The magnitude of SARS-CoV-2–specific T cell responses correlates inversely with human disease severity, suggesting T cell involvement in primary control. Whereas many COVID-19 vaccines focus on establishing humoral immunity to viral spike protein, vaccine-elicited T cell immunity may bolster durable protection or cross-reactivity with viral variants. To better enable mechanistic and vaccination studies in mice, we identified a dominant CD8 T cell SARS-CoV-2 nucleoprotein epitope. Infection of human ACE2 transgenic mice with SARS-CoV-2 elicited robust responses to H2-D b/N 219-227, and 40% of HLA-A* 02+ COVID-19 PBMC samples isolated from hospitalized patients responded to this peptide in culture. In mice, im prime-boost nucleoprotein vaccination with heterologous vectors favored systemic CD8 T cell responses, whereas intranasal boosting favored respiratory immunity. In contrast, a single iv immunization with recombinant adenovirus established robust CD8 T cell memory both systemically and in the respiratory mucosa.