BMJ  2007;334:760 (14 April), doi:10.1136/bmj.39177.580729.BE

Editorials

Stockpiling smallpox virus

Other viruses pose greater public health threats, so isn't it time to move on?

Emotions still run high over the stocks of smallpox virus placed into the P4 freezers of Atlanta and Novosibirsk more than 30 years ago by the World Health Organization. In this week's BMJ, two articles present opposing views on whether the United States and Russia should destroy their stocks of smallpox virus (Variola).^{1 2}

One argument for maintaining smallpox stocks is that they are needed to develop safer vaccines.¹ Our current effective vaccine is safe when used judiciously—not for mass vaccination of populations, but for targeting those at risk after screening out people with a history of HIV, leukaemia, or eczema at higher risk of complications after vaccination.³ Moreover, new vaccines are based on Vaccinia, not smallpox.⁴ No new vaccine can be tested for efficacy until human cases of smallpox reappear.

Another argument is that smallpox stocks are needed to assess antiviral agents for the treatment of smallpox. Again, no agent can be properly tested until human cases reappear. Moreover, the production of an effective antiviral is unlikely to be profitable, given the likely number of cases, and the altruism of manufacturers will probably be limited. An antiviral agent might even be of limited use in practice. Many cases are identified late, after the appearance of irreversible sequelae. Others are identified at exposure, well before onset of symptoms, when vaccination provides substantial protection and reduces the mortality rate if not the occurrence. Immunoglobulin from vaccinated people and even from survivors of smallpox (the first available and the second theoretically available) could similarly modify outcomes.

A third argument is that stocks are needed to develop better diagnostic tests. We already have rapid and sensitive tests for orthopoxvirus.⁴ The need to distinguish between smallpox and zoonotic orthopoxviruses would not be an immediate priority in the context of potential terrorism, as the emergency test should emphasise sensitivity, not specificity. If the introduction of smallpox did produce multiple cases, the epidemiological pattern of severity would provide a fairly accurate diagnosis. In fact, the unique appearance of a patient with early severe smallpox would quickly be disseminated via the media, and subsequent cases would be recognised by lay people. Control would proceed whether or not every diagnosis had been confirmed. Even the classic differential diagnostic alternative of Varicella poses few problems in an unvaccinated population, as confusion in the past was created largely by smallpox modified by past vaccination.

So what then are the arguments for destroying smallpox stocks? The major benefit of destroying the stocks is a reduction in the probability that smallpox cases will reappear.² The virus originally stored in one of these facilities may be the only source available, because as time goes by with no indication to the contrary it becomes less likely that other clandestine stocks exist. The danger of escape is increased by dissemination to investigators and other laboratories.

However, even if smallpox were to be introduced into the population, it would not attain the proportions that it did in medieval times. Under current Western social circumstances of small family size and highly efficient communication, the number of cases is unlikely to be large.⁵ Most cases of smallpox are acquired at the bedside, whether in urban hospitals⁶ or in rural villages,⁴ and transmission between houses occurs through social relationships. If a large outbreak did occur, it would probably be the result of simultaneous exposures to the same (hospital) bedside rather than extended transmission.⁶ If a chain of transmission does not die out on its own, it would quickly be contained by the standard control techniques of public health and hospital epidemiologists.⁵ The unique appearance of an infectious case; the interval of roughly two weeks between exposure and symptoms; and the triad of surveillance, isolation, and effective vaccination would act together to ensure that control is established within a few case generations. Neither a widespread nor a long term epidemic is probable, whether judged from past history,⁶ from extrapolation of the experience with severe acute respiratory syndrome,⁷ or from any of the recent mathematical models.^{8 9 10 11} The net impact of an introduction would be comparable to a large common source outbreak of a severe disease caused by an agent such as hantavirus or encephalitis virus, although that impact might be substantially augmented by complications if mass vaccination were to be initiated.⁵

Thus, a case can be made for destroying the stocks, given the absence of compelling contrary arguments, although the stocks do not pose a great threat. Destroying the stocks would have two added benefits—it would fulfil the commitment made by the US in 1990 to destroy stocks after the genome had been identified and it would circumvent any pressures to return stocks to their countries of origin.²

Another real benefit would be the permanent elimination of this question as a distraction. More important problems need to be dealt with. Even more dangerous viruses may be found in P4 and lesser facilities. Release of the highly virulent recombinant 1918 influenza virus would be a real catastrophe,¹² yet retention and distribution of recombinant strains for study is enthusiastically justified on the basis of the need for effective prevention, diagnosis, and treatment.

Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

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Competing interests: None declared.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. Agwunobi JO. Should the US and Russia destroy their stocks of smallpox virus? No. BMJ 2007 doi: 10.1136/bmj.39156.490799.BE[Free Full Text]
2. Hammond E. Should the US and Russia destroy their stocks of smallpox virus? Yes. BMJ 2007 doi: 10.1136/bmj.39155.695255.94[Free Full Text]
3. Grabenstein JD, Winkenwerder W Jr. US military smallpox vaccination program experience. JAMA 2003;289:3278-82.[Abstract/Free Full Text]
4. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. History of international public health no 6. Geneva: WHO, 1988.
5. Mack TM. A different view of smallpox and vaccination. N Engl J Med 2003;348:460-3.[Free Full Text]
6. Mack TM. Smallpox in Europe, 1950-1971. J Infect Dis 1972;125:161-9.[ISI][Medline]
7. Mack TM. Ghosts of pandemics past. Lancet 2005;365:1370-2.[CrossRef][ISI][Medline]
8. Eichner M. Case isolation and contact tracing can prevent the spread of smallpox. Am J Epidemiol 2003;158:118-28.[Abstract/Free Full Text]
9. Kretchmar M, van den Hof S, Wallinga J, van Wijngaarden J. Ring vaccination and smallpox control. Emerg Infect Dis 2004;10:832-41.[ISI][Medline]
10. Eubank S, Guclu H, Kumar VS, Marathe MV, Srinivasan A, Toroczkai Z, et al. Modelling disease outbreaks in realistic urban social networks. Nature 2004;429:180-4.[CrossRef][Medline]
11. Riley S, Ferguson NM. Smallpox transmission and control: spatial dynamics in Great Britain. Proc Natl Acad Sci USA 2006;103:12637-42.[Abstract/Free Full Text]
12. Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, Ebihara H, et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 2007;445:2319-23.

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