Dosing interval is a major factor determining the quality of T cells induced by SARS-CoV-2 mRNA and adenoviral vaccines

Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We employ an activation induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells following mild SARS-CoV-2 infection or following one or two doses of mRNA-LNP or adenoviral vectored COVID-19 vaccines. Our findings reveal broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared to SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2 specific T cells and inform the optimization of mRNA vaccination remens.