No evidence of immune exhaustion after repeated SARS-CoV-2 vaccination in vulnerable and healthy populations

Jenna M. Benoit, Jessica A. Breznik, Ying Wu, Allison Kennedy, Li-Min Liu, Braeden Cowbrough, Barbara Baker, Megan Hagerman, Catherine M. Andary, Maha Mushtaha, Nora Abdalla, Jamie D. McNicol, Gail Gauvreau, Paul Y. Kim, Judah A. Denburg, Andrew P. Costa, Darryl P. Leong, Ishac Nazy, MyLinh Duong, Jonathan L. Bramson, Maggie J. Larché, Chris P. Verschoor () and Dawn M. E. Bowdish ()
Additional contact information
Jenna M. Benoit: McMaster University
Jessica A. Breznik: McMaster University
Ying Wu: McMaster University
Allison Kennedy: McMaster University
Li-Min Liu: McMaster University
Braeden Cowbrough: McMaster University
Barbara Baker: McMaster University
Megan Hagerman: McMaster University
Catherine M. Andary: McMaster University
Maha Mushtaha: McMaster University and Hamilton Health Sciences
Nora Abdalla: McMaster University and Hamilton Health Sciences
Jamie D. McNicol: McMaster University
Gail Gauvreau: McMaster University
Paul Y. Kim: McMaster University
Judah A. Denburg: McMaster University
Andrew P. Costa: McMaster University
Darryl P. Leong: McMaster University
Ishac Nazy: McMaster University
MyLinh Duong: McMaster University
Jonathan L. Bramson: McMaster University
Maggie J. Larché: McMaster University
Chris P. Verschoor: McMaster University
Dawn M. E. Bowdish: McMaster University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Frequent SARS-CoV-2 vaccination in vulnerable populations has raised concerns that this may contribute to T cell exhaustion, which could negatively affect the quality of immune protection. Herein, we examined the impact of repeated SARS-CoV-2 vaccination on T cell phenotypic and functional exhaustion in frail older adults in long-term care (n = 23), individuals on immunosuppressive drugs (n = 10), and healthy adults (n = 43), in Canada. Spike-specific CD4+ and CD8+ T cell levels did not decline in any cohort following repeated SARS-CoV-2 vaccination, nor did the expression of exhaustion markers on spike-specific or total T cells increase. T cell production of multiple cytokines (i.e. polyfunctionality) in response to the spike protein of SARS-CoV-2 did not decline in any cohort following repeated vaccination. None of the cohorts displayed elevated levels of terminally differentiated T cells following multiple SARS-CoV-2 vaccinations. Thus, repeated SARS-CoV-2 vaccination was not associated with increased T cell exhaustion in older frail adults, immunosuppressed individuals, or healthy adults.

Date: 2025
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DOI: 10.1038/s41467-025-60216-3

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