Investigating the Factors that Influence Pan-Betacoronavirus Infection and Immune Protection

Emerging RNA viruses are a significant threat to global public health due to high mutation rates and extensive prevalence in animal and avian reservoir species. Three highly pathogenic coronaviruses have jumped from the animal reservoir into the human population in recent history, causing significant disease and economic disruption. Due to the size of not only the coronavirus reservoir but also the reservoir harboring other pathogenic viruses, transmission events and human disease will likely continue. The factors that drive virus host range and transmission potential as well as the factors that drive potential broad-based immunity are important for future preparedness for viral outbreaks. SARS-CoV-2 is one of the most historically significant emerging coronaviruses. The SARS-CoV-2 spike glycoprotein is the major host range determinant and target for the host immune response. Here, we investigated the molecular determinants of SARS-CoV-2 host range via mutational analysis of the receptor ACE2. We found that only minor changes to the ACE2 binding site were necessary to support productive SARS-CoV-2 infection on an otherwise nonpermissive receptor. To probe the antigenic relationship of the spike proteins in the Sarbecovirus subgenus and inform the potential for spike-mediated cross protection, we conducted a series of vaccination and heterologous challenge studies using an alphavirus vectored self-amplifying RNA vaccine platform and lethal SARS-CoV-2 mouse challenge model. We found that, within the Sarbecovirus subgenus, heterologous spike proteins protected from severe disease in a clade-dependent manner. We also identified a mechanistic linkage between spike S2 domain-specific IgG2a, FcgRIV affinity, and immune cell function which we then confirmed in subsequent RNAseq experiments and domain-specific vaccination challenge studies. The capacity for FcR cellular function to protect from coronavirus disease was also confirmed by introducing Fc-ablating mutations into therapeutic monoclonal antibodies in our mouse challenge model. Finally, preliminary work with a SARS-CoV-2 Omicron BA.1 model confirmed the cross-protective phenotype we previously observed and provided insight into the utility of the alphavirus vaccine platform. Together this work proposes a novel mechanism for coronavirus cross-protection mediated by FcR function and provides evidence for novel spike-based vaccine antigens for both SARS-CoV-2 vaccine development and future responses to emerging coronaviruses.