When comparing the polyfunctional profile of spike-specific CD4+ T cells according to the nature and sequence of exposures, our data show that in the context of a single exposure, CD4 responses to natural infection were enriched in polyfunctional cells (producing IFN-γ, IL-2, and TNF-α) compared with those who received a single dose of Ad26.COV2.S (Figure 4A). Here, CD4 is linked to infection.