Efficacy of ST-246 versus lethal poxvirus challenge in immunodeficient mice

Abstract

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.

Fig. 1.

Virulence of F13L-KO in Nude and SCID mice. Nude and SCID mice (as indicated in each panel) were intranasally challenged (day 0) with the wild-type VV-WR (WR) or the F13L-KO virus (KO) at doses ranging from 10² pfu to 10⁶ pfu, as indicated in the legend. Survival percentages are shown. Legend applies to both panels.

Fig. 2.

Efficacy of ST-246 vs. lethal VV-WR challenge in Nude and SCID mice. Nude and SCID mice (as indicated in each panel) were intranasally challenged (day 0) with the wild-type VV-WR at doses ranging from 10³ pfu to 10⁵ pfu. At each challenge dose (as indicated in the legend), one group was treated with vehicle (Veh.) (dashed lines), and the other was treated with ST-246 (solid lines) for 21 consecutive days. Mice were monitored for evidence of disease and were killed if moribund. Survival percentages are shown. Legend applies to both panels.

Fig. 3.

Efficacy of ST-246 vs. lethal VV-WR challenge in B cell and/or T cell deficient mice. Immunodeficient mice (as indicated in the legend) and BALB/c mice as controls were intranasally challenged with a 10 × LD₅₀ dose of the wild-type VV-WR on day 0 (n = 5 mice per group). Each immunodeficient mouse model was treated daily with vehicle (dashed lines) or with ST-246 (solid lines) for 14 consecutive days starting at the time of challenge. (A) Survival percentages after challenge. (B) Average weights reported as a percentage of the starting weight. Weight observations were discontinued when animals died (≈70% starting weight) or recovered weight approached 100%. (C) Average disease scores.