Harnessing immunopeptidomics for next-generation vaccines against intracellular bacterial pathogens.

Unregulated and unmonitored use of antibiotics worldwide has transformed bacteria into “superbugs” that are non-responsive to most commonly used antibiotics. There is a strong need to explore new strategies that are effective enough to control non-responsive bacterial infections to commonly used antibiotics. Currently, vaccines are acknowledged as potent and very effective tools to help combat antimicrobial resistance associated with intracellular bacterial pathogens. However, the challenge for the researchers and clinicians lies in selecting the bacterial antigens as a potential vaccine candidate. Recent advances in mass spectrometry-based proteomics, specifically immunopeptidomics, have paved the way for a more precise and comprehensive identification of untargeted bacterial epitopes present on the exteriors of the infected cells. This review explores how immunopeptidomics is redefining vaccine development against resistant bacterial pathogens. The technology’s ability to identify non-canonical and immunodominant T-cell epitopes addresses critical gaps in current strategies, particularly for intracellular pathogens where traditional antigen screening often falls short. By synthesizing recent advances, we highlight the potential of immunopeptidomics to accelerate the design of next-generation vaccines while examining remaining translational challenges. Integrating this high-resolution antigen discovery platform into vaccine pipelines represents a critical step toward mitigating the global threat of untreatable bacterial infections.