Prior Vaccination Modulates Immune Response in COVID-19 Breakthrough Infections

A recent study investigating breakthrough COVID-19 infections during the SARS-CoV-2 delta variant surge found that individuals with prior vaccination exhibited a less activated immune response compared with unvaccinated individuals. The findings suggest that prior vaccination modulates innate immune activation, potentially mitigating excessive inflammatory responses. Sex-specific differences were also observed, with women displaying increased immune activation during breakthrough infections.

As the COVID-19 pandemic has progressed, most infections now occur in individuals who have prior exposure to SARS-CoV-2, either through infection or vaccination. Understanding how prior vaccination influences immune responses in breakthrough infections is essential for optimizing long-term vaccine strategies against emerging variants. While vaccines have been shown to reduce severe disease and mortality, the impact of prior vaccination on innate and adaptive immune activation during infection remains unclear.

To explore this, researchers conducted single-cell transcriptomic, proteomic, and functional profiling of immune responses in both unvaccinated and vaccinated individuals with primary and breakthrough SARS-CoV-2 infections during the Delta wave. By comparing these groups, the study aimed to characterize the differences in immune activation, particularly within innate immune cell populations.

Breakthrough infections were associated with a less activated transcriptomic profile in monocytes and natural killer (NK) cells compared to infections in unvaccinated individuals. Pathways involved in monocyte migratory potential and NK cell proliferation were downregulated in vaccinated individuals, suggesting that prior vaccination prevents excessive immune activation. An increase in transcriptomic and proteomic activation of multiple innate immune cell subsets was observed during breakthrough infections in female participants, indicating potential sex-based differences in immune response modulation.

“Prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns,” the authors concluded. “These insights underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.”

Reference

Chan L, Pinedo K, Stabile MA, et al. Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection. Sci Transl Med. 2025;17(783):eadq1086. doi:10.1126/scitranslmed.adq1086