Blockade of IFN-I improves adaptive immune responses and immune coverage after vaccination

Abstract IFN-I is a main innate antiviral defense critical for the activation of adaptive immunity. However, we hypothesized that acute viral clearance by IFN-I could limit antigen availability following initial antigen encounter, which could in turn, reduce the priming of the adaptive immune system. To test this hypothesis, we immunized mice with different vaccines or acute viruses together with a low dose of an IFN-I receptor-blocking antibody to induce a short-term abrogation of IFN-I signaling. This resulted in transient increase in antigen levels followed by antigen clearance. Importantly, short-term IFN-I blockade during coronavirus, flavivirus, rhabdovirus, or arenavirus immunization resulted in a potent improvement of adaptive immune responses, which conferred improved protection following future re-infections. Short-term IFN-I modulation also improved immune coverage elicited by viral vaccines or acute viral infections. In particular, administration of an HIV-1 vaccine together with the IFN-I blocker generated highly cross-reactive antibody responses against other HIV-1 clades; and similarly, immunization with a mouse coronavirus (MHV) together with the IFN-I blocker generated more cross-reactive antibody responses against other related coronaviruses, including SARS CoV-2. These data demonstrate a novel mechanism by which innate immunity modulates the magnitude and breadth of adaptive immune responses, providing insights for rational vaccine design.