Every year, almost 150,000 people, especially children younger than five, die from infections with Shigella, the leading cause of bacterial diarrheal mortality. Antibiotics (over)use is causing increased levels of antimicrobial resistance (AMR), and Shigella is listed as a high-priority pathogen on the WHO AMR watchlist. Vaccination is a very effective strategy to mitigate AMR and reduce mortality, yet to date, no Shigella vaccines are on the market. Previous vaccine candidates failed to cross-protect across serotypes or were hampered by a lack of antigen knowledge. This project aims to discover and evaluate novel candidate antigens for a first-in-class Shigella mRNA vaccine. Antigen discovery will be performed using immunopeptidomics, an innovative technology that allows the identification of bacterial immunopeptides presented on the surface of infected cells by mass spectrometry. Highly presented bacterial antigens will be evaluated as vaccine candidates based on multiple parameters, including stable expression by human host cells using an innovative screening assay I aim to develop. The best candidates will be encoded in mRNA-liquid nanoparticle vaccine formulations and tested for their immunogenicity and protective efficacy using advanced cellular and mouse models for Shigella infection. Together, this work might lead to a much-needed vaccine against shigellosis, while also addressing fundamental gaps in our knowledge to develop next-generation bacterial mRNA vaccines.