Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells

Vaccine-specific CD4 + T cell, CD8 + T cell, binding antibody, and neutralizing antibody responses to the 25-μg Moderna mRNA-1273 vaccine were examined over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing cross-reactive T cell memory impacts vaccine-generated immunity. Vaccine-generated spike-specific memory CD4 + T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of T follicular helper cells and IFNγ-expressing cells. Spike-specific CD8 + T cells were generated in 88% of subjects, with equivalent memory at 6 months post-boost compared to COVID-19 cases. Lastly, subjects with pre-existing cross-reactive CD4 + T cell memory had increased CD4 + T cell and antibody responses to the vaccine, demonstrating the biological relevance of SARS-CoV-2–cross-reactive CD4 + T cells.