Abstract
COVID-19 vaccines provide robust protection against severe disease, hospitalization, and death. Neutralizing antibodies are a strong correlate of protection and can prevent SARS-CoV-2 infection of the lungs. We used a conventional laboratory mouse model combined with high- or low-dose vaccination to understand the early immunological response following SARS-CoV-2 infection in the lungs of vaccinated mice. The lungs of high-dose vaccinated mice were completely protected against SARS-CoV-2 infection whereas low-dose vaccinated mice were partially protected. We observed a greater influx of total monocytes, macrophages, dendritic cells, neutrophils, and eosinophils in the lungs of low-dose vaccinated mice compared to naïve infected mice. The different proportions of innate immune cells in the lungs indicated that infection in low-dose vaccinated mice induces a unique inflammatory environment compared to naïve infected or uninfected mice. A prominent feature of infection of low-dose vaccinated mice was infiltration of eosinophils in the lungs, which we observed across different COVID-19 vaccines and SARS-CoV-2 variants. Single cell transcriptional profiling of lung parenchymal immune cells showed that viral RNA was predominantly associated with eosinophils. Eosinophils from low-dose vaccinated mice were transcriptionally distinct from naïve mice after challenge and showed an IFN-γ biased signature. Further, monocytes from low-dose vaccinated mice expressed eotaxin-2, suggesting a monocyte-eosinophil signaling axis. Antibody mediated depletion of eosinophils in low-dose vaccinated mice resulted in increased virus replication and dissemination in the lungs. These findings demonstrate the protective nature of eosinophils during SARS-CoV-2 infection in the context of vaccination and highlight quantitative and qualitative differences in the immune response in a model for vaccine breakthrough infection.