High-resolution mapping and characterization of epitopes in COVID-19 patients

Fine scale delineation of epitopes recognized by the antibody response to SARS-CoV-2 infection will be critical to understanding disease heterogeneity and informing development of safe and effective vaccines and therapeutics. The Serum Epitope Repertoire Analysis (SERA) platform leverages a high diversity random bacterial display library to identify epitope binding specificities with single amino acid resolution. We applied SERA broadly, across human, viral and viral strain proteomes in multiple cohorts with a wide range of outcomes from SARS-CoV-2 infection. We identify dominant epitope motifs and profiles which effectively classify COVID-19, distinguish mild from severe disease, and relate to neutralization activity. We identify a repertoire of epitopes shared by SARS-CoV-2 and endemic human coronaviruses and determine that a region of amino acid sequence identity shared by the SARS-CoV-2 furin cleavage site and the host protein ENaC-alpha is a potential cross-reactive epitope. Finally, we observe decreased epitope signal for mutant strains which points to reduced antibody response to mutant SARS-CoV-2. Together, these findings indicate that SERA enables high resolution of antibody epitopes that can inform data-driven design and target selection for COVID-19 diagnostics, therapeutics and vaccines. ### Competing Interest Statement The authors declare the following competing interests: ownership of stocks or shares at Serimmune, paid employment at Serimmune, board membership at Serimmune, and patent applications on behalf of Serimmune. ### Funding Statement SARS-CoV-2 sample collection and curation by the Yale IMPACT team was supported by the Yale COVID-19 resource research fund. Serimmune is a privately held company and no external funding or service was received. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Yale Cohort: Yale University IRB, Approved SBCH Cohort: Santa Barbara Cottage Health IRB (SBCH IRB), Waived (Human Subjects Exemption, de-identified remnant samples) BCA Cohort: New York Blood Center (NYBC) IRB, Waived (de-identified remnant samples) LabCorp Cohort: LabCorp clinical network IRB, Waived (de-identified remnant samples) BioIVT Cohort: BioIVT clinical network IRB, Waived (de-identified remnant samples) All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Motif enrichment and PIWAS data have been made available at: