Although smallpox vaccines have been developed and procured for the SNS, they cannot completely prevent disease or attenuate the illness if given too late following exposure. Smallpox antivirals are needed for treatment or post-exposure prophylaxis. Early results from laboratory studies suggest that the drug cidofovir may be an effective treatment against the smallpox virus. (In 1996, the Food and Drug Administration [FDA] approved the use of cidofovir to treat cytomegalovirus infections.) NIAID-supported scientists are doing studies with animals to better understand the drug's ability to treat smallpox.

Based on encouraging study results, NIAID applied to FDA to use cidofovir as an experimental treatment for smallpox in the event of a bioterrorist-initiated re-emergence. Although it is effective against smallpox, cidofovir must be given intravenously and its use often results in life-threatening kidney toxicity. To circumvent the drug delivery and toxicity problems, NIAID has supported the development of brincidofovir, a derivative of cidofovir that can be given orally instead of by intravenous injection and that may have fewer side-effects. NIAID has supported brincidofovir from discovery through three Phase 1 clinical studies. In addition to its activity against smallpox, brincidofovir has activity against several other viruses that can infect humans, including herpes, adeno and polyoma viruses.

NIAID has also provided support from discovery through Phase 2 clinical development for a second therapeutic for smallpox, tecovirimat. Tecovirimat has a different mechanism of action from that of cidofovir or brincidofovir and is specifically active against smallpox and closely related members of the poxvirus family.

NIAID has successfully transitioned both brincidofovir and tecovirimat to BARDA for further clinical development.