Ensuring Continued Safety from an Ancient Scourge

NIAID Now | August 14, 2018

For centuries, smallpox menaced communities around the globe, killing three out of every 10 infected people and leaving survivors permanently scarred. The variola virus, which causes smallpox, is estimated to have killed 300 million people in the 20th century alone. A massive vaccination campaign using vaccinia virus, a variola relative, put smallpox in the history books and the disease was declared eradicated by the World Health Organization in 1980.

Since then, smallpox vaccination for the general public has been largely discontinued because the virus is no longer present in nature, although stocks of smallpox virus are retained for research purposes in high security biological containment facilities in the United States and Russia. Without the immune protection provided by vaccination, the population of people vulnerable to smallpox is increasing and, if smallpox virus were to be used as a weapon of bioterror, the consequences could be severe. Recognizing this, NIAID supported the development of a small molecule drug, TPOXX (tecovirimat or ST-246), that could be used to treat smallpox infections. The research on TPOXX was also supported by the HHS Biomedical Advanced Research and Development Authority (BARDA), the Centers for Disease Control and Prevention, and the Department of Defense.

Using an NIAID Small Business Innovation Research (SBIR) grant, SIGA Technologies, a company headquartered in New York City with research facilities in Corvallis, Oregon, started developing TPOXX in 2003. NIAID SBIR and contract funds supported preclinical studies of TPOXX, including research in test tubes and animals that assessed the compound’s safety and efficacy, its mechanism of action, and the degree to which the virus responded to drug exposure by developing resistance. Following the discovery and preclinical phases of research, NIAID and BARDA provided funding for three Phase 1 and 2 clinical trials to test safety and pharmacokinetics of an oral formulation of TPOXX. The project was then supported by BARDA through further clinical trials and advanced development to fulfill requirements for drug approval by the U.S. Food and Drug Administration (FDA).

The effectiveness of TPOXX was tested in high security biological containment laboratories in multiple animal species that were infected with poxviruses similar to variola virus. During development, the FDA approved emergency use of TPOXX to treat five people in the United States who had developed complications after exposure to vaccines for smallpox or rabies. (Like the smallpox vaccine, the rabies vaccine contains a modified, weakened vaccinia virus.) In all cases, infections were resolved, and the patients were discharged from the hospital.

Information from NIAID and BARDA-supported trials was included in SIGA’s New Drug Application to the FDA, which was submitted in November 2017. In July 2018, the FDA announced approval of TPOXX as the first antiviral specifically for treating smallpox. BARDA purchased two million courses of TPOXX for the Strategic National Stockpile under Project BioShield for use in the event of an outbreak.

Content last reviewed on August 14, 2018