Antimicrobial resistance (AMR) is a mounting global crisis, projected by the WHO to cause up to 10 million deaths annually by 2050. Pseudomonas aeruginosa is among six “ESKAPE” pathogens—a group of multi-drug-resistant (MDR) organisms responsible for most nosocomial infections worldwide. Vaccines offer a powerful yet underutilised solution to antibiotic-resistant infections, though efforts over the past 50 years to develop a clinically effective vaccine against P. aeruginosa have repeatedly failed. We have developed a cutting-edge antigen discovery pipeline to validate highly immunogenic protein targets for a multi-epitope, T-cell-driven vaccine. We undertook a comprehensive in silico analysis that enabled the identification of T-cell epitopes with strong immunogenic potential. These were ranked and then assessed in vitro for their ability to induce robust, long-term T-cell responses.  The most promising candidates then progressed to in vivo evaluation in acute and chronic murine infection models. Following prime-boost immunisation, mice were challenged with P. aeruginosa and three lead candidates—PA1, PA2, and PA3—were individually assessed for their protective efficacy. All three proteins significantly reduced bacterial burden and improved clinical scores.  PA2 and PA3 notably reduced weight loss following infection, and a combination vaccine of PA2&3 further enhanced protection.   We are now focusing on optimisation of vaccine formulation and delivery whilst exploring the therapeutic potential in established infection. This vaccine and others generated using our discovery pipeline will reduce the burden on antibiotic use and drive a sustainable, long-term solution to safeguard global health.