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.