Compromised humoral functional evolution tracks with SARS-CoV-2 mortality

Zohar, Tomer; Loos, Carolin; Fischinger, Stephanie; Atyeo, Caroline; Wang, Chuangqi; Slein, Matthew D.; Burke, John; Yu, Jingyou; Feldman, Jared; Hauser, Blake Marie; Caradonna, Tim; Schmidt, Aaron; Cai, Yongfei; Streeck, Hendrik; Ryan, Edward T.; Barouch, Dan H.; Charles, Richelle C.; Lauffenburger, Douglas; Alter, Galit

The urgent need for an effective SARS-CoV-2 vaccine has forced development to progress in the absence of well-defined correlates of immunity. While neutralization has been linked to protection against other pathogens, whether neutralization alone will be sufficient to drive protection against SARS-CoV-2 in the broader population remains unclear. Therefore, to fully define protective humoral immunity we dissected the early evolution of the humoral response in 193 hospitalized individuals ranging from moderate-to severe. Although robust IgM and IgA responses evolved in both survivors and non-survivors with severe disease, non-survivors showed attenuated IgG responses, accompanied by compromised Fcɣ-receptor binding and Fc-effector activity, pointing to deficient humoral development rather than disease-enhancing humoral immunity. In contrast, individuals with moderate disease exhibited delayed responses that ultimately matured. These data highlight distinct humoral trajectories associated with resolution of SARS-CoV-2 infection and the need for early functional humoral immunity.