Fcγ receptor-dependent antibody effector functions are required for vaccine protection against infection by antigenic variants of SARS-CoV-2

• Published in: bioRxiv
• Main Authors: Mackin, Samantha R, Desai, Pritesh, Whitener, Bradley M, Karl, Courtney E, Liu, Meizi, Baric, Ralph S, Edwards, Darin K, Chicz, Taras M, McNamara, Ryan P, Alter, Galit, Diamond, Michael S
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 28.11.2022; Cold Spring Harbor Laboratory
• Edition: 1.1
• Subjects: Alveoli; Antibodies; Antigenic variants; Antiviral activity; Biotechnology; CD16 antigen; COVID-19; Fc receptors; Immune serum; Immunization; Infections; Macrophages; Microbiology; mRNA; Receptor mechanisms; Respiratory tract diseases; Severe acute respiratory syndrome coronavirus 2; Spike protein; Strains (organisms); Vaccines
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2022.11.27.518117

Emerging SARS-CoV-2 variants with antigenic changes in the spike protein are neutralized less efficiently by serum antibodies elicited by legacy vaccines against the ancestral Wuhan-1 virus. Nonetheless, these vaccines, including mRNA-1273 and BNT162b2, retained their ability to protect against severe disease and death, suggesting that other aspects of immunity control infection in the lung. Although vaccine-elicited antibodies can bind Fc gamma receptors (FcγRs) and mediate effector functions against SARS-CoV-2 variants, and this property correlates with improved clinical COVID-19 outcome, a causal relationship between Fc effector functions and vaccine-mediated protection against infection has not been established. Here, using passive and active immunization approaches in wild-type and Fc-gamma receptor (FcγR) KO mice, we determined the requirement for Fc effector functions to protect against SARS-CoV-2 infection. The antiviral activity of passively transferred immune serum was lost against multiple SARS-CoV-2 strains in mice lacking expression of activating FcγRs, especially murine FcγR III (CD16), or depleted of alveolar macrophages. After immunization with the preclinical mRNA-1273 vaccine, protection against Omicron BA.5 infection in the respiratory tract also was lost in mice lacking FcγR III. Our passive and active immunization studies in mice suggest that Fc-FcγR engagement and alveolar macrophages are required for vaccine-induced antibody-mediated protection against infection by antigenically changed SARS-CoV-2 variants, including Omicron strains.