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.Funding Information: This work was supported by This work was supported by NIH grant R01AI163395 to WM,le Ministère de l’Économie et de l’Innovation du Québec, Programme de soutien aux organismes de recherche et d’innovation, Foundation du CHUM, CIHR grant nos. 352417 and 177958, a CFI grant, 41027 and a Canada Research Chair on Retroviral Entry no. RCHS0235 950-232424 to AF; Canada’s COVID-19 Immunity Task Force (CITF) & Canada Foundation for Innovation (CFI) #41027 to AF, CIHR fellowships to GBB, le Ministère de l’Économie et de l’Innovation du Québec, Fondation du CHU Sainte-Justine Fonds de recherché du Québec – Santé #281662 to PB. Declaration of Interests: The authors declare no competing interests. Ethical Approval Statement: All participants consented to the study (CER #2020-004). PBMCs from healthy individuals as a source of effector cells in our ADCC assay were obtained under CRCHUM institutional review board (protocol #19.381). Research adhered to the standards indicated by the Declaration of Helsinki. All participants were adults and provided informed written consent prior to enrollment in accordance with Institutional Review Board approval.All animal experiments were approved by the Institutional Animal Care and Use Committees (IACUC) of and Institutional Biosafety Committee of Yale University (IBSCYU).