Smallpox was a severe infectious disease caused by variola virus, characterized by fever and a distinctive rash that developed into deep-seated pustules. It spread between people and frequently caused death or permanent scarring. An international campaign combining vaccination with case detection and outbreak containment interrupted natural transmission. The World Health Organization (WHO) intensified the campaign in 1967, and the World Health Assembly formally declared global eradication on May 8, 1980. Smallpox is the first human infectious disease eradicated worldwide. (cdc.gov)
Cause and transmission
Variola is a virus belonging to the genus Orthopoxvirus, which also includes vaccinia and cowpox viruses. Two historically recognized forms were variola major and variola minor. Variola major caused the more severe disease, whereas variola minor, also called alastrim, generally followed a milder course, with a case-fatality rate below 1 percent. These forms should be distinguished from the clinical categories describing how the illness appeared in individual patients. (cdc.gov)
Humans were the source of transmission; no animal or insect reservoir sustained smallpox. Infection usually followed prolonged, close face-to-face contact through inhalation of virus-containing respiratory droplets. Contaminated bedding, clothing, lesion fluid, and scabs could also transmit infection. Airborne spread over greater distances occurred occasionally in enclosed settings, including hospitals. Patients were considered infectious from the appearance of sores in the mouth or throat until their last scab had fallen off. (cdc.gov)
Clinical course
The incubation period usually lasted 10–14 days, with a reported range of 7–19 days. During this interval, infected people had no symptoms and were not contagious. The initial illness involved high fever, severe malaise, headache, and backache, sometimes accompanied by vomiting or abdominal pain. This early symptomatic phase preceded the characteristic skin eruption. (cdc.gov)
Lesions first appeared in the mouth and throat, followed by the face and extremities, and then the trunk. The rash was concentrated more heavily on the face and limbs than on the trunk and could involve the palms and soles. Spots progressed through raised lesions and fluid-filled vesicles into firm, deep-seated pustules, then crusted and formed scabs. Within a particular body region, lesions typically remained at the same developmental stage. (cdc.gov)
Ordinary smallpox accounted for most historical cases. Other clinical forms included modified disease, associated with previous vaccination, and the particularly severe flat and hemorrhagic forms. Historical case fatality was approximately 30 percent overall among unvaccinated patients, although outcomes varied by disease form. Permanent pitted scars were common; blindness was a less frequent complication. Recovery generally provided prolonged immunity against reinfection. (cdc.gov)
Diagnosis
Historical diagnosis relied heavily on the pattern of fever and rash. Chickenpox and other illnesses producing vesicles or pustules can resemble smallpox, making clinical differentiation important. Deep, firm lesions, a febrile illness preceding the rash, and lesions at the same stage within one body region were major distinguishing features. (cdc.gov)
Modern laboratory confirmation uses variola-specific polymerase chain reaction testing to detect viral DNA. A generic orthopoxvirus test or identification of a poxvirus by electron microscopy does not, by itself, establish smallpox. Specialized reference laboratories and coordinated public health procedures govern testing because of the consequences of a confirmed case and the absence of naturally circulating disease. (cdc.gov)
Prevention and historical control
Before vaccination, variolation deliberately exposed susceptible people to material from smallpox lesions. Although it reduced the risk of death compared with naturally acquired infection, it could cause smallpox and transmit the disease to others. In 1796, Edward Jenner demonstrated protection using material from cowpox lesions. This work established the foundation of smallpox vaccination. (cdc.gov)
Later smallpox vaccines used vaccinia virus, rather than variola virus. They therefore cannot cause smallpox, although replication-competent vaccinia vaccines can cause their own infections and complications. Vaccination stimulated protective immunity, including cross-reactive antibodies against related orthopoxviruses. Freeze-dried vaccine and the bifurcated needle made large-scale administration practical during the eradication campaign. Routine vaccination of the general public ceased after eradication. (cdc.gov)
Global eradication
The intensified eradication programme combined widespread immunization with surveillance, rapid investigation, isolation, and vaccination around detected cases. This targeted approach, often termed ring vaccination, helped interrupt remaining chains of transmission. The last naturally occurring case was recorded in Somalia in October 1977. A laboratory-associated outbreak in Birmingham, England, in 1978 occurred after natural transmission had ended. Global certification followed in December 1979, before the World Health Assembly’s declaration in 1980. (cdc.gov)
Treatment and post-eradication status
Historical treatment was primarily supportive. The United States approved the antiviral drugs tecovirimat in 2018 and brincidofovir in 2021 for smallpox treatment. Because eradication precluded efficacy trials in people with smallpox, evidence supporting these treatments came from laboratory and animal studies rather than demonstrated clinical effectiveness in human smallpox patients. (cdc.gov)
Live variola virus remains in two WHO-authorized repositories: the US Centers for Disease Control and Prevention in Atlanta and the VECTOR research centre in Koltsovo, Russia. WHO oversees permitted research, repository inspections, and emergency preparedness, including vaccine reserves. Eradication means that natural transmission has ended, not that every laboratory sample of the causative virus has been destroyed. (who.int)