Pathogens and Immunity (Nov 2023)

Dynamics of T-cell Responses Following COVID-19 mRNA Vaccination and Breakthrough Infection in Older Adults

  • Sneha Datwani,
  • Rebecca Kalikawe,
  • Francis Mwimanzi,
  • Sarah Speckmaier,
  • Richard Liang,
  • Yurou Sang,
  • Rachel Waterworth,
  • Fatima Yaseen,
  • Hope Lapointe,
  • Evan Barad,
  • Mari DeMarco,
  • Daniel Holmes,
  • Janet Simons,
  • Julio Montaner,
  • Marc Romney,
  • Zabrina Brumme,
  • Mark Brockman

DOI
https://doi.org/10.20411/pai.v8i1.613
Journal volume & issue
Vol. 8, no. 1

Abstract

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Introduction: While older adults generally mount weaker antibody responses to a primary COVID-19 vaccine series, T-cell responses remain less well characterized in this population. We compared SARS-CoV-2 spike-specific T-cell responses after 2- and 3-dose COVID-19 mRNA vaccination and subsequent breakthrough infection in older and younger adults. Methods: We quantified CD4+ and CD8+ T-cells reactive to overlapping peptides spanning the ancestral SARS-CoV-2 spike protein in 40 older adults (median age 79) and 50 younger health care workers (median age 39), all COVID-19 naive, using an activation-induced marker assay. T-cell responses were further assessed in 24 participants, including 8 older adults, who subsequently experienced their first SARS-CoV-2 breakthrough infection. Results: A third COVID-19 mRNA vaccine dose significantly boosted spike-specific CD4+ and CD8+ T-cell frequencies to above 2-dose levels in older and younger adults. T-cell frequencies did not significantly differ between older and younger adults after either dose. Multivariable analyses adjusting for sociodemographic, health, and vaccine-related variables confirmed that older age was not associated with impaired cellular responses. Instead, the strongest predictors of CD4+ and CD8+ T-cell frequencies post-third-dose were their corresponding post-second-dose frequencies. Breakthrough infection significantly increased both CD4+ and CD8+ T-cell frequencies, to comparable levels in older and younger adults. Exploratory analyses revealed an association between HLA-A*02:03 and higher post-vaccination CD8+ T-cell frequencies, which may be attributable to numerous strong-binding HLA-A*02:03-specific CD8+ T-cell epitopes in the spike protein. Conclusion: Older adults mount robust T-cell responses to 2- and 3-dose COVID-19 mRNA vaccination, which are further boosted following breakthrough infection.

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