Potent and dose-sparing next-generation SARS-CoV-2 vaccine, mRNA-1283, induces polyfunctional and durable T cell immunity.

Cell-mediated immunity contributes to durable protection against severe COVID-19, particularly as antibody responses wane or viral variants partially evade neutralization. Here, we characterize SARS-CoV-2-specific T cell responses elicited by a next-generation COVID-19 vaccine, mRNA-1283, which encodes the receptor-binding and N-terminal domains of the spike protein, in a phase 1 randomized clinical trial (NCT04813796). COVID-19-naïve, healthy adults (18-55 years) received two doses of mRNA-1283 (10 µg, 30 µg, or 100 µg), two doses of mRNA-1273 (100 µg; full-length spike comparator), or a single-dose regimen of mRNA-1283. Using intracellular cytokine staining, we show that two-dose regimens of mRNA-1283 or mRNA-1273 induce Th1-biased, polyfunctional spike-specific CD4+ and CD8+ T cell responses that were maintained through Day 209. TCRβ sequencing demonstrated significant increases in the breadth and frequency of SARS-CoV-2-associated TCRs, which correlated with functional spike-specific T cell responses. Therefore, the low-dose (10 µg) regimen of the next-generation COVID-19 vaccine, mRNA-1283, induces polyfunctional and durable CD4+ and CD8+ T cell immunity comparable to the standard 100 µg mRNA-1273 vaccine, supporting a dose-sparing strategy without compromising long-term cellular protection against severe COVID-19.