@article{ad66f84a1419449f975b3b89c845947c,
title = "Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses",
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+ 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.",
keywords = "CD8 T cells, COVID-19, epitopes, protection, sarbecovirus, SARS-CoV-2, vaccine, variants",
author = "Anusha Nathan and Rossin, \{Elizabeth J.\} and Clarety Kaseke and Park, \{Ryan J.\} and Ashok Khatri and Dylan Koundakjian and Urbach, \{Jonathan M.\} and Singh, \{Nishant K.\} and Arman Bashirova and Rhoda Tano-Menka and Fernando Senjobe and Waring, \{Michael T.\} and Alicja Piechocka-Trocha and Garcia-Beltran, \{Wilfredo F.\} and Iafrate, \{A. John\} and Vivek Naranbhai and Mary Carrington and Walker, \{Bruce D.\} and Gaiha, \{Gaurav D.\}",
note = "Funding Information: We thank Alejandro Balazs and Evan Lam for assistance with pseudotyped lentivirus infectivity assays; Maia Pavlovic, David Gregory, and Mark Poznansky for access to COVID-19 vaccinee specimens; and Shiv Pillai, Vinay Mahajan, and David Collins for their scientific advice. Access to convalescent patient samples was facilitated by the MassCPR. This study was supported by NIH grants P01 DK011794-51A1 (A.K.), R01AI149704 (B.D.W.), UM1AI144462 (G.D.G. and B.D.W.), and DP2AI154421 (G.D.G.) and a grant from the MassCPR (B.D.W. and G.D.G.). Additional support was provided by the Howard Hughes Medical Institute (B.D.W.); the Ragon Institute of MGH, MIT and Harvard (B.D.W. and G.D.G.); the Mark and Lisa Schwartz Foundation and Enid Schwartz (B.D.W.); and Sandy and Paul Edgerly . E.J.R. is supported by the Heed Ophthalmic Foundation . G.D.G. is supported by the Bill and Melinda Gates Foundation , a Burroughs Wellcome Career Award for Medical Scientists, and the Gilead HIV Research Scholars Program . This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research under contract HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH , Frederick National Lab, Center for Cancer Research. The graphical abstract was prepared using BioRender. Funding Information: We thank Alejandro Balazs and Evan Lam for assistance with pseudotyped lentivirus infectivity assays; Maia Pavlovic, David Gregory, and Mark Poznansky for access to COVID-19 vaccinee specimens; and Shiv Pillai, Vinay Mahajan, and David Collins for their scientific advice. Access to convalescent patient samples was facilitated by the MassCPR. This study was supported by NIH grants P01 DK011794-51A1 (A.K.), R01AI149704 (B.D.W.), UM1AI144462 (G.D.G. and B.D.W.), and DP2AI154421 (G.D.G.) and a grant from the MassCPR (B.D.W. and G.D.G.). Additional support was provided by the Howard Hughes Medical Institute (B.D.W.); the Ragon Institute of MGH, MIT and Harvard (B.D.W. and G.D.G.); the Mark and Lisa Schwartz Foundation and Enid Schwartz (B.D.W.); and Sandy and Paul Edgerly. E.J.R. is supported by the Heed Ophthalmic Foundation. G.D.G. is supported by the Bill and Melinda Gates Foundation, a Burroughs Wellcome Career Award for Medical Scientists, and the Gilead HIV Research Scholars Program. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The graphical abstract was prepared using BioRender. Conceptualization, A.N. E.J.R. and G.D.G.; methodology, A.N. E.J.R. and G.D.G.; software, A.N. and E.J.R.; investigation, A.N. E.J.R. C.K. R.J.P. A.K. D.K. J.U. N.K.S. A.B. R.T.M. F.S. M.T.W. A.T. W.C.B. V.N. and G.D.G.; writing ? original draft, A.N. E.J.R. and G.D.G.; writing ? review \& editing, A.N. E.J.R. C.K. R.J.P. A.K. D.K. J.U. N.K.S. R.T.M. A.T. V.N. M.C. B.D.W. and G.D.G.; funding acquisition, A.J.I. M.C. B.D.W. and G.D.G.; resources, A.K. M.C. B.D.W. and G.D.G.; supervision, M.T.W. A.J.I, M.C. B.D.W. and G.D.G. E.J.R. and G.D.G. have filed patent application PCT/US2021/028245. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in science. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "19",
doi = "10.1016/j.cell.2021.06.029",
language = "English",
volume = "184",
pages = "4401--4413.e10",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "17",
}
SDG 3 Good Health and Well-being