Almujri, Salem SalmanStylianou, ElenaNicastri, AnnalisaSatti, ImanKorompis, MarcellusLi, ShuailinVoss, Christopher J. DeAlvarez, Marco Polo PeraltaTanner, RachelBettencourt, Paulo J. G.Ternette, NicolaMcShane, Helen2025-09-052025-09-052025-07-21Almujri, S. S., Stylianou, E., Nicastri, A., & Satti, I. et al. (2025). MetE: a promising protective antigen for tuberculosis vaccine development. Frontiers in Immunology, 16, Article 1593263. https://doi.org/10.3389/fimmu.2025.15932631664-32242524d86c-d02f-4404-96b5-32c2259e55f6http://hdl.handle.net/10400.14/54680Introduction: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a significant global health concern. The existing vaccine, Bacillus Calmette-Guérin (BCG), provides inconsistent protection, highlighting the pressing need for a more effective vaccine. We aimed to identify novel MTB antigens and assess their protective efficacy as TB vaccine candidates. Methods: Using immunopeptidomics, we identified 64 and 80 unique mycobacterial antigens derived from BCG and MTB, respectively. We prioritised antigens based on HLA allele coverage through an immunoinformatics approach. Results: The candidates, hisD, metE, and mmpL12, delivered as DNA vaccines, were evaluated for efficacy in mice using the ex vivo Mycobacterial Growth Inhibition Assay (MGIA) and metE was identified as a promising candidate. In vivo murine MTB challenge experiments confirmed the protective efficacy conferred by metE when formulated as recombinant protein with AS01™ or AddaS03™ adjuvants, compared to the naïve group. The immunogenic profiles of metE formulated in the two different adjuvants differed, with metE-AS01™ inducing antigen-specific IFN-?, TNF-?, IL-2, IL-17, IgG1 and IgG2a-c, while metE-AddaS03™ induced TNF-?, IL-2, IL-17, IL-4, IgM, IgG1, IgG2b. Conclusion: Our findings highlight metE as a promising protective antigen for future TB vaccine development.engAntigen discoveryHLA/MHCImmunoinformaticsImmunopeptidomicsMass spectrometryMycobacterium tuberculosisTuberculosisVaccinesresearch article10.3389/fimmu.2025.1593263105012460584PMC1231905440761798001542659100001