Landscape and selection of vaccine epitopes in SARS-CoV-2

Genome Medicine

Robert J. Woods¹  Oliver C. Grant¹  Krzysztof Krajewski²  Timothy O’Donnell³  Julia Kodysh³  Allison Woods⁴  Misha Fini⁴  Kelly S. Olsen⁵  Christof C. Smith⁵  Wolfgang Beck⁵  Benjamin G. Vincent⁶  Erik Garrison⁷  Brandon Carpenter⁸  Caryn Willis⁸  Maria Sambade⁸  Kaylee M. Gentry⁸  Sarah Entwistle⁸  Eric Routh⁸  Adam M. Sandor⁸  Jason Garness⁸  Steven Vensko⁸  Mark Heise⁹  Alex Rubinsteyn^1,10  Jenny P. Y. Ting^1,11  Jared Weiss^1,12  Volker Stadler^1,13  Kirsten Heiss^1,13  Carsten Haber^1,13 

[1] Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA;Department of Biochemistry and Biophysics, UNC School of Medicine, Chapel Hill, NC, USA;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Department of Microbiology and Immunology, UNC School of Medicine, Chapel Hill, NC, USA;Department of Microbiology and Immunology, UNC School of Medicine, Chapel Hill, NC, USA;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7295, 27599-7295, Chapel Hill, NC, USA;Department of Microbiology and Immunology, UNC School of Medicine, Chapel Hill, NC, USA;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7295, 27599-7295, Chapel Hill, NC, USA;Computational Medicine Program, UNC School of Medicine, Chapel Hill, NC, USA;Curriculum in Bioinformatics and Computational Biology, UNC School of Medicine, Chapel Hill, NC, USA;Division of Hematology, Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA;Genomics Institute, University of California, Santa Cruz, CA, USA;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7295, 27599-7295, Chapel Hill, NC, USA;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7295, 27599-7295, Chapel Hill, NC, USA;Department of Genetics, UNC School of Medicine, Chapel Hill, NC, USA;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7295, 27599-7295, Chapel Hill, NC, USA;Department of Genetics, UNC School of Medicine, Chapel Hill, NC, USA;Computational Medicine Program, UNC School of Medicine, Chapel Hill, NC, USA;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7295, 27599-7295, Chapel Hill, NC, USA;Department of Genetics, UNC School of Medicine, Chapel Hill, NC, USA;Institute for Inflammatory Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;Center for Translational Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7295, 27599-7295, Chapel Hill, NC, USA;Division of Medical Oncology, Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA;PEPperPRINT GmbH, Heidelberg, Germany;

关键词: SARS-CoV-2;    COVID-19;    vaccine;    T cell;    B cell;   

DOI  :  10.1186/s13073-021-00910-1

来源: Springer

【 摘 要 】

BackgroundEarly in the pandemic, we designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation. The rationale for this design was to drive both humoral and cellular immunity with high specificity while avoiding undesired effects such as antibody-dependent enhancement (ADE).MethodsWe explored the set of computationally predicted SARS-CoV-2 HLA-I and HLA-II ligands, examining protein source, concurrent human/murine coverage, and population coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, sequence conservation, source protein abundance, and coverage of high frequency HLA alleles. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering for surface accessibility, sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites.ResultsFrom 58 initial candidates, three B cell epitope regions were identified. From 3730 (MHC-I) and 5045 (MHC-II) candidate ligands, 292 CD8+ and 284 CD4+ T cell epitopes were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we proposed a set of 22 SARS-CoV-2 vaccine peptides for use in subsequent murine studies. We curated a dataset of ~ 1000 observed T cell epitopes from convalescent COVID-19 patients across eight studies, showing 8/15 recurrent epitope regions to overlap with at least one of our candidate peptides. Of the 22 candidate vaccine peptides, 16 (n = 10 T cell epitope optimized; n = 6 B cell epitope optimized) were manually selected to decrease their degree of sequence overlap and then synthesized. The immunogenicity of the synthesized vaccine peptides was validated using ELISpot and ELISA following murine vaccination. Strong T cell responses were observed in 7/10 T cell epitope optimized peptides following vaccination. Humoral responses were deficient, likely due to the unrestricted conformational space inhabited by linear vaccine peptides.ConclusionsOverall, we find our selection process and vaccine formulation to be appropriate for identifying T cell epitopes and eliciting T cell responses against those epitopes. Further studies are needed to optimize prediction and induction of B cell responses, as well as study the protective capacity of predicted T and B cell epitopes.

【 授权许可】

CC BY