Overall, except for Orf1ab2210–2218- and S976–984-specific-CD8+ T cells, the unvaccinated severely ill and fatal patients (i.e., patients with severity 3, 4, and 5) had significantly higher frequencies of exhausted CD8+ T cells co-expressing PD-1+TIGIT+ or TIM-3+CTLA-4 compared to unvaccinated asymptomatic COVID-19 patients with little to no disease (i.e., patients with severity 0, 1, and 2). This evidence concerns the gene CD8A and COVID-19.