SARS-CoV-2 mRNA vaccination elicits broad and potent Fc effector functions to VOCs in vulnerable populations.

SARS-CoV-2 variants have continuously emerged even as highly effective vaccines have been widely deployed. Reduced neutralization observed against variants of concern (VOC) raises the question as to whether other antiviral antibody activities are similarly compromised, or if they might compensate for lost neutralization activity. In this study, the breadth and potency of antibody recognition and effector function was surveyed in both healthy individuals as well as immunologically vulnerable subjects following either natural infection or receipt of an mRNA vaccine. Considering pregnant women as a model cohort with higher risk of severe illness and death, we observed similar binding and functional breadth for healthy and immunologically vulnerable populations. In contrast, considerably greater functional antibody breadth and potency across VOC was associated with vaccination than prior infection. However, greater antibody functional activity targeting the endemic coronavirus OC43 was noted among convalescent individuals, illustrating a dichotomy in recognition between close and distant human coronavirus strains that was associated with exposure history. Probing the full-length spike and receptor binding domain (RBD) revealed that antibody-mediated Fc effector functions were better maintained against full-length spike as compared to RBD. This analysis of antibody functions in healthy and vulnerable populations across a panel of SARS-CoV-2 VOC and extending through endemic alphacoronavirus strains suggests the differential potential for antibody effector functions to contribute to protecting vaccinated and convalescent subjects as the pandemic progresses and novel variants continue to evolve. One Sentence Summary: As compared to natural infection with SARS-CoV-2, vaccination drives superior functional antibody breadth raising hopes for candidate universal CoV vaccines.