Epitope profiling reveals binding signatures of SARS-CoV-2 immune response in natural infection and cross-reactivity with endemic human CoVs

A major goal of current severe acute respiratory syndrome coronavirus 2 (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 vaccine design, diagnostics, and development of therapeutics. Here, we develop a pan-coronavirus phage display library to map antibody binding sites at high resolution within the complete viral proteomes of all known human-infecting coronaviruses in patients with mild or moderate/severe coronavirus disease 2019 (COVID-19). We find that the majority of immune responses to SARS-CoV-2 are targeted to the spike protein, nucleocapsid, and ORF1ab and include sites of mutation in current variants of concern. Some epitopes are identified in the majority of samples, while others are rare, and we find variation in the number of epitopes targeted between individuals. We find low levels of SARS-CoV-2 cross-reactivity in individuals with no exposure to the virus and significant cross-reactivity with endemic human coronaviruses (CoVs) in convalescent sera from patients with COVID-19. [Display omitted] •Pan-coronavirus phage display library maps epitopes in patients with COVID-19•Most immune responses target SARS-CoV-2 S, N, and ORF1ab sequences•Certain epitopes include sites of mutation in SARS-CoV-2 variants of concern•Evidence for cross-reactivity between SARS-CoV-2 and endemic human CoVs Stoddard et al. map common and rare coronavirus epitopes in individuals with mild or moderate/severe COVID-19 and healthy, pre-pandemic individuals. They find a subset of epitopes with residues that are mutated in SARS-CoV-2 variants of concern and show evidence for cross-reactivity between SARS-CoV-2 and commonly circulating human coronaviruses.