Abstract
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.
Highlights
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
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
We report here a design methodology for selecting SARS-CoV-2 vaccine peptides which combines linear B cell epitopes with both CD4+ and CD8+ T cell epitopes, as well as an evaluation of our strategy based on a murine vaccination study and a comparison with a curated dataset of published SARS-CoV-2 T cell epitopes (Fig. 1)
Summary
We designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation. Type 1 and Type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, respectively, with Th1 polarization capable of inducing moderate antibody production [15] Because of these considerations, most groups developing vaccines for SARSCoV-2 have focused on promoting Th1 response due to safety concerns and demonstrated efficacy of Th1 response [16]. Most groups developing vaccines for SARSCoV-2 have focused on promoting Th1 response due to safety concerns and demonstrated efficacy of Th1 response [16] To this end, we deduced that vaccines targeting humoral (B cells) and cytotoxic arms (CD8+ T cells) with concurrent helper signalling (CD4+ T cells), delivered with adjuvants promoting Th1 polarization, may provide optimal immunity against SARS-CoV-2
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