%0 Journal Article %J Cell %D 2021 %T Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses %A Nathan, Anusha %A Rossin, Elizabeth J %A Kaseke, Clarety %A Park, Ryan J %A Khatri, Ashok %A Koundakjian, Dylan %A Urbach, Jonathan M %A Singh, Nishant K %A Bashirova, Arman %A Tano-Menka, Rhoda %A Senjobe, Fernando %A Waring, Michael T %A Piechocka-Trocha, Alicja %A Garcia-Beltran, Wilfredo F %A Iafrate, A John %A Naranbhai, Vivek %A Carrington, Mary %A Walker, Bruce D %A Gaiha, Gaurav D %K CD8-Positive T-Lymphocytes %K COVID-19 %K COVID-19 Vaccines %K Epitopes, T-Lymphocyte %K HLA Antigens %K Humans %K SARS-CoV-2 %K Spike Glycoprotein, Coronavirus %X The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape convalescent and vaccine-induced antibody responses has renewed focus on the development of broadly protective T-cell-based vaccines. Here, we apply structure-based network analysis and assessments of HLA class I peptide stability to define mutationally constrained CD8+ T cell epitopes across the SARS-CoV-2 proteome. Highly networked residues are conserved temporally among circulating variants and sarbecoviruses and disproportionately impair spike pseudotyped lentivirus infectivity when mutated. Evaluation of HLA class I stabilizing activity for 18 globally prevalent alleles identifies CD8+ T cell epitopes within highly networked regions with limited mutational frequencies in circulating SARS-CoV-2 variants and deep-sequenced primary isolates. Moreover, these epitopes elicit demonstrable CD8+ T cell reactivity in convalescent individuals but reduced recognition in recipients of mRNA-based vaccines. These data thereby elucidate key mutationally constrained regions and immunogenic epitopes in the SARS-CoV-2 proteome for a global T-cell-based vaccine against emerging variants and SARS-like coronaviruses. %B Cell %V 184 %P 4401-4413.e10 %8 2021 08 19 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/34265281?dopt=Abstract %R 10.1016/j.cell.2021.06.029