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Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses
Cell  (IF41.582),  Pub Date : 2021-06-30, DOI: 10.1016/j.cell.2021.06.029
Anusha Nathan, Elizabeth J. Rossin, Clarety Kaseke, Ryan J. Park, Ashok Khatri, Dylan Koundakjian, Jonathan M. Urbach, Nishant K. Singh, Arman Bashirova, Rhoda Tano-Menka, Fernando Senjobe, Michael T. Waring, Alicja Piechocka-Trocha, Wilfredo F. Garcia-Beltran, A. John Iafrate, Vivek Naranbhai, Mary Carrington, Bruce D. Walker, Gaurav D. Gaiha

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.