C3d Complement Activation and Antibody Immunity in Convalescent COVID-19: Insights From Adults and Children.

Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the complement pathway becomes activated, generating the stable split product C3d. Although C3d can modulate B cell responses through complement receptor 2 (CR2) in experimental systems, it remains unclear how circulating C3d relates to antibody responses after SARS-CoV-2 infection in humans. Here, we examined plasma C3d levels and their associations with SARS-CoV-2-specific antibody responses and clinical characteristics in convalescent adults and children. In adults, older age, male sex, and a history of severe COVID-19 were independently associated with higher C3d levels. C3d concentrations positively correlated with receptor-binding domain (RBD)-specific antibody-dependent cellular phagocytosis (ADCP), neutralizing antibody (nAb) titer, and anti-spike IgM, IgG, IgG1, and IgG3 levels. In children, C3d levels were significantly lower than in adults and correlated with anti-spike and anti-RBD IgG titers. These findings demonstrate that systemic complement activation, reflected by circulating C3d, is positively associated with SARS-CoV-2 antibody responses in both age groups. As this cross-sectional study cannot determine causality, further mechanistic and longitudinal studies are needed to define the role, if any, of C3d in shaping adaptive immunity to SARS-CoV-2.