This study utilized two pools of 15-aa overlapping S peptides for in vitro simulation, with one pool consisting of S-I peptides derived from the N-terminal region and the other pool containing S-II peptides from the C-terminal of S. Unlike the primarily S2-reactive CD4+ T cell response observed in healthy donors, the CD4+ T cells from COVID-19 patients equally targeted the S-I and S-II peptide pools. Here, CD4 is linked to COVID-19.