Author: Nathan, Anusha; Rossin, Elizabeth J.; Kaseke, Clarety; Park, Ryan J.; Khatri, Ashok; Koundakjian, Dylan; Urbach, Jonathan M.; Singh, Nishant K.; Bashirova, Arman; Tano-Menka, Rhoda; Senjobe, Fernando; Waring, Michael T.; Piechocka-Trocha, Alicja; Garcia-Beltran, Wilfredo F.; Iafrate, A. John; Naranbhai, Vivek; Carrington, Mary; Walker, Bruce D.; Gaiha, Gaurav D.
Title: Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses Cord-id: kraqses1 Document date: 2021_6_30
ID: kraqses1
Snippet: The emergence of 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 across the Sarbecovirus subgenus, and disproportion
Document: The emergence of 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 across the Sarbecovirus subgenus, 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 mRNA-based vaccine recipients. 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 sarbecoviruses.
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