tetano
Editor, Senior Moderator
Cell
. 2021 Jun 30;S0092-8674(21)00797-2.
doi: 10.1016/j.cell.2021.06.029. Online ahead of print.
Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses
Anusha Nathan[SUP] 1 [/SUP], Elizabeth J Rossin[SUP] 2 [/SUP], Clarety Kaseke[SUP] 3 [/SUP], Ryan J Park[SUP] 4 [/SUP], Ashok Khatri[SUP] 5 [/SUP], Dylan Koundakjian[SUP] 3 [/SUP], Jonathan M Urbach[SUP] 3 [/SUP], Nishant K Singh[SUP] 6 [/SUP], Arman Bashirova[SUP] 7 [/SUP], Rhoda Tano-Menka[SUP] 3 [/SUP], Fernando Senjobe[SUP] 8 [/SUP], Michael T Waring[SUP] 9 [/SUP], Alicja Piechocka-Trocha[SUP] 9 [/SUP], Wilfredo F Garcia-Beltran[SUP] 10 [/SUP], A John Iafrate[SUP] 11 [/SUP], Vivek Naranbhai[SUP] 12 [/SUP], Mary Carrington[SUP] 13 [/SUP], Bruce D Walker[SUP] 14 [/SUP], Gaurav D Gaiha[SUP] 15 [/SUP]
Affiliations
Abstract
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[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] 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.
Keywords: CD8(+) T cells; COVID-19; SARS-CoV-2; epitopes; protection; sarbecovirus; vaccine; variants.
. 2021 Jun 30;S0092-8674(21)00797-2.
doi: 10.1016/j.cell.2021.06.029. Online ahead of print.
Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses
Anusha Nathan[SUP] 1 [/SUP], Elizabeth J Rossin[SUP] 2 [/SUP], Clarety Kaseke[SUP] 3 [/SUP], Ryan J Park[SUP] 4 [/SUP], Ashok Khatri[SUP] 5 [/SUP], Dylan Koundakjian[SUP] 3 [/SUP], Jonathan M Urbach[SUP] 3 [/SUP], Nishant K Singh[SUP] 6 [/SUP], Arman Bashirova[SUP] 7 [/SUP], Rhoda Tano-Menka[SUP] 3 [/SUP], Fernando Senjobe[SUP] 8 [/SUP], Michael T Waring[SUP] 9 [/SUP], Alicja Piechocka-Trocha[SUP] 9 [/SUP], Wilfredo F Garcia-Beltran[SUP] 10 [/SUP], A John Iafrate[SUP] 11 [/SUP], Vivek Naranbhai[SUP] 12 [/SUP], Mary Carrington[SUP] 13 [/SUP], Bruce D Walker[SUP] 14 [/SUP], Gaurav D Gaiha[SUP] 15 [/SUP]
Affiliations
- PMID: 34265281
- DOI: 10.1016/j.cell.2021.06.029
Abstract
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[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] 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.
Keywords: CD8(+) T cells; COVID-19; SARS-CoV-2; epitopes; protection; sarbecovirus; vaccine; variants.