LAUSR

A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. To study the biology of afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG–Fc-gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from patients with COVID-19 induced inflammatory cytokine production and robust infiltration of the lung by immune cells. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by messenger RNA SARS-CoV-2 vaccines were highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. Vaccine-elicited IgG did not promote an inflammatory lung response. These results show that human IgG-FcγR interactions regulate inflammation in the lung and define distinct lung activities mediated by the IgG that are associated with protection against, or progression to, severe COVID-19. Description Divergent early antibody structures are associated with severe COVID-19 and are functionally distinct from mRNA vaccine–elicited antibodies in vivo. Afucosylated antibodies Severe coronavirus disease 2019 (COVID-19) is associated with a hyperactive inflammatory response, but the mechanisms driving this response remain unclear. Here, Chakraborty et al. investigated the role of antibody fucosylation in driving COVID-19 severity. The authors found that severe COVID-19 was associated with increased abundance of non-neutralizing, afucosylated immunoglobulin G (IgG) antibodies, which were not present in those with milder disease or in those receiving COVID-19 mRNA vaccines. The authors administered immune complexes formed by spike protein and antibodies from patients with severe or mild COVID-19, as well as vaccine-elicited antibodies, to the lungs of mice expressing human Fc receptors, finding that antibodies from individuals with severe COVID-19 drove inflammatory cytokine production and immune cell infiltration into the lung. Together, these findings implicate early non-neutralizing, afucosylated IgG antibodies in COVID-19.