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

Mackin, S. R.; Desai, P.; Whitener, B. M.; Karl, C. E.; Liu, M.; Baric, R. S.; Edwards, D. K.; Chicz, T. M.; McNamara, R. P.; Alter, G.; Diamond, M. S.

doi:10.1101/2022.11.27.518117

bioRxiv · 10.1101/2022.11.27.518117

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

Mackin, S. R.·Desai, P.·Whitener, B. M.·Karl, C. E.·Liu, M.·Baric, R. S.·Edwards, D. K.·Chicz, T. M.·McNamara, R. P.·Alter, G.·Diamond, M. S.

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Abstract

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 (Fc{gamma}Rs) 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 (Fc{gamma}R) 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 Fc{gamma}Rs, especially murine Fc{gamma}R 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 Fc{gamma}R III. Our passive and active immunization studies in mice suggest that Fc-Fc{gamma}R engagement and alveolar macrophages are required for vaccine-induced antibody-mediated protection against infection by antigenically changed SARS-CoV-2 variants, including Omicron strains.

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Mackin, S. R., Desai, P., Whitener, B. M., Karl, C. E., Liu, M., Baric, R. S., Edwards, D. K., Chicz, T. M., McNamara, R. P., Alter, G., Diamond, M. S.. 2022-11-29. Fc-gamma receptor-dependent antibody effector functions are required for vaccine protection against infection by antigenic variants of SARS-CoV-2. https://doi.org/10.1101/2022.11.27.518117

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