Epitope profiling reveals binding signatures of SARS-CoV-2 immune response and cross-reactivity with endemic HCoVs

Stoddard, Caitlin I.; Galloway, Jared; Chu, Helen Y.; Shipley, Mackenzie M.; Itell, Hannah L.; Wolf, Caitlin R.; Logue, Jennifer K.; Magedson, Ariana; Sung, Kevin; Garrett, Meghan; Crawford, Katharine H.D.; Laserson, Uri; Matsen, Frederick A.; Overbaugh, Julie

A major goal of current SARS-CoV-2 vaccine efforts is to elicit antibody responses that confer protection. Mapping the epitope targets of the SARS-CoV-2 antibody response is critical for innovative vaccine design, diagnostics, and development of therapeutics. Here, we developed a phage display library to map antibody binding sites at high resolution within the complete viral proteomes of all human-infecting coronaviruses in patients with mild or moderate/severe COVID-19. The dominant immune responses to SARS-CoV-2 were targeted to regions spanning the Spike protein, Nucleocapsid, and ORF1ab. Some epitopes were identified in the majority of samples while others were rare, and we found variation in the number of epitopes targeted by different individuals. We also identified a set of cross-reactive sequences that were bound by antibodies in SARS-CoV-2 unexposed individuals. Finally, we uncovered a subset of enriched epitopes from commonly circulating human coronaviruses with significant homology to highly reactive SARS-CoV-2 sequences.