tetano
Editor, Senior Moderator
Nat Commun
. 2026 Oct 6;17(1):11382.
doi: 10.1038/s41467-026-78444-6.
Bo Zhang 1 2 3 , Youyi Fong 1 2 3 , Chenchen Yu 1 , Shiyu Chen 1 , Valentin Voillet 1 4 , Bhavesh Borate 1 , Katharine Schwedhelm 1 , Zhe Chen 5 , Jing Wang 6 , Nadine G Rouphael 7 , Angela R Branche 8 , David J Diemert 9 , Ann R Falsey 8 , Daniel S Graciaa 7 , Lindsey R Baden 10 , Sharon E Frey 11 , Jennifer A Whitaker 12 , Susan J Little 13 , Satoshi Kamidani 14 15 , Emmanuel B Walter 16 , Richard M Novak 17 , Richard Rupp 18 , Lisa A Jackson 19 , Craig A Magaret 1 , Lindsay N Carpp 1 , Tara M Babu 20 , Angelica C Kottkamp 21 , Anne F Luetkemeyer 22 , Lilly C Immergluck 23 24 , Rachel M Presti 25 , Martín Bäcker 26 , Patricia L Winokur 27 , Siham M Mahgoub 28 , Paul A Goepfert 29 , Dahlene N Fusco 30 , Robert L Atmar 12 , Christine M Posavad 31 32 , Jinjian Mu 33 , Mat Makowski 33 , Mamodikoe K Makhene 34 , Seema U Nayak 34 , Paul C Roberts 34 , Dean Follmann 35 , Stephen C De Rosa 1 , M Juliana McElrath 1 , Peter B Gilbert 36 37 38 ; Coronavirus Variant Immunologic Landscape Trial (COVAIL) Study Team
Affiliations Expand
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.
. 2026 Oct 6;17(1):11382.
doi: 10.1038/s41467-026-78444-6.
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 1 2 3 , Youyi Fong 1 2 3 , Chenchen Yu 1 , Shiyu Chen 1 , Valentin Voillet 1 4 , Bhavesh Borate 1 , Katharine Schwedhelm 1 , Zhe Chen 5 , Jing Wang 6 , Nadine G Rouphael 7 , Angela R Branche 8 , David J Diemert 9 , Ann R Falsey 8 , Daniel S Graciaa 7 , Lindsey R Baden 10 , Sharon E Frey 11 , Jennifer A Whitaker 12 , Susan J Little 13 , Satoshi Kamidani 14 15 , Emmanuel B Walter 16 , Richard M Novak 17 , Richard Rupp 18 , Lisa A Jackson 19 , Craig A Magaret 1 , Lindsay N Carpp 1 , Tara M Babu 20 , Angelica C Kottkamp 21 , Anne F Luetkemeyer 22 , Lilly C Immergluck 23 24 , Rachel M Presti 25 , Martín Bäcker 26 , Patricia L Winokur 27 , Siham M Mahgoub 28 , Paul A Goepfert 29 , Dahlene N Fusco 30 , Robert L Atmar 12 , Christine M Posavad 31 32 , Jinjian Mu 33 , Mat Makowski 33 , Mamodikoe K Makhene 34 , Seema U Nayak 34 , Paul C Roberts 34 , Dean Follmann 35 , Stephen C De Rosa 1 , M Juliana McElrath 1 , Peter B Gilbert 36 37 38 ; Coronavirus Variant Immunologic Landscape Trial (COVAIL) Study Team
Affiliations Expand
- PMID: 42982837
- PMCID: PMC13736861
- DOI: 10.1038/s41467-026-78444-6
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.