Cross-reactive antibody responses against SARS-CoV-2 and seasonal common cold coronaviruses

Beyond SARS-CoV-2, six more coronaviruses infect humans (hCoVs), four of which cause only mild symptoms (seasonal/common cold hCoVs) 12. Previous exposures to seasonal hCoVs may elicit immunological memory that could benefit the course of SARS-CoV-2 infections 3. While cross-reactive T cells epitopes of SARS-CoV-2 and seasonal hCoVs have been reported in individuals unexposed to SARS-CoV-2 4-6, potential antibody-based cross-reactivity is incompletely understood. Here, we have probed for high resolution antibody binding against all hCoVs represented as 1,539 peptides with a phage-displayed 7 antigen library. We detected broad serum antibody responses against peptides of seasonal hCoVs in up to 75% of individuals. Recovered COVID-19 patients exhibited distinct antibody repertoires targeting variable SARS-CoV-2 epitopes, and could be accurately classified from unexposed individuals (AUC=0.96). Up to 50% of recovered patients also mounted antibody responses against unique epitopes of seasonal hCoV-OC43, that were not detectable in unexposed individuals. These results indicate substantial interindividual variability and antibody cross-reactivity between hCoVs from the direction of SARS-CoV-2 infections towards seasonal hCoVs. Our accurate high throughput assay allows profiling preexisting antibody responses against seasonal hCoVs cost-effectively and could inform on their protective nature against SARS-CoV-2.