Smallpox is caused by Variola virus, a member of the Poxviridae family, which is a large, brick-shaped, double-stranded DNA virus. It is one of the larger viruses, measuring approximately 100 nm by 300 nm. Despite its relatively large size it cannot be seen under a light microscope, and transmission electron microscopy must be utilized (Fig. 1 and 2; photo credit: Fred Murphy and Sylvia Whitfield, Centers for Disease Control and Prevention (CDC)). This virus has played a significant role in world history.

In the late eighteenth century, Edward Jenner observed that milkmaids with cowpox lesions on their hands seemed insusceptible to smallpox. His subsequent experiments indicated that intentionally inoculating individuals with cowpox gave them immunity to smallpox and vaccination was born.

Smallpox is also of interest because it is the first (and, so far, only) species ever intentionally eradicated by humans. After nearly a decade of planning, the World Health Organization (WHO) launched the Global Smallpox Eradication Programme in 1967, with the goal of completely eradicating smallpox within ten years. This was considered an attainable goal because no reservoir outside of human beings was known to exist, and there was no asyptomatic carrier stage of the disease. Mass vaccinations were carried out in endemic countries using the serologically-related Vaccinia virus (Fig. 3, transmission electron micrograph; photo credit: Fred Murphy and Sylvia Whitfield, CDC). The program was successful and the last recorded case of naturally-occurring smallpox was documented in Somalia in 1977 (Fig. 4; photo credit: WHO).

The incubation period of smallpox is approximately 2 weeks with abrupt onset of fever, chills, and myalgia. The characteristic rash follows 3 to 4 days later and is most prominent on the head and extremities (Fig. 5; photo credit: Barbara Rice, CDC). The lesions are firm papulovesicles that become pustular (Fig. 6; photo credit: WHO) over 2 weeks and then heal. The virus is very easily spread via respiratory droplets and by exposure to the dried crusts from the pustules and contaminated fomites. The mortality rate from the disease could be as high as 35%.

The CDC considers smallpox to be a biological warfare Category A agent. This indicates that the use of smallpox in a biological attack would cause a serious public health threat. Because smallpox was eradicated almost 30 years ago, populations have no acquired immunity to the organism, and it is doubtful that the vaccinated population (a small percentage of the total population) has retained any immunity. Additionally, the highly contagious nature of the virus and its ability to survive in the environment further compound the danger.