CD4 and COVID-19: Taken together, these results (1) demonstrate an important role of SARS-CoV-2-specific CD4+ and CD8+ T cells directed against highly conserved structural and non-structural SARS-CoV-2 epitopes in protection from severe COVID-19 symptoms, (2) highlight the potential importance of these highly conserved “asymptomatic” epitopes in mounting protected CD4+ and CD8+ T cell responses against multiple SARS-CoV-2 VOCs, and (3) support targeting these conserved epitopes with a vaccine.