Another 2 propose that other researchers elsewhere be permitted to synthesize smallpox fragments up to 500 bp in their labs but prohibited from synthesizing longer ones and, with microarrays, permitted to include the whole variola genome, just as long as individual array fragments are no longer than 80 bp. The 6 recommendations the committee approved last week were all proposed by its technical subcommittee in 2003ref.
    The World Health Organization (WHO) announced on Fri 18 May 2007 that it is postponing for at least 4 years any decision on when to destroy the world's last known stockpiles of smallpox virus, a deadly virus eradicated nearly 30 years go. There is no treatment for the viral disease that killed millions of people a year as recently as the 1960s and left many more blind and scarred. In 1979, it became the 1st disease officially stamped out after a worldwide vaccination campaign. The United States and Russia, however, which hold the only known stockpiles of the virus in high-security laboratories, have long resisted calls to destroy them in case smallpox is found to exist elsewhere. The 60th annual World Health Assembly, the top decision-making body of the United Nations agency, reaffirmed a previous commitment to destroy the remaining stockpiles, but agreed to postpone any decision on when this should happen until its 2011 meeting. In 2010, the WHO secretariat will carry out a review of all research undertaken and still planned, in order that the 64th World Health Assembly may reach global consensus on the timing of the destruction of existing variola smallpox virus stocks. A previous 2002 deadline for destroying smallpox virus was delayed by WHO until new vaccines or treatments for smallpox were found, after the United States said it would keep stocks on hand to combat any re-emergence of the
    disease. That decision was made in the wake of the "September 11" suicide plane attacks on the United States, which stirred fears that deadly viruses could fall into the hands of terrorist groupsref.
    Experimental animal models : none except IV inoculation in monkeys.
    It is considered by CDC as a category A biological weapon.

    Web resources : Bibliography : Cyril W. Dixon's : Smallpox. (London: J. & A. Churchill, Ltd., 1962)

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