Smallpox, a devastating infectious disease dreaded throughout much of recorded history, is caused by the variola virus, a member of the poxviridae family. In the 20th century alone, smallpox deaths worldwide numbered in the millions. In 1980, after an intensive program of immunization with vaccinia virus, a related but relatively nonpathogenic virus, the World Health Organization (WHO) declared the disease eradicated. By 1983, all known stocks of variola virus were in two WHO collaborating centers: the US Centers for Disease Control and Prevention (CDC) in Atlanta and (after a transfer in 1994) the Russian State Research Center of Virology and Biotechnology (the Vektor Institute) in Novosibirsk. The WHO Committee on Orthopoxvirus Infections voted on several occasions to recommend destruction of the stocks, but each time the decision was deferred to permit more research on live variola virus. A 1999 National Academies report summarized and assessed scientific needs for live variola virus (1).

The concern that undeclared stocks of variola virus might exist and that they might be used as a bioterrorist weapon (2) was heightened in late 2001 by the deliberate release of Bacillus anthracis, the agent of anthrax, in the weeks after the September 11, 2001, attacks. That concern prompted a voluntary nationalpreparedness effort to vaccinate healthcare workers, first responders, and members of the military against smallpox. However, given the substantial side effects, the risks associated with the smallpox vaccine, and the absence of information about an imminent bioterrorist attack, vaccination was not accepted by all members of those groups, nor was it recommended for the general public by the government (3).