PopCover-2.0. Improved Selection of Peptide Sets With Optimal HLA and Pathogen Diversity Coverage

Abstract

The use of minimal peptide sets offers an appealing alternative for design of vaccines and T cell diagnostics compared to conventional whole protein approaches. T cell immunogenicity towards peptides is contingent on binding to human leukocyte antigen (HLA) molecules of the given individual. HLA is highly polymorphic, and each variant typically presents a different repertoire of peptides. This polymorphism combined with pathogen diversity challenges the rational selection of peptide sets with broad immunogenic potential and population coverage. Here we propose PopCover-2.0, a simple yet highly effective method, for resolving this challenge. The method takes as input a set of (predicted) CD8 and/or CD4 T cell epitopes with associated HLA restriction and pathogen strain annotation together with information on HLA allele frequencies, and identifies peptide sets with optimal pathogen and HLA (class I and II) coverage. PopCover-2.0 was benchmarked on historic data in the context of HIV and SARS-CoV-2. Further, the immunogenicity of the selected SARS-CoV-2 peptides was confirmed by experimentally validating the peptide pools for T cell responses in a panel of SARS-CoV-2 infected individuals. In summary, PopCover-2.0 is an effective method for rational selection of peptide subsets with broad HLA and pathogen coverage. The tool is available at https://services.healthtech.dtu.dk/service.php?PopCover-2.0.

Peptide-Based Vaccines for Tuberculosis

“…Therefore, how to choose epitopes with strong immunogenicity and antigenicity but low toxicity and allergenicity is a challenge for peptide-based vaccine design. To overcome these obstacles, some new algorithms, models or servers have been developed, including IEDB MHC I immunogenicity, IEDB CD4 T cell immunogenicity prediction, MARIA, BciPep, and PopCover-2.0 for immunogenicity (67)(68)(69)(70)(71), VaxiJen 2.0 and ANTIGENpro for antigenicity (72,73), AllerTOP v 2.0, AllergenFP v.1.0, AlgPred 2.0, and Allermatch ™ for allergenicity (74)(75)(76)(77), ToxinPred and T3DB for toxicity (78,79). In addition, other useful tools have been developed to help scientists design more effective peptide-based vaccines, such as IEDB Clusters with Similar Sequences for epitope cluster analysis (80), PIP-EL for proinflammatory peptides prediction (81), and PreAIP for anti-inflammatory peptides prediction (82).…”

The MegaPool Approach to Characterize Adaptive CD4+ and CD8+ T Cell Responses

“…Given that each HLA molecule has a different set of peptide specificities, HLA polygeny and polymorphism are a powerful force, amplifying the diversity of epitope repertoires recognized in humans (for review, see, e.g., Little & Parham, 1999;Madden, 1995;Parham, 1988;Sidney et al, 2008;Stevanovic, 2002). At the same time, this large diversity poses unique challenges for approaches to measure T cell responses (McKinney et al, 2013;Nilsson et al, 2021;Sidney et al, 2020). Utilizing just a handful of epitopes and HLA molecules will most likely result in biased and incomplete coverage of the T cell responses and provide a skewed and incomplete assessment of responses.…”

“…At the same time, this large diversity poses unique challenges for approaches to measure T cell responses (McKinney et al., 2013; Nilsson et al., 2021; Sidney et al., 2020). Utilizing just a handful of epitopes and HLA molecules will most likely result in biased and incomplete coverage of the T cell responses and provide a skewed and incomplete assessment of responses.…”