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Traditional antimicrobial treatments consist of drugs which target different essential functions in pathogens. Nevertheless, bacteria continue to evolve new mechanisms to evade this drug-mediated killing with surprising speed on the deployment of each new drug and antibiotic worldwide, a phenomenon called antimicrobial resistance (AMR). Nowadays, AMR represents a critical health threat, for which new medical interventions are urgently needed. By 2050, it is estimated that the leading cause of death will be through untreatable AMR pathogens. Although antibiotics remain a first-line treatment, non-antibiotic therapies such as prophylactic vaccines and therapeutic monoclonal antibodies (mAbs) are increasingly interesting alternatives to limit the spread of such antibiotic resistant microorganisms. For the discovery of new vaccines and mAbs, the search for effective antigens that are able to raise protective immune responses is a challenging undertaking. In this context, outer membrane vesicles (OMV) represent a promising approach, as they recapitulate the complete antigen repertoire that occurs on the surface of Gram-negative bacteria. In this review, we present Escherichia coli and Pseudomonas aeruginosa as specific examples of key AMR threats caused by Gram-negative bacteria and we discuss the current status of mAbs and vaccine approaches under development as well as how knowledge on OMV could benefit antigen discovery strategies.

Gonorrhea, caused by Neisseria gonorrhoeae (GC) represents a significant public health threat that may be mitigated by an effective vaccine. Vaccines containing N. meningitidis outer membrane vesicles (OMVs), such as 4CMenB, demonstrated moderate effectiveness in preventing GC infections. Here, we developed NgG, an investigational GC vaccine based on Generalized Modules for Membrane Antigens (GMMA). NgG includes genetically detoxified OMVs from the FA1090 strain, engineered to reduce endotoxin activity and limit immune interference. NgG induced a robust immune response in mice and outperformed the comparator vaccine 4CMenB in several serological and functional tests. Immunization with GMMA from a FA1090 mutant, where major oligosaccharide epitopes are incomplete or absent, revealed that NgG lipooligosaccharide plays a major role in the breadth of functional responses, with protein component also contributing in some GC strains. These results suggest that NgG has the potential to block GC infection through various mechanisms, supporting further vaccine development.