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The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination.

ABSTRACT: SARS-CoV-2 infection and vaccination generates enormous host-response heterogeneity and an age-dependent loss of immune-response quality. How the pre-exposure T cell repertoire contributes to this heterogeneity is poorly understood. We combined analysis of SARS-CoV-2-specific CD4⁺ T cells pre- and post-vaccination with longitudinal T cell receptor tracking. We identified strong pre-exposure T cell variability that correlated with subsequent immune-response quality and age. High-quality responses, defined by strong expansion of high-avidity spike-specific T cells, high interleukin-21 production, and specific immunoglobulin G, depended on an intact naive repertoire and exclusion of pre-existing memory T cells. In the elderly, T cell expansion from both compartments was severely compromised. Our results reveal that an intrinsic defect of the CD4⁺ T cell repertoire causes the age-dependent decline of immune-response quality against SARS-CoV-2 and highlight the need for alternative strategies to induce high-quality T cell responses against newly arising pathogens in the elderly.

SUBMITTER: Saggau C

PROVIDER: S-EPMC9372089 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination.

Saggau Carina C Martini Gabriela Rios GR Rosati Elisa E Meise Silja S Messner Berith B Kamps Ann-Kristin AK Bekel Nicole N Gigla Johannes J Rose Ruben R Voß Mathias M Geisen Ulf M UM Reid Hayley M HM Sümbül Melike M Tran Florian F Berner Dennis K DK Khodamoradi Yascha Y Vehreschild Maria J G T MJGT Cornely Oliver O Koehler Philipp P Krumbholz Andi A Fickenscher Helmut H Kreuzer Oliver O Schreiber Claudia C Franke Andre A Schreiber Stefan S Hoyer Bimba B Scheffold Alexander A Bacher Petra P

Immunity 20220812 10

SARS-CoV-2 infection and vaccination generates enormous host-response heterogeneity and an age-dependent loss of immune-response quality. How the pre-exposure T cell repertoire contributes to this heterogeneity is poorly understood. We combined analysis of SARS-CoV-2-specific CD4<sup>+</sup> T cells pre- and post-vaccination with longitudinal T cell receptor tracking. We identified strong pre-exposure T cell variability that correlated with subsequent immune-response quality and age. High-qualit ...[more]

PMID: 35985324

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Project description:The immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) becomes increasingly complex as individuals receive different combinations of vaccine doses and encounter breakthrough infections. Our study focused on the immunogenicity observed over a two-year period in healthy individuals who completed a two-dose series and then experienced booster and/or Omicron infection. In June 2023, we recruited 78 healthcare workers who had previously participated in clinical research initiated in March 2021 at a single medical center in South Korea. At 1, 5, 11, and 25 months after a second dose, we assessed SARS-CoV-2-specific humoral and cellular immune responses. Longitudinal monitoring revealed a significant decline in humoral immunity levels after the second vaccine dose, followed by a substantial increase post-third vaccination or breakthrough infection. In contrast, stable cellular immune responses were consistently observed, with peak humoral and cellular immune measures reached at 25 months after the second dose. Among infection-naïve participants, three-dose vaccinated individuals had decreased neutralizing activity against wild-type (WT) and negative activities against Omicron subvariants BA.2 and BA.4/5, whereas those who received a fourth dose of bivalent BNT had significantly increased neutralizing activity (p < 0.05). All immune metrics tended to increase as the number of vaccine doses increased. Among participants with 4-exposure, homologous vaccination (mRNA × 4) led to higher humoral immunity, whereas heterologous vaccination (ChAd × 2/mRNA × 2) induced stronger cellular responses against multiple SARS-CoV-2 variants by enzyme-linked immunospot assays (p < 0.05). Immune responses from bivalent vaccines or Omicron infection did not show statistically significant differences among exposure number-matched participants (p > 0.05). Omicron exposure significantly increased cross-neutralizing activity, but magnitude of cellular immunity was not significantly altered by Omicron exposure. Our longitudinal study highlights the evolving complexity of SARS-CoV-2 immune responses, showing enhanced immunity with multiple vaccine doses and robust cellular responses from heterologous vaccination. These findings emphasize the need for ongoing surveillance to optimize vaccination strategies against emerging variants.

Dataset Information

The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination.

Publications

The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination.

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