PROJECT SUMMARY We have elucidated a strategy to improve viral vaccines by combining IFN-I receptor antibodies with the vaccine. Our data show that this approach improves the efficacy of multiple viral vaccines, including the clinically approved yellow fever vaccine and experimental HIV vaccines in mice. Such data provide impetus for testing whether IFN- modulation can also improve the efficacy of HIV vaccines in primates and humanized mice challenged intravenously with HIV. These data are potentially translatable to humans, since there is a similar antibody that has undergone extensive clinical testing in humans to block IFN-I (Anifrolumab).