Functional Convalescent Plasma Antibodies and Pre-Infusion Titers Shape Early Severe COVID-19 Immune Response

Transfer of convalescent plasma (CP) was proposed early during the SARS-CoV-2 pandemic as an accessible therapy, yet trial results worldwide have been mixed, potentially due to the heterogeneous nature of CP. Here we perform deep profiling of SARS-CoV-2-specific antibody isotype, subclass, Fc-receptor binding, and Fc-mediated functional assays in CP units, and also in plasma from hospitalized COVID-19 patients before and after CP administration.  Though recipients exhibit expanded SARS-CoV-2 specific humoral immune responses, CP units possess more functional antibodies than recipient plasma.  CP functional profiles influence recipient humoral immune profiles, depending on their pre-CP SARS-CoV2 specific antibody titers. Specifically, CP-derived SARS-CoV-2 Spike-specific and Nucleocapsid-specific antibody functions both are important for the antiviral activity of CP in patients with varying levels of anti-spike protein IgG. These insights into functional antibodies in CP may inform a better understanding of correlates of immunity in ongoing large-scale CP trials and for the design of next generation monoclonal antibody therapeutic cocktails.