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Eosinophils protect against SARS-CoV-2 following a vaccine breakthrough infection

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE274118 | GEO | 2025/08/08

REPOSITORIES: GEO

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Project description:In the last two years, the coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a scientific and social challenge worldwide. Vaccines have been the most effective intervention for reducing virus transmission and disease severity. However, virus genetic variants are still circulating among vaccinated individuals with different symptomatology disease cases. Understanding the protective or disease associated mechanisms in vaccinated individuals is relevant to advance in vaccine development and implementation. To address this objective, serum protein profiles were characterized by quantitative proteomics and data analysis algorithms in four cohorts of vaccinated individuals uninfected and SARS-CoV-2 infected with asymptomatic, nonsevere and severe disease symptomatology. The results showed that immunoglobulins were the most overrepresented proteins in infected cohorts when compared to PCR-negative individuals. The immunoglobulin profile varied between different infected cohorts and correlated with protective or disease associated capacity. Overrepresented immunoglobulins in PCR-positive individuals correlated with protective response against SARS-CoV-2, other viruses, and thrombosis in asymptomatic cases. In nonsevere cases, correlates of protection against SARS-CoV-2 and HBV together with risk of myasthenia gravis and allergy and autoantibodies were observed. Patients with severe symptoms presented risk for allergy, chronic idiopathic thrombocytopenic purpura, and autoantibodies. The analysis of underrepresented immunoglobulins in PCR-positive compared to PCR-negative individuals identified vaccine-induced protective epitopes in various coronavirus proteins including the Spike receptor-binding domain RBD. Non-immunoglobulin proteins were associated with COVID-19 symptoms and biological processes. These results evidence host-associated differences in response to vaccination and the possibility of improving vaccine efficacy against SARS-CoV-2.

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Eosinophils protect against SARS-CoV-2 following a vaccine breakthrough infection

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