Functional PBMC CyTOF profiling COVID-19 breakthrough infections

At this stage in the COVID-19 pandemic, most infections are 'breakthrough' infections that occur in individuals with prior SARS-CoV-2 exposure. To refine long-term vaccine strategies against emerging variants, this study examines both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Conclusion: Breakthrough infections were characterized by a significantly less activated transcriptomic profile in monocytes and CD56dim natural killer (NK) cells, with induction of pathways limiting monocyte migratory potential and NK cell proliferation. Furthermore, we observed a female-specific trend of increased transcriptomic activation of multiple innate immune cell subsets during breakthrough infections. 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. Randomized samples across different CyTOF staining days; included batch control for every CyTOF staining day; used CytoNorm to correct for batch effects