The threat of
smallpox as a bioweapon and the emerging threat of human
monkeypox, among other poxviral diseases, highlight the need for effective poxvirus countermeasures.
ST-246, which targets the F13L
protein in vaccinia virus and its homologs in other orthopoxvirus species, provides full protection from lethal poxviral disease in numerous animal models and seems to be safe in humans. All previous evaluations of
ST-246 efficacy have been in immunocompetent animals. However, the risk of severe poxviral disease is greater in immunodeficient hosts. Here we report on the efficacy of
ST-246 in preventing or treating lethal poxviral disease in immunodeficient mice. After lethal challenge with the Western Reserve strain of
vaccinia, Nude, SCID, and J(H) knockout mice additionally depleted of CD4(+) and CD8(+) T cells were not fully protected by
ST-246, although survival was significantly extended. However, CD4(+) T cell deficient, CD8(+) T cell deficient, J(H) knockout, and J(H) knockout mice also deficient for CD4(+) or CD8(+) T cells survived lethal challenge when treated with
ST-246 starting on the day of challenge. Delaying treatment until 72 h after
infection reduced
ST-246 efficacy in some models but provided full protection from lethal challenge in most. These findings suggest that
ST-246 may be effective in controlling
smallpox or other pathogenic orthopoxviruses in some immunodeficient human populations for whom the
vaccine is contraindicated.