Serological Analysis Reveals an Imbalanced IgG Subclass Composition Associated with COVID-19 Disease Severity

Yates, Jennifer L.; Ehrbar, Dylan J.; Hunt, Danielle T.; Girardin, Roxie; Dupuis, Alan P.; Payne, Anne F.; Sowizral, Mycroft; Varney, Scott; Kulas, Karen E.; Demarest, Valerie L.; Howard, Kelly M.; Carson, Kyle; Hales, Margaux; Ejemel, Monir; Li, Qi; Wang, Yang; Mantis, Nicholas J; McDonough, Kathleen A.; Lee, William T.

COVID-19 is associated with a wide spectrum of disease severity, ranging from asymptomatic to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity, and the levels of circulating SARS-CoV-2-specific antibodies, including virus neutralizing titers. Through a serological analysis of serum samples from 536 convalescent healthcare workers, we found that SARS-CoV-2-specific and virus-neutralizing antibody levels were indeed elevated in individuals that experienced severe disease. The severity-associated increase in SARS-CoV-2-specific antibody was dominated by IgG, with an IgG subclass ratio skewed towards elevated receptor binding domain (RBD)- and S1-specific IgG3. However, RBD- and S1-specific IgG1, rather than IgG3 were best correlated with virus-neutralizing titers. We propose that Spike-specific IgG3 subclass utilization contributes to COVID-19 disease severity through potent Fc-mediated effector functions. These results have significant implications for SARS-CoV-2 vaccine design, and convalescent plasma therapy.