Virus-specific CD8+ T cells ameliorate recovery from respiratory infections and persist long-term as cross-reactive memory pools. Understanding human epitope-specific CD8+ T cell responses directly ex vivo is needed to better define the role of CD8+ T cells in primary viral infection, long-term memory persistence and their subsequent recall following re-infection and/or vaccination. We performed in-depth analyses of tetramer-specific CD8+ T cells specific for influenza viruses and SARS-CoV-2 directly ex vivo following infection and vaccination. We identified novel immunodominant CD8+ T-cell epitopes for influenza A and B viruses and found prominent memory CD8+ T-cell pools directed towards novel broadly cross-reactive epitopes in blood and lungs of healthy individuals. In contrast to robust influenza-specific CD8+ T cells elicited after influenza virus infection, CD8+ T cells were not engaged into an immune response following influenza vaccination. Furthermore, we defined immunodominance hierarchy of CD8+ T cell responses directed against SARS-CoV-2 epitopes in adults and children. We found similar profiling of SARS-CoV-2-specific T-cell responses at quantitative, phenotypic and clonal levels in adults and children who seroconverted. In children, more prominent tetramer-specific T-cell responses were associated with seropositivity rather than PCR status alone. In contrast to influenza vaccination, COVID-19 vaccines elicited robust CD8+ T cell immunity in healthy individuals and immunosuppressed patients, suggesting that COVID-19 vaccination can be still effective in immunosuppressed patients of varying diseases. Overall, our studies provide key insights into ex vivo CD8+ T cell responses directed towards influenza A and B viruses as well as SARS-CoV-2 following infection and vaccination.