Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection
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.
Authors
- Madeline J. Lee (ORCID: https://orcid.org/0000-0001-5039-6806)
- Susan Holmes (ORCID: https://orcid.org/0000-0002-2208-8168)
- Wenming Zhang (ORCID: https://orcid.org/0000-0002-9298-8460)
- Elizabeth J. Zudock (ORCID: https://orcid.org/0000-0001-9058-7842)
- Ruth O’Hara (ORCID: https://orcid.org/0000-0001-6583-4995)
- Kassandra Pinedo
- Ruoxi Pi (ORCID: https://orcid.org/0000-0002-2491-0979)
- Rosen Mann
- Samuel Yang (ORCID: https://orcid.org/0000-0003-1123-9036)
- Drina Bogusch
- Donald Schreiber (ORCID: https://orcid.org/0000-0003-1111-310X)
- Rebecca E. Hamlin (ORCID: https://orcid.org/0000-0001-7336-6028)
- Komal Kumar
- Michal Caspi Tal (ORCID: https://orcid.org/0000-0003-2550-6246)
- Mikayla A. Stabile
- James Quinn (ORCID: https://orcid.org/0000-0002-3694-2118)
- Nimish Kathale
- Kari Christine Nadeau (ORCID: https://orcid.org/0000-0002-2146-2955)
- Jennifer A. Newberry (ORCID: https://orcid.org/0000-0002-2948-0111)
- Maureen Caracena Ty (ORCID: https://orcid.org/0000-0001-5108-7714)
- Kalani Ratnasiri (ORCID: https://orcid.org/0000-0001-5953-0004)
- Hena Din (ORCID: https://orcid.org/0000-0002-0137-769X)
- Taylor Hollis
- Shu‐Chen Lyu (ORCID: https://orcid.org/0000-0002-0563-362X)
- Bali Pulendran (ORCID: https://orcid.org/0000-0001-6517-4333)
- Evan Do
- Nancy Q. Zhao (ORCID: https://orcid.org/0000-0001-6217-854X)
- Leslie Chan (ORCID: https://orcid.org/0000-0002-5064-140X)
- Rosemary Vergara (ORCID: https://orcid.org/0000-0001-5406-3785)
- Anita Visweswaran
- Andra L. Blomkalns (ORCID: https://orcid.org/0000-0001-5760-6351)
- Michele Ugur
- Jonasel Roque
- Kathleen D. Press (ORCID: https://orcid.org/0000-0002-6548-7513)
- Monali Manohar (ORCID: https://orcid.org/0000-0002-1869-2645)
- James Krempski (ORCID: https://orcid.org/0000-0003-4901-5791)
- Lauren de la Parte
- Giovanny J. Martínez-Colón (ORCID: https://orcid.org/0000-0001-6792-8004)
- Angela J. Rogers (ORCID: https://orcid.org/0000-0001-6969-6200)
- Kathryn Jee
- Laura J. Simpson
- Euan Angus Ashley (ORCID: https://orcid.org/0000-0001-9418-9577)
- Iris Chang (ORCID: https://orcid.org/0009-0007-1971-8513)
- Andrea Baird
- Catherine A. Blish (ORCID: https://orcid.org/0000-0001-6946-7627)
- Arjun Rustagi (ORCID: https://orcid.org/0000-0002-6921-1012)
- Julia L. McKechnie
- Thanmayi Ranganath (ORCID: https://orcid.org/0000-0001-9865-2119)
- Kazim Haider
- Andrea Fernandes (ORCID: https://orcid.org/0000-0002-2855-4262)
- Aaron J. Wilk (ORCID: https://orcid.org/0000-0003-1430-5852)
- Georgie Nahass
- Rachel Brewer
- Geoffrey T. Ivison (ORCID: https://orcid.org/0000-0002-3612-0069)
- S. Pienkos
- Kim Q.T. Tran
Institutions
- Harvard University (US)
- Chan Zuckerberg Initiative (United States) (US)
- Stanford University (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-01-29
- DOI
- https://doi.org/10.1126/scitranslmed.adq1086
- Citations
- 18
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 14.35
Funders
- Bill and Melinda Gates Foundation
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases