SARS-CoV-2 crossreactive B-cells outnumber seasonal coronavirus spike-specific clones at the end of the COVID-19 pandemic.

How B-cell responses towards seasonal human coronaviruses (sHCoVs) impacted those towards SARS-CoV-2 has been widely studied, yet potential reverse effects are ill-defined. We compared sHCoV immune responses between cross-sectional pre-pandemic and end-pandemic cohorts of immunocompetent adults. We assessed Spike (S) reactive IgG and IgA serum and B-cell responses towards sHCoVs and dominant SARS-CoV-2 variants, and evaluated their contribution to OC43 neutralization. Pre-pandemic individuals were uniformly sHCoV IgG and IgA seropositive, yet SARS-CoV-2 S-reactivity was negligible. End-pandemic donors, had predominant SARS-CoV-2 responses that in part cross-reacted with sHCoV which accounted for higher serum NL63, HKU1 and OC43 antibody levels. This effect was strongest for OC43 S2 and this cross-reactive response contributed to OC43 serum neutralization. We conclude that SARS-CoV-2-specific immune responses impacted sHCoVs responses, particularly for OC43. This could have implications for immune protection and offers insights for the development of pan-coronavirus treatments and vaccines.