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EDITORIALS: Thomas Mack Stockpiling smallpox virus BMJ 2007; 334: 760 [Full text]

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Smallpox – still a concern

Dennis E. Hruby, Robert Jordan, Douglas W. Grosenbach, and Tove' C. Bolken.   (11 May 2007)

Smallpox – still a concern 11 May 2007
Dennis E. Hruby, Chief Scientific Officer SIGA Technologies, Inc 4575 SW Research Way, Suite 230 Corvallis, OR 97333, Robert Jordan, Douglas W. Grosenbach, and Tove' C. Bolken. Send response to journal: Re: Smallpox – still a concern	In the April issue of BMJ, two articles appeared which expressed opposing opinions on the question of whether existing stocks of smallpox virus should be destroyed 1 2. In an editorial concerning these contributions, Dr. Mack took the view that “other viruses pose greater public health threats, so isn’t it time to move on?” 3 He favored the destruction of existing smallpox stocks and discounted the need for improved vaccines, antiviral drugs and better diagnostic tests. We take issue with this conclusion and his supporting arguments. First, the threat of human orthopoxvirus disease is still very real. Although smallpox was declared eradicated in 1979 4, it exists in freezers at CDC and Russia and is believed to exist elsewhere as well 5 6. Based on this, it has been subjected to a Material Threat Assessment Analysis by the U.S. government and declared a bona fide threat 7. Furthermore, the threat of orthopoxvirus disease is not limited to smallpox. Monkeypox virus is endemic in Africa and genetically-engineered poxvirus bioweapons are certainly within the competency of a determined individual. Likewise, viruses such as cowpox virus or camelpox virus, exist in nature and are highly similar to smallpox virus 8. None of us can predict how many mutations or recombination events may be required to turn these benign viruses into the next pandemic agent. Thus, we would argue having effective countermeasures available will both provide therapeutic options for patients today and as an insurance policy against future poxvirus pathogens. Second, Dr. Mack discounts the need for continued vaccine research as we have an effective vaccine that “is safe when used judiciously”3. In the event of a bioterrorism attack we will not have the luxury of time or pre-screening. Rather a vaccine will be widely given to the exposed populace. As the current vaccine is contraindicated for use in as many as 25 % of the population 9, this will undoubtedly result in extensive and unnecessary morbidity and mortality 10 11. There is still a need for improved vaccines and ways to make existing vaccines safer. Third, despite Dr. Mack’s pessimism a number of smallpox antiviral drugs are in development by the biotechnology industry, most notably ST- 246 12. ST-246 is an extremely potent, selective and non-toxic drug 12. In animal trials ranging from mice to non-human primates it has shown the ability to prevent death and all clinical manifestations of disease, even when administered late in the disease course 12-15. Thus this drug seems to provide both prevention and treatment of disease in the animals, and will likely extend to the human. There currently are no therapeutic options available to treat smallpox patients. Furthermore, co- administration of the drug together with vaccine in animals appears to improve immunogenicity and is likely to reduce side-effects, thereby ameliorating some of the issues with the current vaccine 16. Fourth, the need for real-time diagnostic capabilities remains high. As the recent case of eczema vaccinatum in Chicago illustrates 17 18, it is critical to quickly and accurately identify disease etiology. Distinguishing between herpes, contact dermatitis, staphylococcal infection and smallpox is essential to provide the correct therapy and supportive care, and to protect the care-givers and surrounding populace. Finally, Dr. Mack argues that even in the event smallpox is introduced into the population, it can and will be contained by “the standard control techniques of public health and hospital epidemiologists” 3. He uses SARS and hantaviruses as examples to support his conclusion. SARS is not smallpox. Smallpox is the most efficient and deadly human pathogen ever described. It is highly unlikely that current public practices would work as well as Dr. Mack envisions. Recall the outbreak of monkeypox, which is far less infectious and transmissible that smallpox, in the Midwestern States of the U.S. in 2003 19-21. Seventy-one infections occurred before this agent was identified and the infections contained 19. In the case of a smallpox index case, this would undoubtedly be worse as would be the consequences. Furthermore, we are again concerned not only with a “naturally occurring” case of smallpox but also a potential bioterrorism incident. In this case, one would predict the virus would be disseminated in a crowded public location, such as an airport terminal. With the prolonged incubation of the virus (18-21 days until identifiable symptoms appear) coupled with rapid movement of those infected, this would be a potential global catastrophe by the time the sentinel case was identified. The scientific and medical community all fervently hope that we have seen the last of smallpox, but the risk remains and it is real. We believe that it is incumbent upon us to collectively marshal the scientific capabilities of the 21st century to provide effective countermeasures to protect the populace from the consequences of orthopoxvirus infections. Until this goal is achieved, and so long as regulatory agencies ascribe to the view that approved products require testing against the authentic agent, we cannot indulge ourselves in the intellectual comfort that a symbolic destruction of the known US and Russian stocks of smallpox virus would afford. References 1. Agwunobi JO. Should the US and Russia destroy their stocks of smallpox virus? Bmj 2007;334(7597):775. 2. Hammond E. Should the US and Russia destroy their stocks of smallpox virus? Bmj 2007;334(7597):774. 3. Mack T. Stockpiling smallpox virus. Bmj 2007;334(7597):760. 4. Poland GA, Grabenstein JD, Neff JM. The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation program. Vaccine 2005;23(17-18):2078-81. 5. Henderson DA. The looming threat of bioterrorism. Science 1999;283(5406):1279-82. 6. Henderson DA, Inglesby TV, Bartlett JG, Ascher MS, Eitzen E, Jahrling PB, et al. Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. Jama 1999;281(22):2127- 37. 7. HHS Public Health Emergency Medical Countermeasure Enterprise Implementation Plan for Chemical, Biological, Radiological and Nuclear Threats. In: DHHS, editor, 2007:http://www.hhs.gov/aspr/documents/phemce_implplan_041607final.pdf. 8. Gubser C, Hue S, Kellam P, Smith GL. Poxvirus genomes: a phylogenetic analysis. J Gen Virol 2004;85(Pt 1):105-17. 9. Bartlett J, Borio L, Radonovich L, Mair JS, O'Toole T, Mair M, et al. Smallpox vaccination in 2003: key information for clinicians. Clin Infect Dis 2003;36(7):883-902. 10. Fulginiti VA, Papier A, Lane JM, Neff JM, Henderson DA. Smallpox vaccination: a review, part II. Adverse events. Clin Infect Dis 2003;37(2):251-71. 11. Kemper AR, Davis MM, Freed GL. Expected adverse events in a mass smallpox vaccination campaign. Eff Clin Pract 2002;5(2):84-90. 12. Yang G, Pevear DC, Davies MH, Collett MS, Bailey T, Rippen S, et al. An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus Challenge. J Virol 2005;79(20):13139-49. 13. Huggins J, Goff A, Eric M, Twenhafel N, Chapman J, Tate M, et al. Successful Treatment in the Monkeypox and Variola Primate Models of Smallpox by the Oral Drug ST-246. 20th International Conference on Antiviral Research. Westin Mission Hills Resort, Palm Springs, California, 2007. 14. Quenelle DC, Buller RM, Parker S, Keith KA, Hruby DE, Jordan R, et al. Efficacy of delayed treatment with ST-246 given orally against systemic orthopoxvirus infections in mice. Antimicrob Agents Chemother 2007;51(2):689-95. 15. Sbrana E, Jordan R, Hruby DE, Mateo RI, Xiao SY, Siirin M, et al. Efficacy of the antipoxvirus compound ST-246 for treatment of severe orthopoxvirus infection. Am J Trop Med Hyg 2007;76(4):768-73. 16. Grosenbach DW, Jordan R, King DS, Warren TK, Kirkwood-Watts D, Berhanu A. Immune responses to smallpox vaccine given in combination with ST-246, a small-molecule inhibitor of poxvirus dissemination. Manuscript in preparation 2007. 17. Manier J. Smallpox shot infects soldier's toddler son - Boy critically ill; mom also stricken Chicago Tribune 2007 March 17. 18. Fox M. Child Develops Eczema Vaccinatum After Father Has Smallpox Vaccination. Reuters Health Information 2007. 19. CDC. Update: Multistate Outbreak of Monkeypox - Illinois, Indiana, Kansas, Missouri, Ohio, and Winsconsin, 2003. MMWR Weekly 2003;52(27):642- 646. 20. Guarner J, Johnson BJ, Paddock CD, Shieh WJ, Goldsmith CS, Reynolds MG, et al. Monkeypox transmission and pathogenesis in prairie dogs. Emerg Infect Dis 2004;10(3):426-31. 21. Kile JC, Fleischauer AT, Beard B, Kuehnert MJ, Kanwal RS, Pontones P, et al. Transmission of monkeypox among persons exposed to infected prairie dogs in Indiana in 2003. Arch Pediatr Adolesc Med 2005;159(11):1022-5. Competing interests: All of the authors listed on this rebuttal letter are employees of SIGA Technologies, Inc, the company responsible for the development of ST-246.