The COVID-19 pandemic began in March 2020 and has been ongoing for just over two years now. Rapid identification of epitopes targeted during infection or vaccination can detect therapeutic target sites and evaluate vaccine efficacy and durability. Current methods are low throughput and require challenging mapping studies for epitope identification. Here we employed a peptide microarray to rapidly map SARS-CoV-2 spike and nucleocapsid proteins IgM linear epitopes detected after infection and vaccination. Linear epitope sites detected in non-human primates and patients following SARS-CoV-2 infection revealed extensive overlap and tended to localize to functionally important regions and align with reported neutralizing antibody binding sites. Similar overlap was observed following infection and vaccination, but with group-specific epitope clusters, where specific epitopes mapped to sites known or likely to inhibit protein function. The vaccine-specific epitopes mapped to the central helix and heptad repeat 2, implying differential response to the mRNA-based vaccine spike protein. Mapping linear epitopes to structural regions of known functional importance in this manner may aid in discovery of new targets for antibody therapeutics and the evaluation of vaccine response.
