Fc-mediated antibody functions are associated with disease severity in COVID-19.

Introduction: Fc-mediated antibody effector functions play key roles in both antiviral immunity and immunopathology in COVID-19. While antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) contribute to pathogen clearance, they may also be associated with inflammatory responses. The contribution of these pathways-particularly antibody-dependent enhancement (ADE)-to severe COVID-19 remains incompletely understood. We prospectively investigated relationships among ADE, ADCC, and ADCP across multiple SARS-CoV-2 variants from 64 patients with laboratory-confirmed SARS-CoV-2 infection. Methods: Patient Fc-mediated effector activities were profiled. Disease severity was classified using National Institutes of Health criteria. ADE was assessed using pseudotyped SARS-CoV-2 entry into THP-1 cells, whereas Fc gamma receptors (FcγR)IIIa- and FcγRIIa-mediated reporter activities (reflecting ADCC and ADCP surrogate responses, respectively) were assessed using spike-expressing A549 target cells and FcγR-expressing Jurkat-Lucia reporter cells. Functional responses were measured against wild-type SARS-CoV-2 and Omicron sublineages (B.1.1.529, BA.4/BA.5, XBB.1.5). Results: Among 64 participants (40 with mild, 24 with severe COVID-19; median age, 58 years [interquartile range, 45-71], 56% men), anti-spike IgG binding did not differ by severity. ADE activity was significantly higher in severe than mild COVID-19 and remained independently associated with severity in multivariable analysis. FcγRIIa-mediated reporter activity was higher in severe cases in descriptive and univariate analyses, but lost statistical significance after adjustment for age, sex, comorbidities, and variant period. FcγRIIIa-mediated reporter activity did not differ by severity but was reduced against Omicron variants. Plasma from severe cases promoted enhanced FcγR-dependent viral entry in pseudovirus assays; yet, subsequent live Omicron virus infection did not lead to an increase in viral RNA replication-consistent with an abortive infection without evidence of productive viral replication. Conclusion: Our findings suggest that ADE activity is associated with dysregulated Fc-mediated immune responses in severe COVID-19. Although multiple Fcγ receptor-mediated pathways were observed, the independent association of ADE with disease severity supports a potential link with excessive FcγR-mediated myeloid activation. FcγRIIa reporter activity likely reflects overlapping immune signatures rather than an independent pathogenic contribution, whereas FcγRIIIa reporter activity showed no clear relationship with clinical outcomes. These findings highlight the complexity of Fc-effector immunity and support further investigation into therapeutic strategies targeting Fc-FcγR interactions.