Evolution of SARS-CoV-2 T cell responses as a function of multiple COVID-19 boosters

• Published in: Cell reports (Cambridge) Vol. 44; no. 7; p. 115907
• Main Authors: da Silva Antunes, Ricardo, Fajardo-Rosas, Vicente, Yu, Esther Dawen, Gálvez, Rosa Isela, Abawi, Adam, Escarrega, E. Alexandar, Martínez-Pérez, Amparo, Johansson, Emil, Goodwin, Benjamin, Frazier, April, Dan, Jennifer M., Crotty, Shane, Seumois, Grégory, Weiskopf, Daniela, Vijayanand, Pandurangan, Sette, Alessandro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.07.2025; Elsevier
• Subjects: Adaptive Immunity; Adult; Aged; Antibodies, Viral - blood; Antibodies, Viral - immunology; antibody responses; asymptomatic infection; booster vaccination; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; COVID-19; COVID-19 - immunology; COVID-19 - prevention & control; COVID-19 - virology; COVID-19 Vaccines - administration & dosage; COVID-19 Vaccines - immunology; CP: Immunology; exhaustion; Female; Humans; Immunization, Secondary; Immunologic Memory; Male; Middle Aged; mRNA vaccines; SARS-CoV-2; SARS-CoV-2 - immunology; scRNA-seq; Single-Cell Analysis; Spike Glycoprotein, Coronavirus - immunology; T cell responses; T-Lymphocytes - immunology; T-Lymphocytes, Regulatory - immunology; asymptomatic infection; COVID-19; CP: Immunology; scRNA-seq; SARS-CoV-2; T cell responses; exhaustion; mRNA vaccines; booster vaccination; antibody responses
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2025.115907

We investigate the long-term impact of repeated COVID-19 vaccinations on adaptive immunity through a 3-year study of 78 individuals without reported symptomatic infections. We observe distinct dynamics in spike-specific responses across multiple vaccine doses. While antibody levels increase and stabilize with each booster, T cell responses quickly plateau and remain stable. Notably, approximately 30% of participants show evidence suggestive of asymptomatic infections. Single-cell RNA sequencing reveals a diverse and stable landscape of spike-specific T cell phenotypes without signs of exhaustion or functional impairment. Individuals with evidence of asymptomatic infection display increased frequencies of Th17-like CD4+ T cells and GZMKhi/IFNR+ CD8+ T cell subsets. In this group, repeated vaccinations correlate with an increase in regulatory T cells, potentially indicating a balanced immune response that may mitigate immunopathology. By regularly stimulating T cell memory, boosters contribute to a stable and enhanced immune response, which may provide better protection against symptomatic infections. [Display omitted] •≈30% of participants show evidence of asymptomatic infections despite no symptoms•Antibody levels increase with each booster; T cell responses plateau early and stabilize•Single-cell analysis reveals stable T cell phenotypes without exhaustion after boosters•Asymptomatic cases develop more regulatory T cells, potentially preventing pathology da Silva Antunes et al. examine SARS-CoV-2-specific immunity across 3 years of repeated vaccinations. While antibodies increase with each booster, T cells responses plateau early and remain stable without signs of exhaustion or functional impairment. Asymptomatic infections promote Th17-like and regulatory CD4+ T cell expansion, suggesting balanced immunity.