CD4 and COVID-19: Altogether, these results indicate that immunization with the pan-variant SARS-CoV-2 vaccine bearing conserved “universal” B- and T- cell epitope induced cross-protective antibodies, CD8+ and CD4+ T cells that infiltrated the lungs, facilitate virus clearance, and reduced COVID-19-related lung pathology following infection with various multiple SARS-CoV-2 VOCs.