Next-generation vaccines against bacterial pathogens: mRNA and beyond

The global rise of multidrug-resistant (MDR) bacterial infections has exacerbated the need for effective vaccines to prevent these hard-to-treat pathogens. Traditional vaccine approaches have achieved tremendous successes but often fall short for pathogens like <i>Mycobacterium tuberculosis</i> (TB), which evades host immunity through complex mechanisms, and for multidrug-resistant ESKAPE bacteria, where antibiotic resistance and antigenic variability complicate effective vaccine development. The COVID-19 pandemic spurred unprecedented advances in vaccine technology - particularly mRNA vaccines - reviving interest in novel platforms for bacterial diseases. Here we review next-generation vaccine strategies, focusing on nucleic acid-based platforms such as mRNA, DNA, and self-amplifying RNA (saRNA), as well as viral vector vaccines. We also examine nanoparticle technologies that serve as delivery systems or adjuvant platforms across these approaches. We discuss the unique opportunities of mRNA vaccines to induce both robust antibody and T-cell responses required for intracellular infections like TB, as well as the challenges of antigen discovery and delivery (e.g. lipid nanoparticles). Each platform's mechanism, immunogenic profile, current development status, and challenges are analyzed, including comparative insights. We highlight recent progress such as mRNA vaccine candidates against TB entering clinical trials and saRNA prototypes protecting against plague in animals. Finally, we provide a perspective on the future of vaccine strategies to combat antimicrobial resistance (AMR) - emphasizing the integration of multiple platforms, global collaborative efforts, regulatory pathways, and the translational hurdles that must be overcome to bring these next-generation vaccines from bench to bedside.