Live Imaging of SARS-CoV-2 Infection in Mice Reveals Neutralizing Antibodies Require Fc Function for Optimal Efficacy

Abstract

Neutralizing antibodies (NAbs) are effective in treating COVID-19 but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment in prophylaxis and therapy of K18-hACE2 mice intranasally infected with SARS-CoV-2-nanoluciferase. We visualized sequential spread of virus from the nasal cavity to the lungs followed by systemic spread to various organs including the brain, culminating in death. Highly potent NAbs from a COVID-19 convalescent subject prevented, and also effectively resolved, established infection when administered within three days of infection. In addition to direct neutralization, in vivo efficacy required Fc effector functions of NAbs, with contributions from monocytes, neutrophils and natural killer cells, to dampen inflammatory responses and limit immunopathology. Thus, our study highlights the requirement of both Fab and Fc effector functions for an optimal in vivo efficacy afforded by NAbs against SARS-CoV-2.Funding: This work was supported by NIH grants P50AI150464 to WM and PJB; R33AI122384 and RO1AI145164 to PK; George Mason University Fast Grants to MSL and PJB; P20GM125498 (awarded to UVM Translational Global Infectious Disease Research Center) to EAB; le Ministère de l’Économie et de l’Innovation du Québec, Programmede soutien aux organismes de recherche et d’innovation, Foundation du CHUM, Canadian Institutes of Health Research (CIHR) foundation grant #352417 & Rapid Research Funding Opportunity #FRN440388 to JDD and G.A.D, 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 and DEK & #36287 to JDD. and GAD; FRQS Merit Research Scholarship to DEK; CIHR fellowships to JP, SPA and GBB,MITACS Accélération postdoctoral fellowship to RG; Fred Hutch COVID-19 Research Fund to LS and ATM.Conflict of Interest: The authors declare no competing interests.Ethical Approval: 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 experiments were approved by the Institutional Animal Care and Use Committees (IACUC) of and Institutional Biosafety Committee of Yale University (IBSCYU). All standard operating procedures and protocols for IVIS imaging of SARS-CoV-2 infected animals under ABSL-3 conditions were approved by IACUC, IBSCYU and YARC.