Distinct T cell correlates of COVID-19 risk before and after a second booster in previously SARS-CoV-2 infected versus naïve COVAIL trial participants

Bo Zhang; Youyi Fong; Chenchen Yu; Shiyu Chen; Valentin Voillet; Bhavesh Borate; Katharine Schwedhelm; Zhe Chen; Jing Wang; Nadine G. Rouphael; Angela R. Branche; David J. Diemert; Ann R. Falsey; Daniel S. Graciaa; Lindsey R. Baden; Sharon E. Frey; Jennifer A. Whitaker; Susan J. Little; Satoshi Kamidani; Emmanuel B. Walter; Richard M. Novak; Richard Rupp; Lisa A. Jackson; Craig A. Magaret; Lindsay N. Carpp; Tara M. Babu; Angelica C. Kottkamp; Anne F. Luetkemeyer; Lilly C. Immergluck; Rachel M. Presti; Martín Bäcker; Patricia L. Winokur; Siham M. Mahgoub; Paul A. Goepfert; Dahlene N. Fusco; Robert L. Atmar; Christine M. Posavad; Jinjian Mu; Mat Makowski; Mamodikoe K. Makhene; Seema U. Nayak; Paul C. Roberts; Dean Follmann; Stephen C. De Rosa; M. Juliana McElrath; Peter B. Gilbert; Coronavirus Variant Immunologic Landscape Trial (COVAIL) Study Team

doi:10.1038/s41467-026-78444-6

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Distinct T cell correlates of COVID-19 risk before and after a second booster in previously SARS-CoV-2 infected versus naïve COVAIL trial participants

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Distinct T cell correlates of COVID-19 risk before and after a second booster in previously SARS-CoV-2 infected versus naïve COVAIL trial participants

Bo Zhang, Youyi Fong, Chenchen Yu, Shiyu Chen, Valentin Voillet, Bhavesh Borate, Katharine Schwedhelm, Zhe Chen, Jing Wang, Nadine G. Rouphael, …

Nature communications

10/06/2026

DOI: 10.1038/s41467-026-78444-6

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Abstract

The relationship between SARS-CoV-2-specific T cell responses and COVID-19 risk is incompletely understood, particularly after variant-adapted booster receipt. We assessed Spike-specific and Nucleocapsid-specific CD4+ and CD8+ T cell responses, measured by validated 27-color intracellular cytokine staining assay, as correlates of COVID-19 risk over 6 months in COVAIL recipients of a second SARS-CoV-2 booster on Day 1 (D1). Among one-dose mRNA recipients, D15 CD4 + T cell IFN-γ and/or IL-2 Spike BA.4/5 responses correlated inversely with COVID-19 risk for previously-infected (non-naïve) [hazard ratio (HR) = 0.62 (95% CI 0.39, 0.99) per 3-fold increase], but not SARS-CoV-2 naïve [HR = 1.03 (0.81, 1.32)], participants (22 non-naïve, 122 naïve cases). Spike-specific CD4+ T cells and neutralizing antibodies each independently predicted COVID-19 in non-naïve participants [Cox bivariate model HRs per standard deviation: D1 Spike CD4 + T cell 0.81 (0.68, 0.96), D15 titer 0.43 (0.27, 0.69), co-correlatep < 0.001]. Among non-naïve participants, high Spike-specific CD4+ T cell responses and neutralizing antibody titers marked low risk, as did polyfunctional Spike-specific CD4+ T cells expressing ≥ three cytokine(s)/markers. At the same high D15 CD4+ Spike-specific T cell levels, risk was lower for non-naïve vs. naïve participants, suggesting that these T cell responses are a proxy for unmeasured protective immune mechanism(s) operant post-SARS-CoV-2 infection.

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Title: Subtitle: Distinct T cell correlates of COVID-19 risk before and after a second booster in previously SARS-CoV-2 infected versus naïve COVAIL trial participants
Creators: Bo Zhang - University of Washington
Youyi Fong - Fred Hutch Cancer Center
Chenchen Yu - Fred Hutch Cancer Center
Shiyu Chen - Fred Hutch Cancer Center
Valentin Voillet - Fred Hutch Cancer Center
Bhavesh Borate - Fred Hutch Cancer Center
Katharine Schwedhelm - Fred Hutch Cancer Center
Zhe Chen - University of Pennsylvania
Jing Wang - Frederick National Laboratory for Cancer Research
Nadine G. Rouphael - Emory University
Angela R. Branche - University of Rochester
David J. Diemert - George Washington University
Ann R. Falsey - University of Rochester
Daniel S. Graciaa - HOPE Clinic
Lindsey R. Baden - Brigham and Women's Hospital
Sharon E. Frey - Saint Louis University
Jennifer A. Whitaker - Baylor College of Medicine
Susan J. Little - University of California San Diego
Satoshi Kamidani
Emmanuel B. Walter - Duke University
Richard M. Novak - University of Illinois Chicago
Richard Rupp - The University of Texas Medical Branch at Galveston
Lisa A. Jackson - Kaiser Permanente Washington Health Research Institute
Craig A. Magaret - Fred Hutch Cancer Center
Lindsay N. Carpp - Fred Hutch Cancer Center
Tara M. Babu - Fred Hutch Cancer Center
Angelica C. Kottkamp - Manhattan Psychiatric Center
Anne F. Luetkemeyer - University of California, San Francisco
Lilly C. Immergluck - Morehouse School of Medicine
Rachel M. Presti - Washington University in St. Louis
Martín Bäcker - Long Island University
Patricia L. Winokur - University of Iowa, Infectious Diseases
Siham M. Mahgoub - Howard University Hospital
Paul A. Goepfert - University of Alabama at Birmingham
Dahlene N. Fusco - Tulane University
Robert L. Atmar - Baylor College of Medicine
Christine M. Posavad - Fred Hutch Cancer Center
Jinjian Mu - Emmes (United States)
Mat Makowski - Emmes (United States)
Mamodikoe K. Makhene - National Institute of Allergy and Infectious Diseases
Seema U. Nayak - National Institute of Allergy and Infectious Diseases
Paul C. Roberts - National Institute of Allergy and Infectious Diseases
Dean Follmann - National Institute of Allergy and Infectious Diseases
Stephen C. De Rosa - Fred Hutch Cancer Center
M. Juliana McElrath - Fred Hutch Cancer Center
Peter B. Gilbert - Fred Hutch Cancer Center
Coronavirus Variant Immunologic Landscape Trial (COVAIL) Study Team
Resource Type: Journal article
Publication Details: Nature communications
DOI: 10.1038/s41467-026-78444-6
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: Springer Nature
Language: English
Electronic publication date: 10/06/2026
Academic Unit: Infectious Diseases; Medicine Administration; Internal Medicine
Record Identifier: 9985243882902771

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