Journal Article

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

Olsen, Kelly S., Woods, Allison, Stadler, Volker, Heise, Mark, Beck, Wolfgang, Gentry, Kaylee M., Heiss, Kirsten, Vensko, Steven, Haber, Carsten, Fini, Misha, Entwistle, Sarah, Grant, Oliver C., Smith, Christof C., Garrison, Erik, Ting, Jenny P. Y., Willis, Caryn, Carpenter, Brandon, Weiss, Jared, Garness, Jason, Routh, Eric, Sandor, Adam M., Kodysh, Julia, O’Donnell, Timothy, Woods, Robert J., Rubinsteyn, Alex, Sambade, Maria, Vincent, Benjamin G., Krajewski, Krzysztof

2021

Overview

Background Early 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). Methods We 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. Results From 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. Conclusions Overall, 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Amino Acid Sequence / Analysis / Animals / Antibodies / Antigenic determinants / B cell / B cells / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / CD4 antigen / CD8 antigen / Cell-mediated immunity / Computational Biology - methods / Conserved sequence / Coronaviruses / COVID-19 / COVID-19 - prevention & control / COVID-19 - virology / COVID-19 vaccines / COVID-19 Vaccines - administration & dosage / COVID-19 Vaccines - chemistry / Enzyme-linked immunosorbent assay / Epidemics / Epitope mapping / Epitopes, B-Lymphocyte - chemistry / Epitopes, B-Lymphocyte - immunology / Epitopes, T-Lymphocyte - chemistry / Epitopes, T-Lymphocyte - immunology / Female / Gene frequency / Generalized linear models / Glycoproteins / Glycosylation / Haplotypes / Health aspects / Histocompatibility antigen HLA / Histocompatibility Antigens Class I - chemistry / Histocompatibility Antigens Class I - metabolism / Histocompatibility Antigens Class II - chemistry / Histocompatibility Antigens Class II - metabolism / Human Genetics / Humans / Humoral immunity / Immunogenicity / Ligands / Localization / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Male / Medical research / Medicine, Experimental / Medicine/Public Health / Metabolomics / Mice / Mice, Inbred BALB C / Pandemics / Patients / Peptides / Peptides - chemistry / Peptides - immunology / Protein sources / Proteins / SARS-CoV-2 / SARS-CoV-2 - isolation & purification / SARS-CoV-2 - metabolism / Scientific equipment and supplies industry / Severe acute respiratory syndrome coronavirus 2 / Spatial discrimination / Spike glycoprotein / Spike Glycoprotein, Coronavirus - chemistry / Spike Glycoprotein, Coronavirus - immunology / Systems Biology / T cell / T cells / United States / Vaccination / vaccine / Vaccines / Viral infections