Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination.

Group 2B β-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. Here, we evaluate the mechanisms of cross-sarbecovirus protective immunity, currently less clear yet important for pan-sarbecovirus vaccine development, using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination does not prevent virus replication, it protects against lethal heterologous disease outcomes in both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clade 2 bat sarbecovirus challenge models. The spike vaccines tested primarily elicit a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. Rather, non-neutralizing antibody functions, mechanistically linked to FcgR4 and spike S2, mediate cross-protection in wild-type mice. Protection is lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs. [Display omitted] • Non-neutralizing antibodies mediate pan-sarbecovirus protection • Antibody-mediated cross-protection is lost in absence of FcR function • S2-specific antibodies are a strong correlate of protective FcR effector function • Full-length spike elicits the broadest pan-sarbecovirus protection Using a lethal model for β-coronavirus infection, Adams et al. described heterologous protection from disease that was driven by non-neutralizing antibodies through Fc-receptor-dependent mechanisms. These results reveal important protective correlates for inclusion into the design and testing of future pan-coronavirus vaccines. [ABSTRACT FROM AUTHOR]