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 immuno-globulin 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.

Automated summary

This study reveals the heterogeneity of immune response and age-dependent decline in immune response quality caused by SARS-CoV-2 infection and vaccination. The pre-exposure T cell repertoire is found to be correlated with immune response quality, with high-quality responses depending on intact naive repertoire and exclusion of pre-existing memory T cells. In elderly individuals, T cell expansion from both compartments is severely compromised.