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15 March 2004

Volume 38, Number 6
Clinical Infectious Diseases 2004;38:882–889
This article is in the public domain, and no copyright is claimed.
1058-4838/2004/3806-0019
DOI: 10.1086/381976
CONFRONTING BIOLOGICAL WEAPONS INVITED ARTICLE

Looking Back at Smallpox

Mike Bray1 and

Mark Buller2

1Biodefense Clinical Research Branch, Office of Clinical Research, Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and 2Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri

Smallpox apparently arose through transfer of variola virus to humans from another animal species. By causing a brief infection that required close contact for transmission and engendered solid immunity, the agent was always vulnerable to simple isolation measures. The high replicative fidelity of the viral DNA polymerase limited variola’s ability to adapt to humans and preserved orthopoxviral antigenic cross‐reactivity, so that vaccinia vaccination protected against smallpox. Host‐derived genes encoding immunomodulatory proteins helped shelter viral replication from innate immune responses. Examination of clinical variants suggests that severity of illness was usually determined by host responses during the incubation period. Control of viral replication was aided by early postexposure vaccination and might be strengthened by additional immunological interventions. Massive inflammatory responses were responsible for major features of illness. Some patients with high levels of circulating virus developed hemorrhagic disease resembling septic shock. Continued study of virus‐host interactions is needed to defend against genetically modified agents.

Received 12 September 2003; accepted 25 November 2003; electronically published 1 March 2004.

Reprints or correspondence: Dr. Mike Bray, Biodefense Clinical Research Branch, OCR/OD/NIAID/NIH, Bethesda, MD 20892 ().

Donald A. Henderson, Thomas V. Inglesby, Jr., and Tara O'Toole, Section Editors

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