A detailed analysis of EM and TEMRA CD8+ T cells in acute COVID-19 allowed us to demonstrate that effector T cell subsets (CD27–CD28– EM3 within total EM subsets and CD27–CD28– effector cells within the total TEMRA subset) were elevated along with decreased levels of EM1 and pE1 cells during the acute phase of SARS-CoV-2 infection. This evidence concerns the gene CD28 and COVID-19.