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The present disclosure includes a multiplexed peptide assay to generate an epitope-resolved view of antibody reactivity across all human coronaviruses (CoVs). PepSeq accurately classifies SARS-CoV-2 exposure status and reveals epitopes across the Spike and Nucleocapsid proteins. Two of these represent recurrent reactivities to conserved, functionally-important sites in the S2 subunit of Spike, regions that we show are also targeted for the endemic CoVs in pre-pandemic controls. At one of these sites, we demonstrate that the SARS-CoV-2 response strongly and recurrently cross-reacts with the endemic virus hCoV-OC43. The disclosed epitope-resolved analysis reveals new CoV targets for the development of diagnostics, vaccines and therapeutics, including a site that may have broad neutralizing potential.