mRNA vaccines for multidrug-resistant bacteria: promise, challenges, and microbiome-informed strategies.

Antimicrobial resistance (AMR) has made multidrug-resistant organisms (MDROs), particularly ESKAPE-E pathogens (including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp, and Escherichia coli), a major threat to modern medicine. Although novel antibiotics, antimicrobial stewardship, and infection prevention remain essential, such interventions are unlikely to offset projected AMR trends on their own. Vaccines can help to mitigate AMR by preventing infections and reducing antibiotic exposure. WHO estimates that vaccines targeting 23 pathogens (excluding Neisseria gonorrhoea) could reduce global antibiotic need by 22%, equivalent to 2·5 billion defined daily doses annually. In the mRNA era, modular vaccine platforms enable rapid design of protein antigens and multivalent constructs, with emerging preclinical proof of concept against selected bacterial pathogens. In this Personal View, we argue that mRNA vaccines should be considered enabling platforms for selected protein-based MDRO targets rather than universal solutions for antibacterial vaccine development. We propose a microbiome-informed framework that distinguishes systemic protection from mucosal decolonisation and aligns antigen selection, delivery route, and trial endpoints with colonisation dynamics, microbiome resilience, and AMR reduction goals.