ST-246 started 2 or 3 days, but not 4 days, postinfection protected mice from lethal challenge with IHD-J-Luc VACV. BALB/c mice were infected with IHD-J-Luc as described in Fig. 1 and were treated for a total of 5 days with vehicle on days 2 to 6 (●) or with ST-246 at 100 mg/kg on days 2 to 6 (♢), days 3 to 7 (△), or days 4 to 8 (□) (A to E). Mice were observed for lethality (A) and were subjected to bioimaging daily for 10 days (B to E). Total fluxes in the nasal cavity (B), lungs (C), spleen (D), and liver (E) were determined and used to calculate the mean total flux ± the SD using a Student t test. (F to I) AUCs were calculated for fluxes from individual mice for days 1 to 10 in the nasal cavities (F), lungs (G), spleens (H), and livers (I) of mice that received ST-246 on day 2 to 6 and days 3 to 7 only. The data are shown as mean AUCs ± 2×SE for groups of 6 mice per group. The experiment was performed twice with similar results.