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

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. Vaccines to SARS-CoV-2 clearly stimulate virus specific T cell and antibody responses but T cell-mediated protection is challenging to show. Here the authors use PBMC samples from an open-label clinical trial of different prototype and variant-specific COVID-19 vaccine boosters to examine the function and phenotype of T cell populations and how T cell response levels associate with risk of, and with protection against, symptomatic SARS-CoV-2 infection.

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Publication Details

Journal
Nature Communications
Published
2026-10-06
DOI
https://doi.org/10.1038/s41467-026-78444-6
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
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article

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

Angela R Branche, Robert L. Atmar, Martín Bäcker, Lilly Cheng Immergluck et al.
Nature Communications
SARS-CoV-2 and COVID-19 Research
article

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

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

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. Vaccines to SARS-CoV-2 clearly stimulate virus specific T cell and antibody responses but T cell-mediated protection is challenging to show. Here the authors use PBMC samples from an open-label clinical trial of different prototype and variant-specific COVID-19 vaccine boosters to examine the function and phenotype of T cell populations and how T cell response levels associate with risk of, and with protection against, symptomatic SARS-CoV-2 infection.

Nature Communications
Tulane University (US), University of Iowa (US), Brigham and Women's Hospital (US), San Francisco General Hospital (US), National Institutes of Health (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), Harvard University (US), Howard University (US), Long Island University (US), Kaiser Permanente Washington Health Research Institute (US), Emory University (US), Duke University (US), University of California, San Francisco (US), Baylor College of Medicine (US), George Washington University (US), University of Washington (US), Washington University in St. Louis (US), University of Rochester Medical Center (US), University of Alabama at Birmingham (US), University of California San Diego (US), University of Illinois Chicago (US), Fred Hutch Cancer Center (US), Howard University Hospital (US), Emmes (United States) (US), Duke Medical Center (US), Frederick National Laboratory for Cancer Research (US), National Institute of Allergy and Infectious Diseases (US), Children's Healthcare of Atlanta (US), Saint Louis University (US), University of Rochester (US), The University of Texas Medical Branch at Galveston (US), New York University (US), Morehouse School of Medicine (US), University of Pennsylvania (US)
Openalex Percentile: Top 11%
SARS-CoV-2 and COVID-19 Research
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