Cross-reactive coronavirus antibodies with diverse epitope specificities and extra-neutralization functions

Shiakolas, Andrea R.; Kramer, Kevin J.; Wrapp, Daniel; Richardson, Simone I.; Schäfer, Alexandra; Wall, Steven; Wang, Nianshuang; Janowska, Katarzyna; Pilewski, Kelsey A.; Venkat, Rohit; Parks, Rob; Manamela, Nelia P.; Raju, Nagarajan; Fechter, Emilee Friedman; Holt, Clinton M.; Suryadevara, Naveenchandra; Chen, Rita E.; Martinez, David R.; Nargi, Rachel S.; Sutton, Rachel E.; Ledgerwood, Julie E.; Graham, Barney S.; Diamond, Michael S.; Haynes, Barton F.; Acharya, Priyamvada; Carnahan, Robert H.; Crowe, James E.; Baric, Ralph S.; Morris, Lynn; McLellan, Jason S.; Georgiev, Ivelin S.

The continual emergence of novel coronavirus (CoV) strains, like SARS-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. Coronavirus spike (S) proteins share common structural motifs that could be vulnerable to cross-reactive antibody responses. To study this phenomenon in human coronavirus infection, we applied a high-throughput sequencing method called LIBRA-seq (Linking B cell receptor to antigen specificity through sequencing) to a SARS-CoV-1 convalescent donor sample. We identified and characterized a panel of six monoclonal antibodies that cross-reacted with S proteins from the highly pathogenic SARS-CoV-1 and SARS-CoV-2 and demonstrated a spectrum of reactivity against other coronaviruses. Epitope mapping revealed that these antibodies recognized multiple epitopes on SARS-CoV-2 S, including the receptor binding domain (RBD), N-terminal domain (NTD), and S2 subunit. Functional characterization demonstrated that the antibodies mediated a variety of Fc effector functions in vitro and mitigated pathological burden in vivo. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies that may be useful for preventing potential future coronavirus outbreaks.