CBRNE - Smallpox

Updated: Jul 21, 2021
  • Author: Christopher J Hogan, MD; Chief Editor: Duane C Caneva, MD, MSc  more...
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Practice Essentials

Smallpox (variola) represents both the zenith and nadir of human achievement with respect to disease. It is the only disease that has been eradicated through a concerted and extensive effort that transcended political and ideologic boundaries. Because of these efforts, not one documented naturally occurring case of this infection, which once caused high mortality rates, has occurred since October 26, 1977. (The last naturally occurring case involved an unvaccinated hospital cook in Somalia.) Smallpox officially was declared eradicated by the World Health Organization (WHO) in 1980. On the other hand, smallpox also represents one of the most devastating potential biological weapons ever conceived. [1, 2, 3]

A child with variola is shown below.

Small child with pustular lesions of variola. Phot Small child with pustular lesions of variola. Photo used with permission of the World Health Organization (WHO).

For centuries, smallpox affected political and social agendas. Epidemics plagued Europe and Asia until Edward Jenner developed a vaccine in 1796; he subcutaneously inoculated patients with the milder cowpox virus. The viral illness incidence of infection in Europe steadily declined afterward.

In the Americas, smallpox decimated the native population, who never had been exposed to variola, when it followed closely behind the European explorers in the 1600s. The British forces at Fort Pitt (Pittsburgh, Pa) unsuccessfully tried to weaken Native American forces during the French and Indian War by giving them smallpox-contaminated blankets and goods. [4]  Whether because of this or through natural spread, the subsequent epidemic carried a mortality rate of 50% among native tribes.

Farr first accurately predicted variola infection rates in the 1830s. Once the disease and its method of spread were understood better, smallpox vaccination became mandatory in developed countries in the early 1900s. The discovery of the vaccinia virus and its subsequent use to develop a vaccine enabled aggressive immunization by the WHO, which led to variola eradication in 1977.

The variola virus no longer exists outside of a few laboratories around the world. The official virus repositories are at the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga, and the Institute of Viral Preparations in Moscow, Russia. Viral stocks also exist at the Russian State Research Center of Virology and Biotechnology in Koltsovo. The WHO Committee on Orthopoxvirus Infections has proposed multiple dates for destruction of the remaining viral stocks, only to be delayed under pressure from various factions.

Various sources from the former Soviet Union allege that the Russian military had pursued and currently pursues an active biological warfare program. For instance, the Russian government confirmed a suspected outbreak from an accidental release of aerosolized anthrax near a military microbiology laboratory in 1992. In 1980, the Soviet Union commenced large-scale production of the smallpox virus and genetic recombination of strains that are more virulent. Since the fall of the Soviet Union, concern exists that this expertise may be used in other countries. The extent of smallpox stockpiles in other countries is unknown but may be significant since the collapse of the Soviet Union.

Variola, prior to eradication, carried a mortality rate of 30% in unvaccinated persons. Vaccination of the general population in the United States ceased after 1980, and vaccination in military personnel was discontinued in 1989. Currently, the populace in the United States is considered immuno-naive to the variola virus. Forty-two percent of the US population was never vaccinated, and an estimated 53% of the US population has received the smallpox vaccine. [5]

Two vaccination programs were started in the aftermath of the 9/11 attacks, one a military program that inoculated 730,580 persons, and a voluntary vaccination for health care workers that ultimately inoculated 37,901 individuals. Vaccinated individuals theoretically retain immunity for approximately 10 years, although the duration has never been fully evaluated. Because of the ease of production and aerosolization of the virus (only 10-100 virus particles are needed for infection), smallpox is a potential biological weapon.



Variola is a member of the Orthopoxvirus genus, of which cowpox, monkeypox, orf, and molluscum contagiosum are also members. Poxviruses are the largest animal viruses, larger than some bacteria. They have a large genome, composed of 200 kilobase (kb) double-stranded DNA enclosed in a double membrane layer. Poxviruses are the only viruses that can replicate in cell cytoplasm without the need of a nucleus.

A boy with monkeypox is shown in the images below.

Boy with monkeypox in Democratic Republic of the C Boy with monkeypox in Democratic Republic of the Congo in 1996. Note the centrifugal distribution as was typical of smallpox. Courtesy of William Clemm.
Boy with monkeypox in Democratic Republic of the C Boy with monkeypox in Democratic Republic of the Congo in 1996. Note synchronicity of lesions as was typical of smallpox. Courtesy of William Clemm.

Although the variola virus was believed to infect only humans, infection has recently been elicited in crab-eating macaques when exposed to large amounts of injected and aerosolized virus, thus potentially providing an in vivo source of research that was previously unavailable. The virus is acquired from inhalation, although virus particles can remain viable on fomites (clothing, bedding, surfaces) for approximately 1 week.

The virus initially replicates in respiratory tract epithelial cells. From there, a massive asymptomatic viremia ensues, resulting in focal infection of the skin, intestines, lungs, kidneys, and brain. The multiplication in the skin epithelial cells first leads to a rash, progressing into deep-seated pustules approximately 14 days after inoculation. A cell-mediated immune response is responsible for pustule formation, demonstrated by studies using immunocompromised rabbits, which do not produce these characteristic lesions. Patients who survive an initial infection often have severely deformed skin from the pustules and subsequent granulation tissue formation.



The variola virus is the only known cause of smallpox. The disease affects mainly humans (and some primates in laboratory experiments), and no animal or arthropod vectors exist.

The laboratories in the world known to house the smallpox virus are the US Centers for Disease Control and Prevention in Atlanta, Ga; the Russian State Research Center of Virology and Biotechnology in Koltsovo; and the Institute of Viral Preparations in Moscow, Russia.



United States

No recent case of systemic smallpox has been reported in the United States. [6] Since vaccination commenced, isolated cases of vaccinia virus illnesses from vaccine recipients and their close contacts have occurred. Since the September 11, 2001 terrorist attacks, vigilance for smallpox cases has heightened, given the high potential impact from its use as a weapon of mass destruction. From January 2002 through June 2004, the CDC received 43 consultations regarding suspected smallpox cases. Ultimately, most of those persons with suspected variola were diagnosed with varicella (53% of all the suspected variola cases).


Since the last wild documented case in 1977, only 2 deaths from smallpox have been reported, one from a laboratory worker who infected her mother and the second from a photographer with an office next to the laboratory space where the accidental exposure to the virus occurred.



Variola major, or smallpox, has an overall mortality rate of 30%. Variola minor, or alastrim, is a milder form of the virus, carrying a mortality rate of 1%. Four types of variola presentations exist: classic, hemorrhagic, malignant, and modified. Classic smallpox was believed to be the most communicable disease—approximately 30% of susceptible contacts became infected. The malignant and hemorrhagic forms of smallpox are not caused by unique variola strains but are thought to be due to host factors such as a deficient cellular immune response to the virus.

  • Pregnant women have a heightened morbidity rate to variola. In one study prior to virus eradication, the morbidity rate was 27% in vaccinated patients and 61% in unvaccinated patients versus a nonpregnant control morbidity rate of 6% (vaccinated) and 35% (unvaccinated).

  • The hemorrhagic variety of variola also carried a higher mortality rate and led to death more quickly. Patients often died before the pustular lesions formed, but this variety is recognizable by the hemorrhagic lesions that erupt in the mucosal and cutaneous membranes. Comprehensive studies documenting almost 7000 cases of variola found 200 patients had this form of the disease and 192 died. Pregnant women are more likely to develop this variant. Scientists who manufacture biological weapons might attempt to elucidate the mechanisms that lead to the development of hemorrhagic smallpox in victims, which would serve to maximize the terror impact of their weapons.

  • Prior to eradication, the malignant, or flat form, of variola affected 6% of the population and evolved more slowly than the classic presentation. Lesions were not pustular; instead, they consisted of a flattened macule, often described as feeling velvety. The mortality rate for this form approaches 100%.

  • The modified variety of smallpox essentially develops in people with some intact immune response who were previously vaccinated. In a vaccinated population, this version would constitute approximately 15%.

Race-, sex-, and age-related demographics

Note the following:

  • No racial predilection exists.
  • With the exception of pregnant women, males and females are infected in equal proportions.
  • No age predilection exists, although mortality is higher in the extremes of age. In people who are unvaccinated, the distribution of illness mirrors that of the age distribution of the population. However, in India, prior to eradication, 70% of infections were in children younger than 14 years.