David J. McClain, MD
Article Type: 
Feature Article
Winter 2001
Volume Number: 
Issue Number: 

The concept of using variola virus in warfare is an old one. British colonial commanders considered distributing blankets from smallpox victims among Native Americans as a biological weapon.(1-3) During the American Civil War, allegations were made about the use of smallpox as a biological weapon, although there subsequently proved to be no definite evidence for such.(4,5) In the years leading up to and during World War II, the Japanese military explored weaponization of smallpox during the operations of Unit 731 in Mongolia and China.(6,7)

Nevertheless, the actual potential of variola virus as a biological weapon remains controversial. Given the ease of administration and the availability of the vaccinia virus as a vaccine against smallpox,(8) some have argued that smallpox would have limited biological warfare potential.(9) The Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, presently maintains over 12 million doses of vaccinia vaccine in storage, and WHO has in storage enough vaccine to protect 200 to 300 million people.(10) On the other hand, the potency of stockpiled vaccine will gradually decline. The discontinuation of routine vaccination has rendered civilian and military populations more susceptible to a disease that is not only infectious by aerosol but also infamous for its devastating morbidity and mortality. WHO voiced concerns that smallpox "can easily be produced in large quantities in the laboratory and...freeze-dried and its virulence thus preserved for months or years."(11)

Since 1983, there have existed two WHO-approved and -inspected repositories of variola virus: the CDC in the United States and Vector Laboratories in Russia. WHO continues to debate whether, given the completion of sequencing of several reference strains, all stocks of variola virus should be destroyed. Proponents of retaining these smallpox stocks argue that military or terrorist use of variola virus as a weapon would readily be countered by rigorous case contact evaluation and vaccination. Furthermore, they reason that even if the repositories are eliminated, other potential sources of smallpox exist:

° Given the fact that viable variola virus could be recovered from scabs up to 13 years after collection,(12) it is conceivable that cadavers preserved in permafrost(13) or dry crypts(14) could release the virus.

° Virus specimens from the smallpox-eradication campaign may remain unrecognized or unreported.

° Using the published sequence of variola and its significant homology with other Orthopoxviruses, a malevolent laboratory could theoretically engineer a recombinant virus exhibiting variola virus's virulence by starting with monkeypox virus.

Additionally, in the event that smallpox should reemerge under one of the above scenarios, destroying the legitimate repositories of variola virus would hinder investigation into both (a) the mechanisms of viral pathogenesis, so as to effect countermeasures, and (b) detailed molecular epidemiology, so as to establish the precise phylogenetic relationship of an isolate to other known strains. Lastly, extinction of smallpox would disallow study of its unique proteins that interfere with host immune and regulatory functions (e.g., homologues of epidermal growth factor, transforming growth factor, interleukin-1B, interferon-y, and zinc-finger protein).(15,16)

Those who advocate eradication of the official variola virus repositories cite the possibility of accidental or intentional release of the virus as a threat to international public health; political instability in Russia has reemphasized this concern. In addition, retention of these repositories might legitimize clandestine stockpiling or offensive biological warfare research on variola virus. Even if a virulent variola-like poxvirus could be engineered by an offensive biological warfare power, the lack of an animal model that accurately reflects human pathology(17) would severely limit how it could be selected and tested. From the standpoint of understanding Orthopoxvirus biology, published sequence information on variola would be adequate to confirm the identity of any smallpox-like virus that might emerge in the future. Finally, further studies on poxvirus pathogenesis would be much more safely and successfully pursued using a poxvirus that does possess a good animal model, such as ectromelia (i.e., mouse pox).(18) Despite the promise of variola virus's extinction as a biological entity, the prospect of surreptitious weaponization of smallpox remains vexing, and vaccination of military personnel could be seen as a defensive posture implying willingness to use variola virus as a weapon.(19)


1. Heagerty JJ. Four Centuries of Medical History in Canada. Vol 1. Toronto, Ont, Canada: MacMillan; 1928.
2. Parkman F. The Conspiracy of Pontiac. Vol 2. Boston, Mass: Little, Brown; 1969: 44-46.
3. Stearn EW, Stearn AE. The Effects of Smallpox on the Destiny of the Amerindians. Boston, Mass: Bruce Humphries; 1945:44-45.
4. Kean RGH. Inside the Confederate Government. New York, NY: Oxford University Press; 1957: 89.
5. Steiner PE. Disease in the Civil War: Natural Biological Warfare in 1861-1865. Springfield, III: Charles C Thomas;1968:42-43.
6. Harris R, Paxman J. A Higher Form of Killing. New York, NY: Hill and Wang; 1982: 76-79,153.
7. Williams P, Wallace D. Unit 731: Japan's Secret Biological Warfare in World War II. New York, NY: Free Press; 1989:28,213.
8. Henderson DA. The eradication of smallpox. In: Last JM, ed. Maxcy-Rosenau Public Health and Preventive Medicine. 12th ed. Norwalk, Conn: Appleton-Century-Crofts; 1986: 129-138.
9. Fenner F, Henderson DA, Arita 1, Jezek Z, Ladnyi ID. Potential sources for a return of smallpox. In: Smallpox and Its Eradication. Geneva, Switzerland: World Health Organization; 1988: Chap 30: 1341.
10. Capps L, Vermund SH, Johnsen C. Smallpox and biological warfare: The case for abandoning vaccination of military personnel. Am J Public Health. 1986;76(10):1229-1231.
11. World Health Organization. Health aspects of chemical and biological weapons: Report of a WHO group of consultants. Geneva, Switzerland: WHO; 1970: 69-70.
12. Wolff HL, Croon JAB. Survival of smallpox virus (variola minor) in natural circumstances. Bull WHO. 1968;38:492-493.
13. Zuckerman AJ. Paleontology of smallpox. Lancet. 1984;2:1454.
14. Baxter PJ, Brazier AM, Young SEJ. Is smallpox a hazard in church crypts? BrJ Industr Med. 1988;45:359-360.
15. Joklik WK, Moss B, Fields BN, Bishop DHL, Sandakhchiev LS. Why the smallpox virus stocks should not be destroyed. Science. 1993;262:1225-1226.
16. Buller RM, Palumbo GJ. Poxvirus pathogenesis. Microbiol Rev. 1991;55:80.
17. Hahon N, Wilson BJ. Pathogenesis of variola in Macaca irus monkeys. Am J Hyg. 1960;71:69-80.
18. Mahy BWJ, Almond JW, Berns KI, et al. The remaining stocks of smallpox virus should be destroyed. Science. 1993;262:1223-1224.
19. Capps L, Vermund SH, Johnsen C. Smallpox and biological warfare: The case for abandoning vaccination of military personnel. Am J Publ Health. 1986;76:1229-1231.

Dr. McClain is a Research Medical Officer, Division of Virology, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland.

Reprinted/Adapted with permission from Textbook of Military Medicine (TMM). McClain DJ. Smallpox. In Sidell FR, Takafuji ET, Franz DR, eds. Medical Aspects of Chemical and Biological Warfare. Washington, DC: Dept of the Army, Office of The Surgeon General, Borden Institute; 1997:540-541.

Originally published in the Medical Sentinel 2001;6(4):129, 136 Copyright © 2001 Association of American Physicians and Surgeons (AAPS).

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