Eosinophils protect against SARS-CoV-2 following a vaccine breakthrough infection
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ABSTRACT:
PROVIDER: PRJNA1144986 | ENA |
REPOSITORIES: ENA
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Project description:Waning immunity and the emergence of immune evasive SARS-CoV-2 variants jeopardize vaccine efficacy and contribute to breakthrough infections. The immune response that promotes vaccine-induced protection against SARS-CoV-2 breakthrough infection remains poorly understood. To model breakthrough infections, we vaccinated mice with a low dose vaccine formulation containing MF59-like adjuvant with prefusion-stabilized SARS-CoV-2 spike protein and challenged with immune evasive B.1.351 variant. Here, we show that eosinophils are required for protection against SARS-CoV-2 during a vaccine breakthrough infection. We found that vaccine breakthrough infection leads to a 2-log reduction in lung viral burden with restricted replication within the large airways as compared to naïve infected mice. Despite reduced antiviral gene expression, infected vaccinated mice show increased immune cell infiltration, characterized by monocytes, interstitial macrophages, and eosinophils, but with reduced activation markers into the lung parenchyma as compared to infected naïve mice. Single cell RNA-seq revealed that viral RNA was highly associated with eosinophils that corresponded to an IFN-γ biased phenotype and expression of antiviral genes including Cystatin B, an inhibitor of cysteine protease involved in SARS-CoV-2 entry via the endosome. Monocytes from infected vaccinated, but not naïve, mice showed high expression for eosinophil chemoattractant Ccl24 (eotaxin-2). Antibody-mediated depletion of eosinophils prior to infection of vaccinated mice resulted in increased virus replication and viral antigen staining deep in the lungs as compared to isotype control infected vaccinated mice. These results demonstrate the importance of eosinophils in vaccine-mediated protection and highlight the need for durable antibody responses that protect against lung infection and inflammation.
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Project description:Hybrid immunity (vaccination + natural infection) to SARS-CoV-2 provides superior protection to re-infection. We performed immune profiling studies during breakthrough infections in mRNA-vaccinated hamsters to evaluate hybrid immunity induction. Vaccine was dosed to induce binding antibody titers against ancestral spike, but not efficient virus neutralization of ancestral SARS-CoV-2 or variants of concern (VoCs). Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha but allowed breakthrough infections in Beta, Delta and Mu-challenged hamsters. Vaccination primed for T cell responses that were boosted by infection. Infection back-boosted neutralizing antibody responses against ancestral virus and VoCs. Hybrid immunity resulted in more cross-reactive sera, reflected by smaller antigenic cartography distances. Transcriptomics post infection reflects both vaccination status and disease course, and suggests a role for interstitial macrophages in vaccine-mediated protection. Therefore, protection by vaccination, even in the absence of neutralizing antibodies, correlates with recall of broadly reactive B- and T-cell responses.
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Project description:At this stage in the COVID-19 pandemic, most infections are 'breakthrough' infections that occur in individuals with prior immunity to SARS-CoV-2 through infection or vaccination. Understanding both innate and adaptive immune induction in the setting of breakthrough infection is critical to refining vaccine strategies to ensure long-term efficacy against emerging variants, yet existing studies have primarily focused on adaptive immune responses. Here, we performed single-cell transcriptomic, proteomic, and functional profiling of innate and adaptive immunity during primary and breakthrough COVID-19 infections by comparing immune responses between unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a significantly less activated transcriptomic profile in CD56dim NK cells and monocytes, with induction of pathways limiting NK cell proliferation and monocyte migratory potential. Furthermore, we observed a female-specific trend of increased transcriptomic activation of CD16+ monocytes and type-2 conventional dendritic cells (cDC2s) during breakthrough infections. Despite these differences, antibody-dependent cellular cytotoxicity responses were similar between breakthrough and primary infection groups. These insights suggest that prior vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.
2025-01-30 | GSE261862 | GEO
Project description:SARS-CoV-2 vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P=3.2 x 10-9), which we replicate in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the Wuhan and Alpha-variant waves compared to non-carriers (HR 0.63, 0.42-0.93, P=0.02). We identify a distinct S-derived peptide that is predicted to bind effectively to HLA-DQB1*06 compared to other equivalent alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days post first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.
| EGAS00001006909 | EGA