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

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

Therapeutic and vaccine-induced cross-reactive antibodies with effector function against emerging Omicron variants

“…Importantly, despite 94-fold reduced in vitro neutralizing activity, prophylactic administration of S309 (sotrovimab parent) protected mice against BQ.1.1 challenge, suggesting that Fc-dependent effector functions can compensate for substantial losses of neutralizing activity. Our observation that vaccine-elicited polyclonal plasma antibodies cross-react and trigger FcγRIIIa signaling, as a surrogate of ADCC, upon recognition of the BQ.1.1 and XBB.1 S glycoproteins, concur with observations made with prior Omicron variants 73–75 and further hint at a protective role for broadly reactive antibodies with effector functions. Our findings are consistent with a model in which the erosion of neutralizing antibody titers due to viral immune evasion is associated with increased frequency of breakthrough infections, while the persistence of functional cross-reactive antibodies contributes to protection against severe COVID-19 76 .…”

Antiviral neutralizing antibodies: from in vitro to in vivo activity

“…The role of FcRs in protection against SARS-CoV-2 strains mediated by passively transferred immune sera and by vaccine-induced polyclonal antibodies was recently investigated in mice (preprint data; not peer reviewed) 188 . It was noted that protection mediated by passive transfer of immune sera was lost in mice lacking expression of activating FcRs, in particular FcγRIII, or depleted of alveolar macrophages.…”

Diverging maternal and infant cord antibody functions from SARS-CoV-2 infection and vaccination in pregnancy

“…Accumulating data suggest that immune responses beyond direct neutralization likely shape protection in subsequent viral challenge (20)(21)(22)(23)(24)(25)55). In animal models testing monoclonal antibodies and vaccination, the absence of Fc domain-Fcg receptor engagement leads to increased viral load and pathology (25,(38)(39)(40)(41)(42).…”

“…Multiple human and animal studies show that leveraging a breadth of immune responses to differentially target several steps in viral infection and pathogenesis is likely necessary to provide durable protection (20)(21)(22)(23)(24)(25). After mRNA vaccination, the primary form of immunity transferred to the fetus is antibodies, specifically IgG.…”

“…SARS-CoV-2 mRNA vaccines and infection generate IgG with neutralizing and antibody Fc effector functions in the non-pregnant (26)(27)(28)(29) and pregnant populations (30)(31)(32)(33)(34)(35). With Fc-Fc receptor engagement on innate and adaptive immune cells (36,37), induced effector functions can prevent disease even after infection has occurred by eliminating infected cells and blocking spread (25,(38)(39)(40)(41)(42)(43)(44). Diversity of the Fc domain through differential subclass and post-translational glycosylation modulates binding to Fc receptors and the spectrum of effector functions (45)(46)(47)(48)(49)(50)(51)(52).…”