Endemic coronavirus infection is associated with SARS-CoV-2 Fc receptor-binding antibodies.

Recent documented infection with an endemic coronavirus (eCoV) is associated with less severe coronavirus disease 2019 (COVID-19), yet the immune mechanism behind this protection has not been fully explored. We measured both antibody and T-cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in SARS-CoV-2-naïve individuals, classified into two groups: those with or without presumed recent eCoV infections. There was no difference in neutralizing antibodies and T-cell responses against SARS-CoV-2 antigens between the two groups. SARS-CoV-2-naïve individuals with recent presumed eCoV infection, however, had higher and significantly correlated levels of Fc receptor (FcR)-binding antibodies against eCoV spikes (S) and SARS-CoV-2 S2. Recent eCoV infection boosts cross-reactive antibodies that can mediate Fc effector functions, and this may play a role in the observed heterotypic immune protection against severe COVID-19. IMPORTANCE: With the recent emergence of SARS-CoV-2 and other pathogenic coronaviruses, it is important to understand how the immune system may protect against disease from future coronavirus outbreaks. We investigated the adaptive immune responses elicited from a "common cold" eCoV and measured the cross-reactivity against SARS-CoV-2 in individuals classified as having or not having a recent eCoV infection. Although both groups had similar cross-reactive T-cell and neutralizing antibody responses, individuals with a recent eCoV infection had higher antibody levels capable of Fc receptor binding. Antibodies with enhanced Fc receptor binding could mediate the killing of virally infected cells through mechanisms such as antibody-dependent cellular cytotoxicity, which may reduce the severity of COVID-19. Antibodies capable of mediating Fc effector functions may be critical for therapies and vaccines against future pathogenic coronavirus outbreaks.