Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection
Science Translational Medicine, 2025
Chan L., Pinedo K., Stabile M., Hamlin R., Pienkos S., Ratnasiri K., Yang S., Blomkalns A., Nadeau K., Pulendran B., O’Hara R., Rogers A., Holmes S., Blish C., Ranganath T., Zhao N., Wilk A., Vergara R., McKechnie J., de la Parte L., Dantzler K., Ty M., Kathale N., Martínez-Colón G., Rustagi A., Ivison G., Pi R., Lee M., Brewer R., Hollis T., Baird A., Ugur M., Tal M., Bogusch D., Nahass G., Haider K., Thi Tran K., Simpson L., Din H., Roque J., Mann R., Chang I., Do E., Fernandes A., Lyu S., Zhang W., Manohar M., Krempski J., Visweswaran A., Zudock E., Jee K., Kumar K., Newberry J., Quinn J., Schreiber D., Ashley E.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Infectious Diseases | Pathophysiology | Plasma | O Olink Target 96 |
Abstract
At this stage in the COVID-19 pandemic, most infections are “breakthrough” infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined 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. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 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.