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

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Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses
Cell ( IF 64.5 ) Pub Date : 2021-06-30 , DOI: 10.1016/j.cell.2021.06.029
Anusha Nathan ₁ , Elizabeth J Rossin ₂ , Clarety Kaseke ₃ , Ryan J Park ₄ , Ashok Khatri ₅ , Dylan Koundakjian ₃ , Jonathan M Urbach ₃ , Nishant K Singh ₆ , Arman Bashirova ₇ , Rhoda Tano-Menka ₃ , Fernando Senjobe ₈ , Michael T Waring ₉ , Alicja Piechocka-Trocha ₉ , Wilfredo F Garcia-Beltran ₁₀ , A John Iafrate ₁₁ , Vivek Naranbhai ₁₂ , Mary Carrington ₁₃ , Bruce D Walker ₁₄ , Gaurav D Gaiha ₁₅

Affiliation

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.
The Broad Institute, Cambridge, MA 02142, USA; Harvard Medical School Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA 02114, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Harvard Radiation Oncology Program, Boston, MA 02114, USA.
Massachusetts General Hospital Endocrine Division and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA.
Basic Science Program, Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD 20892, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Program in Virology, Harvard Medical School, Boston, MA 02115, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, MA 02115, USA.
Department of Pathology, Massachusetts General Hospital, MA 02115, USA.
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.
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.
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.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA.

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.

中文翻译：

针对 SARS-CoV-2 变种和 sarbecoviruses 的结构引导 T 细胞疫苗设计

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 变体的出现，可以逃避恢复期和疫苗诱导的抗体反应，重新引起人们对开发具有广泛保护性的 T 细胞疫苗的关注。在这里，我们应用基于结构的网络分析和 HLA I 类肽稳定性评估来定义SARS-CoV-2 蛋白质组中突变受限的 CD8 ^{+ T 细胞表位。}高度网络化的残基在循环变种和沙病毒中暂时保守，并且在突变时不成比例地损害刺突假型慢病毒的感染性。对 18 个全球流行等位基因的 HLA I 类稳定活性评估确定了 CD8 ⁺高度网络化区域内的 T 细胞表位，在循环的 SARS-CoV-2 变体和深度测序的初级分离株中突变频率有限。此外，这些表位在恢复期个体中引发明显的 CD8 ⁺ T 细胞反应性，但在基于 mRNA 的疫苗接受者中降低了识别能力。因此，这些数据阐明了 SARS-CoV-2 蛋白质组中的关键突变限制区域和免疫原性表位，用于针对新出现的变种和 SARS 样冠状病毒的基于 T 细胞的全球疫苗。

更新日期：2021-08-20

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