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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread relentlessly, associated with a high frequency of respiratory failure and mortality. Children experience largely asymptomatic disease, with rare reports of multisystem inflammatory syndrome in children (MIS-C). Identifying immune mechanisms that result in these disparate clinical phenotypes in children could provide critical insights into coronavirus disease 2019 (COVID-19) pathogenesis. Using systems serology, in this study we observed in 25 children with acute mild COVID-19 a functional phagocyte and complement-activating IgG response to SARS-CoV-2, similar to the acute responses generated in adults with mild disease. Conversely, IgA and neutrophil responses were significantly expanded in adults with severe disease. Moreover, weeks after the resolution of SARS-CoV-2 infection, children who develop MIS-C maintained highly inflammatory monocyte-activating SARS-CoV-2 IgG antibodies, distinguishable from acute disease in children but with antibody levels similar to those in convalescent adults. Collectively, these data provide unique insights into the potential mechanisms of IgG and IgA that might underlie differential disease severity as well as unexpected complications in children infected with SARS-CoV-2. A study of multisystem inflammatory syndrome in children (MIS-C) shows maintenance of elevated levels of monocyte-activating pathogen-specific IgG not seen in children infected with SARS-CoV-2 who do not develop MIS-C., Author(s): Yannic C. Bartsch [sup.1] , Chuangqi Wang [sup.2] , Tomer Zohar [sup.1] [sup.2] , Stephanie Fischinger [sup.1] , Caroline Atyeo [sup.1] , John S. Burke [sup.1] , Jaewon Kang [...]

SARS-CoV-2 mRNA vaccines confer robust protection against COVID-19, but the emergence of variants has generated concerns regarding the protective efficacy of the currently approved vaccines, which lose neutralizing potency against some variants. Emerging data suggest that antibody functions beyond neutralization may contribute to protection from the disease, but little is known about SARS-CoV-2 antibody effector functions. Here, we profiled the binding and functional capacity of convalescent antibodies and Moderna mRNA-1273 COVID-19 vaccine-induced antibodies across SARS-CoV-2 variants of concern (VOCs). Although the neutralizing responses to VOCs decreased in both groups, the Fc-mediated responses were distinct. In convalescent individuals, although antibodies exhibited robust binding to VOCs, they showed compromised interactions with Fc-receptors. Conversely, vaccine-induced antibodies also bound robustly to VOCs but continued to interact with Fc-receptors and mediate antibody effector functions. These data point to a resilience in the mRNA-vaccine-induced humoral immune response that may continue to offer protection from SARS-CoV-2 VOCs independent of neutralization. • mRNA-1273 vaccine induces spike antibodies that are able to leverage FcR binding across VOCs • Convalescent spike antibodies interact with VOCs but exhibit compromised FcR binding • VOCs differentially affect Fc effector functions in natural infection and vaccination • mRNA-1273-induced antibodies might confer protection independent of neutralization SARS-CoV-2 mRNA vaccines provide cross-variant protection against COVID-19. Whether this is mediated strictly via neutralization or is linked to effector functions that may limit, rather than block, transmission remains unknown. Kaplonek et al. show that mRNA-1273-vaccination-induced antibodies preserve Fc effector responses across variants of concern, whereas antibodies induced following natural infection show compromised interactions with Fc-receptors. [ABSTRACT FROM AUTHOR]