The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice

COVID-19 convalescent plasmas (CCPs) are chosen for plasma therapy based on neutralizing titers and anti-Spike immunoglobulin levels. However, specific CCP characteristics that promote SARS-CoV-2 control in recipients are complex and incompletely defined. Using an in vivo imaging approach, we demonstrate that CCPs with low neutralizing and high Fc-effector activity, in contrast to those with poor Fc-function, afford effective prophylaxis and therapy in K18-hACE2 mice lethally challenged with SARS-CoV-2-nLuc. Macrophages and neutrophils significantly contributed to CCP effects during therapy but to a reduced extent under prophylaxis. Both IgG and Ig(M+A) were required during therapy, but the IgG fraction alone was sufficient during prophylaxis. Finally, despite neutralizing poorly, SARS-CoV-2 Wuhan-elicited CCPs delayed Delta and Beta variants of concern (VOC)-induced mortality in mice illustrating the contribution of polyclonal Fc-effector functions in immunity against VOCs. Thus, in addition to neutralization, Fc-effector activity is a significant criterion for CCP selection for therapeutic applications.