Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2

The identification of CD4 T cell epitopes is instrumental for the design of subunit vaccines for broad protection against coronaviruses. Here we demonstrate in COVID-19-recovered individuals a robust CD4 T cell response to naturally processed SARS-CoV-2 spike (S) and nucleoprotein (N), including effector, helper, and memory T cells. By characterizing 2943 S-reactive T cell clones from 34 individuals, we found that 34% of clones and 93% of individuals recognized a conserved immunodominant S346-365 region within the RBD comprising nested HLA-DR- and HLA-DP-restricted epitopes. Using pre- and post-COVID-19 samples and S proteins from endemic coronaviruses, we identify cross-reactive T cells targeting multiple S protein sites. The immunodominant and cross-reactive epitopes identified can inform vaccination strategies to counteract emerging SARS-CoV-2 variants.