CD4 and infection: Overall, these data show that (1) in the case of a single exposure, SARS-CoV-2 infection induces a more robust spike-specific CD4+ T cell response compared with a single dose of Ad26.COV2.S; (2) the number of SARS-CoV-2 exposures, rather than the sequence in which vaccination or infection occur, shapes the SARS-CoV-2 immune response; and (3) exposure to viral variants preserves T cell responses to ancestral spike.