Insufficient epitope-specific T cell clones are responsible for impaired cellular immunity to inactivated SARS-CoV-2 vaccine in older adults.

Aging is a critical risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efficacy. The immune responses to inactivated vaccine for older adults, and the underlying mechanisms of potential differences to young adults, are still unclear. Here we show that neutralizing antibody production by older adults took a longer time to reach similar levels in young adults after inactivated SARS-CoV-2 vaccination. We screened SARS-CoV-2 variant strains for epitopes that stimulate specific CD8 T cell response, and older adults exhibited weaker CD8 T-cell-mediated responses to these epitopes. Comparison of lymphocyte transcriptomes from pre-vaccinated and post-vaccinated donors suggested that the older adults had impaired antigen processing and presentation capability. Single-cell sequencing revealed that older adults had less T cell clone expansion specific to SARS-CoV-2, likely due to inadequate immune receptor repertoire size and diversity. Our study provides mechanistic insights for weaker response to inactivated vaccine by older adults and suggests the need for further vaccination optimization for the old population.