Smallpox, caused by the Variola virus, was one of the most historically devastating human infections, frequently resulting in death or severe disfigurement. The disease was fatal in up to 30% of cases, claiming hundreds of millions of lives over centuries. Since the virus is no longer found in nature, the question of a “cure” for a natural outbreak is largely obsolete. Modern medicine has developed specific treatments and new vaccines, driven primarily by biosecurity concerns, for a potential re-emergence of the virus.
The Global Eradication Success
The World Health Organization (WHO) launched an intensified global campaign in 1967 aimed at eliminating the Variola virus from the human population. This ambitious effort relied on a focused public health strategy rather than simply mass vaccination. The key to the campaign was “surveillance and containment,” which involved quickly identifying every new case of smallpox and offering rewards for reporting infections.
Containment, or “ring vaccination,” involved vaccinating everyone who had been in contact with the infected person and those in their immediate vicinity. This created a protective ring of immunity that prevented the virus from spreading further. The last naturally occurring case was diagnosed in a hospital worker in Merca, Somalia, in 1977. Following this success, the WHO officially declared the global eradication of smallpox in 1980, marking it as the only human infectious disease ever eliminated from the wild.
Modern Antiviral Treatments
While no circulating virus exists to “cure,” modern pharmacological agents have been developed specifically to treat smallpox if it were to re-emerge. The U.S. Food and Drug Administration (FDA) has approved an antiviral known as tecovirimat, or TPOXX, for the treatment of human smallpox disease. Tecovirimat targets the p37 protein in the orthopoxvirus family, which is necessary for the virus to produce extracellular enveloped virions.
These virions are the form of the virus that spreads throughout the body. By inhibiting the p37 protein, tecovirimat blocks the virus from leaving an infected cell, preventing the spread of the infection. Because it was impossible to test the drug’s efficacy on human smallpox patients, tecovirimat was approved under the FDA’s Animal Rule, which relies on adequate and well-controlled animal studies. Other antivirals, such as cidofovir and brincidofovir (TEMBEXA), have also been approved for smallpox treatment, reserved for severe cases or specific circumstances.
Current Vaccine Use and Availability
Following the virus’s eradication, routine public smallpox vaccination was discontinued in the United States in the early 1970s, as the risk of the vaccine’s side effects began to outweigh the risk of infection. Today, the smallpox vaccine is used strictly as a preventative measure for specific, high-risk populations. This includes laboratory personnel who work with orthopoxviruses, some military personnel, and select emergency response teams.
The U.S. Strategic National Stockpile maintains a supply of modern vaccines for emergency preparedness. Two vaccines are available: ACAM2000 and JYNNEOS. ACAM2000 is a replication-competent vaccinia virus vaccine, meaning it can cause a localized infection at the vaccination site that can be contagious to others. JYNNEOS is a live, attenuated, and non-replicating vaccine, offering a safer alternative for individuals with compromised immune systems or certain skin conditions. JYNNEOS is administered as a two-dose series and is also licensed for the prevention of monkeypox.
Viral Storage and Biosecurity
Despite the global eradication, the Variola virus still exists in two authorized laboratories worldwide. These repositories are designated by the WHO to hold the virus for research purposes.
Authorized Repositories
The first is located at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, in the United States. The second is the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia.
The continued existence of these samples drives ongoing biosecurity concerns, prompting research into modern antivirals and safer vaccines. All research conducted using the stored Variola virus is subject to the strict oversight of the WHO’s Advisory Committee on Variola Virus Research. The debate over whether to destroy these samples continues, balancing the risk of accidental or deliberate release against the need for research into countermeasures for a potential re-emergence.