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

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. [Display omitted] •SARS-CoV-2-specific T cell expansion rate indicates immune-response quality•Naive and memory pre-exposure repertoires inversely predict vaccine-response quality•Pre-existing memory T cells are excluded from high-quality vaccination responses•Impaired antigen-specific pre-exposure T cell repertoire as a hallmark of immune aging Determinants of immune-response quality to SARS-CoV-2 remain poorly defined. Saggau et al. examine spike-specific naive and memory T cells pre- and post-vaccination and track pre-existing memory T cell receptors. They define T cell parameters of high-quality vaccine responses and identify high pre-existing memory and low naive T cell contributions as predictors of low-quality responses, particularly in the elderly.