Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination.
Lily E AdamsSarah R LeistKenneth H DinnonAnde WestKendra L GullyElizabeth J AndersonJennifer F LoomeEmily A MaddenJohn M PowersAlexandra SchäferSanjay SarkarIzabella N CastilloJenny S MaronRyan P McNamaraHarry L BerteraMark R ZweigertJaclyn S HigginsBrea K HamptonLakshmanane PremkumarGalit AlterStephanie A MontgomeryVictoria K BaxterMark T HeiseRalph S BaricPublished in: bioRxiv : the preprint server for biology (2022)
Two group 2B β-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. The mechanisms of cross protection driven by the sarbecovirus spike, a dominant immunogen, are less clear yet critically important for pan-sarbecovirus vaccine development. We evaluated the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination did not prevent virus replication, it protected against lethal heterologous disease outcomes in both SARS-CoV-2 and clade 2 bat sarbecovirus HKU3-SRBD challenge models. The spike vaccines tested primarily elicited a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. We found non-neutralizing antibody functions that mediated cross protection in wild-type mice were mechanistically linked to FcgR4 and spike S2-binding antibodies. Protection was 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.