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Vaccine development has historically overlooked human leukocyte antigen (HLA) diversity, resulting in vaccines that may be effective for some populations but fail to provide sufficient protection across the globe. HLA genes are greatly polymorphic, with over 30,000 alleles around the world, and different ethnic groups exhibit distinct HLA frequencies. This genetic variation affects which pathogen-derived peptides can be presented to T-cells, directly impacting vaccine efficacy. The key knowledge gap was understanding which antigens would trigger immune responses across genetically diverse populations, as current approaches to preclinical testing largely rely on cell lines of Caucasian descent.

Baker et al. aimed to develop a globally representative approach to identifying vaccine antigens by analysing immunopeptide profiles across cell lines representing worldwide HLA diversity. Using a panel of 30 cell lines from the 1000 Genomes Project (covering 75% of the world’s most common HLA alleles and representing 70% of global populations), the team from the Foster lab used mild acid elution (MAE) to capture MHC-presented peptides from cell surfaces, followed by LC-MS/MS analysis.

Samples were analysed using an EASY-nLC 1000 coupled to a timsTOF Pro via a CaptiveSpray ion source. Peptides were separated on an IonOpticks Aurora® Ultimate™ 25×75 CSI C18 UHPLC column heated to 50°C, using 45-minute gradients for MAE samples.

This exploratory study identified 7 MHC class I and 11 MHC class II common binding motifs shared across the cell line panel. The researchers validated their approach using Salmonella enterica and SARS-CoV-2 Spike protein, detecting known immunogenic regions including OmpC (which provides 100% protection against lethal S. enterica challenge) across all three tested cell lines. The bioinformatically predicted regions showed substantial overlap with experimentally detected epitopes and previously characterised antigenic regions.

This methodology represents a paradigm shift by incorporating HLA diversity into early-stage antigen discovery before significant resources are invested in clinical trials, potentially increasing vaccine success rates whilst ensuring broad population protection.

Publication
bioRxiv

Authors

Teesha Baker, Lucy Song, Charley Cai, Selwyn Gu, & Leonard J. Foster;

Title

A globally representative immunopeptidomics approach to identify population-wide vaccine candidates