Naturally occurring smallpox has been eradicated but remains a credible threat to the security of the United States due to its potential use as an agent of terror or biowarfare. Given that approximately 25% of the population is contraindicated to receive the vaccine due to direct risk of adverse events or the possibility of placing direct contacts at risk (23), the current smallpox vaccine is inadequate to protect the US population from smallpox. SIGA Technologies (SIGA) is currently conducting NDA-enabling activities seeking FDA approval for ST-246 as a post-exposure therapeutic for smallpox. SIGA is seeking to expand ST-246 indications for use to include it as an adjunct to smallpox vaccination to prevent or treat adverse events due to the vaccine. We and our collaborators have demonstrated in more than 30 animal studies that ST-246 is safe and very effective for the prevention or treatment of orthopoxvirus infection, including variola, the causative agent of smallpox. This suggested to us that ST-246 might also be used to prevent or treat adverse events due to the smallpox vaccine, a live vaccinia virus closely related to variola. We have demonstrated in immunocompetent mice (14) and monkeys that reactogenicity to the vaccine is reduced while protective immunity elicited by the vaccine is not affected. Further, in our Phase I studies, as reported in the Progress Report below, we have determined that ST-246 provides full protection from lethal poxvirus challenge in numerous murine models of immunodeficiency and that immunodeficient mice may be safely vaccinated if treated with ST-246 as an adjunct to the vaccine. Immunodeficient mice that are safely vaccinated are subsequently resistant to lethal challenge suggesting that remaining components of the immune system are able to mediate protection. ST-246 is a promising candidate for inclusion in the Strategic National Stockpile as a component of the Smallpox Response Plan to 1) provide protection from smallpox if an individual is exposed and 2) reduce the occurrence of adverse events due to vaccination. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to advance ST-246 development as an adjunct to the smallpox vaccine through the pre-clinical development phase so that an Investigational New Drug (IND) application may be filed with the Food and Drug Administration upon completion of the proposed studies.