Hybrid immunity shifts the Fc-effector quality of SARS-CoV-2 mRNA vaccine-induced immunity

Abstract

Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data reveal enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced COVID-19, pointing to a hybrid immune advantage with infection-associated immune priming. Beyond neutralizing antibodies and T cell immunity, mounting data point to a potential role for additional antibody effector functions, including opsinophagocytic activity, in the resolution of symptomatic COVID-19. Whether hybrid immunity modifies the Fc-effector profile of the mRNA vaccine-induced immune response remains incompletely understood. Thus, here we profiled the SARS-CoV-2 specific humoral immune response in a group of individuals with and without prior COVID-19. As expected, hybrid Spike-specific antibody titers were enhanced following the primary dose of the mRNA vaccine, but were similar to those achieved by naïve vaccinees after the second mRNA vaccine dose. Conversely, Spike-specific vaccine-induced Fc-receptor binding antibody levels were higher after the primary immunization in individuals with prior COVID-19, and remained higher following the second dose compared to naïve individuals, suggestive of a selective improvement in the quality, rather than the quantity, of the hybrid humoral immune response. Thus, while the magnitude of antibody titers alone may suggest that any two antigen exposures – either hybrid immunity or two doses of vaccine alone - represent a comparable prime/boost immunologic education, we find that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc effector functions against conserved regions of the virus.

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

“…In our experiments, we focused on evaluating Fc mediated effector functions as a possible mechanism of vaccine-mediated protection against antigenic variants. In vitro studies with human convalescent sera have demonstrated that Fc effector functions are retained against antigenically variant strains, and that sera of COVID-19 patients with more severe disease have compromised FcγR binding abilities and effector functions 6,15,19,40 Studies in mice with passively transferred mAbs show that Fc effector functions contribute to protection 41,42 , and this activity is maintained against antigenically distant strains even when neutralizing capacity is compromised 20 . Here, our experiments in mice show that Fc-FcγR interactions contribute to control of SARS-CoV-2 infection in vivo in the context of active or passive immunization, and that alveolar macrophages are a key cell type required for this activity.…”

Omicron‐specific mRNA vaccine induced cross‐protective immunity against ancestral SARS‐CoV‐2 infection with low neutralizing antibodies

“…There are three mechanisms of vaccine‐induced protection against SARS‐CoV‐2 infection that include binding antibodies, neutralizing antibodies and CTLs. The neutralizing antibody can block virus entry and reduce virus transmission 19 . The binding antibody and CTLs are able to clear viruses through cell‐mediated killing 20 .…”

“…16 Interestingly, homologous or heterologous boosters using Wuhan-based vaccines markedly increased neutralizing antibody titers against Omicron sublineages, which may provide sufficient protection against Omicron-induced severe disease. 17 19 The binding antibody and CTLs are able to clear viruses through cell-mediated killing. 20 In the absence of CD8+ T cells, the viral load in the lung cannot be reduced but instead aggravates respiratory distress and/or damage to other organs.…”

Ending transmission of SARS-CoV-2: sterilizing immunity using an intranasal subunit vaccine

“…The superiority of hybrid immunity has been documented when the primary infection was with the Delta VOC, and now, more recently, with the Omicron VOC [59][60][61][62] . Mechanistic studies have uncovered important observations about the quality/quantity of the immune responses that explain the superiority of hybrid immunity over vaccine-induced immunity: (1) potent antibody responses with increased coverage that can neutralize multiple variants 63,64 , (2) the ability to elicit superior Fc-dependent functions 65 , and (3) unique subsets of T cells with the secretion of IFNγ and IL10 66 . Unfortunately, most mechanistic studies have focused on the immune response against the S protein, likely because the approved IM vaccines only target this protein.…”