Clinical Treatment of Smallpox

Treatment options

Treatment of smallpox patients generally involves supportive care. Vaccination with replication-competent smallpox vaccines (i.e., ACAM2000 and APSV) can prevent or lessen the severity of disease if given within 2 to 3 days of the initial exposure. They may decrease symptoms if given within the first week of exposure.

Treating smallpox patients in a healthcare setting requires isolation and adherence to proper infection and environmental controls.

Antivirals

There are three primary antiviral therapies that have shown effectiveness against orthopoxviruses including variola (the virus that causes smallpox) in animals and in vitro studies. However, there is no treatment for smallpox disease that has been tested in people who are sick with the disease and been proven effective in this population.

Tecovirimat

In July 2018, the U.S. Food and Drug Administration (FDA) approved tecovirimat (also referred to as ST-246 or its brand name Tpoxx), the first drug with an indication for treatment of smallpox. Tecovirimat has been used in the treatment of severe adverse events to vaccinia virus vaccination; however, there are limited efficacy data in humans. Tecovirimat's effectiveness against smallpox was established with in vitro studies using related orthopoxviruses as well as variola. Efficacy of tecovirimat treatment has also been demonstrated within multiple animal model studies measuring survival in animals infected with either variola virus or other closely related orthopoxviruses. Furthermore, treatment with tecovirimat minimized signs of morbidity as well as protected from mortality within prairie dogs challenged with monkeypox virus. The safety of tecovirimat was evaluated in 359 healthy human volunteers.

Tecovirimat was approved under the FDA's Animal Rule, which allows efficacy findings from adequate and well-controlled animal studies to support an FDA approval when it is not feasible or ethical to conduct efficacy trials in humans. The FDA Antimicrobial Drugs Advisory Committee voted unanimously (17 to 0) that the benefits of tecovirimat treatment for smallpox outweigh its risks.

Brincidofovir

In June 2021, the FDA approved brincidofovir (also referred to its brand name TEMBEXA) for treatment of smallpox. Brincidofovir's effectiveness against smallpox was established with in vitro studies using related orthopoxviruses as well as variola. Efficacy of brincidofovir treatment has also been demonstrated within multiple animal model studies measuring survival in animals infected with either variola virus or other closely related orthopoxviruses. The safety of brincidofovir was evaluated for non-smallpox indications, primarily in people who received bone marrow transplants. Brincidofovir was approved under the FDA's Animal Rule.

Cidofovir

In laboratory tests, cidofovir has also been shown to stop the growth of the virus that causes smallpox and to be effective in treating animals that had diseases similar to smallpox. Cidofovir has not been tested in people who are sick with smallpox, but has been tested in healthy people and in those with other viral illnesses. Cidofovir is not FDA-approved for the treatment of any orthopoxvirus infections, including smallpox or mpox, but is commercially available. Clinicians could choose to use cidofovir to treat patients with orthopoxvirus infection based on individual risk-benefit assessment under practice of medicine.

Emergency use of smallpox medical countermeasures

During a declared public health emergency involving smallpox, CDC and the Assistant Secretary for Preparedness and Response (ASPR) will provide more detailed guidance regarding the availability and use of smallpox medical countermeasures from the Strategic National Stockpile under their appropriate regulatory mechanism(s) (e.g., IND, EUA, or Emergency Use Instructions [EUI]).