FC MEDIATED PAN-SARBECOVIRUS PROTECTION AFTER ALPHAVIRUS VECTOR VACCINATION

Group 2B β-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. We evaluated the mechanisms of cross-sarbecovirus protective immunity, currently less clear yet critically 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 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.