In this preprint by Ng et al., binding IgG antibodies to conserved epitopes from SARS-CoV-2 S and N proteins were detected by flow cytometry and ELISA in approximately 10% of healthy individuals with a recent history of infection by human endemic coronaviruses (HCoVs). Of note, sera from the same donors were found to have SARS-CoV-2 neutralization activity comparable to that of samples from seropositive patients with COVID-19, which suggests that cross-neutralizing antibodies developed in response to previous HCoV exposure might interfere with SARS-CoV-2 entry into target cells. Further studies are needed to assess the potentially protective role of pre-existing cross-reactive antibodies in healthy individuals in the context of COVID-19 immunopathogenesis.