Background.Severe complications may arise as a result of virus dissemination after smallpox (live vaccinia virus) vaccination, particularly in immunocompromised individuals. We developed a new mouse model for studying the effects of antiviral agents on progressive vaccinia virus infections.

Methods.Hairless mice were treated with cyclophosphamide (100 mg/kg/day) every 4 days starting 1 day before vaccinia virus exposure to wounded skin. Primary lesions progressed in severity, satellite lesions developed, and the infection eventually killed the mice.

Results.Topical treatment with 1%‐cidofovir cream (twice daily for 7 days) was much more effective in reducing the severity of primary lesions and the number of satellite lesions than was parenteral cidofovir treatment (100 mg/kg/day, given every 3 days). Both forms of treatment delayed death. Topical drug treatment markedly reduced virus titers in the skin and snout, whereas parenteral treatment did not, suggesting that the latter treatment resulted in lower drug exposure to skin. Topical treatment starting 9 days after infection delayed death by 10 days, compared with treatment with placebo. Combining topical and parenteral cidofovir treatments provided the greatest reduction in lesion severity and prolongation of life.

Conclusions.Topical cidofovir treatment was superior to parenteral treatment. This new animal model may be useful in evaluation of the efficacy of treatment regimens against complications from smallpox vaccination.