Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses

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

doi:10.1016/j.cell.2021.06.029

Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses

Cell. 2021 Aug 19;184(17):4401-4413.e10. doi: 10.1016/j.cell.2021.06.029. Epub 2021 Jun 30.

Authors

Anusha Nathan¹, Elizabeth J Rossin², Clarety Kaseke³, Ryan J Park⁴, Ashok Khatri⁵, Dylan Koundakjian³, Jonathan M Urbach³, Nishant K Singh⁶, Arman Bashirova⁷, Rhoda Tano-Menka³, Fernando Senjobe⁸, Michael T Waring⁹, Alicja Piechocka-Trocha⁹, Wilfredo F Garcia-Beltran¹⁰, A John Iafrate¹¹, Vivek Naranbhai¹², Mary Carrington¹³, Bruce D Walker¹⁴, Gaurav D Gaiha¹⁵

Affiliations

¹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA.
² The Broad Institute, Cambridge, MA 02142, USA; Harvard Medical School Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA 02114, USA.
³ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Harvard Radiation Oncology Program, Boston, MA 02114, USA.
⁵ Massachusetts General Hospital Endocrine Division and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
⁶ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA.
⁷ Basic Science Program, Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD 20892, USA.
⁸ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Program in Virology, Harvard Medical School, Boston, MA 02115, USA.
⁹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹⁰ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, MA 02115, USA.
¹¹ Department of Pathology, Massachusetts General Hospital, MA 02115, USA.
¹² Department of Medicine, Massachusetts General Hospital, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for the AIDS Programme of Research in South Africa, Durban 4001, South Africa.
¹³ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Basic Science Program, Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; The Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Center for the AIDS Programme of Research in South Africa, Durban 4001, South Africa; Institute for Medical Engineering and Science and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁵ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: ggaiha@mgh.harvard.edu.

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; SARS-CoV-2; epitopes; protection; sarbecovirus; vaccine; variants.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes / immunology
COVID-19 / immunology
COVID-19 / prevention & control
COVID-19 Vaccines / chemistry
COVID-19 Vaccines / immunology*
Epitopes, T-Lymphocyte*
HLA Antigens / immunology
Humans
SARS-CoV-2 / genetics
SARS-CoV-2 / immunology
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / metabolism

Substances

COVID-19 Vaccines
Epitopes, T-Lymphocyte
HLA Antigens
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding