OpcA and PorB are novel bactericidal antigens of the 4CMenB vaccine in mice and humans.

The ability of Neisseria meningitidis Outer Membrane Vesicles (OMV) to induce protective responses in humans is well established and mainly attributed to Porin A (PorA). However, the contribution of additional protein antigens to protection remains to be elucidated. In this study we dissected the immunogenicity of antigens originating from the OMV component of the 4CMenB vaccine in mice and humans. We collected functional data on a panel of strains for which bactericidal responses to 4CMenB in infants was attributable to the OMV component and evaluated the role of 30 OMV-specific protein antigens in cross-coverage. By using tailor-made protein microarrays, the immunosignature of OMV antigens was determined. Three of these proteins, OpcA, NspA, and PorB, triggered mouse antibodies that were bactericidal against several N. meningitidis strains. Finally, by genetic deletion and/or serum depletion studies, we demonstrated the ability of OpcA and PorB to induce functional immune responses in infant sera after vaccination. In conclusion, while confirming the role of PorA in eliciting protective immunity, we identified two OMV antigens playing a key role in protection of infants vaccinated with the 4CMenB vaccine against different N. meningitidis serogroup B strains.

Synergistic activity of antibodies in the multicomponent 4CMenB vaccine.

INTRODUCTION: Vaccines based on multiple antigens often induce an immune response, which is higher than that triggered by each single component, with antibodies acting cooperatively and synergistically in tackling the infection. AREAS COVERED: An interesting example is the antibody response induced by the 4CMenB vaccine, currently licensed for the prevention of Neisseria meningitidis serogroup B (MenB). It contains four antigenic components: Factor H binding protein (fHbp), Neisseria adhesin A (NadA), Neisserial Heparin Binding Antigen (NHBA), and Outer Membrane Vesicles (OMV). Monoclonal and polyclonal antibodies raised by vaccination with 4CMenB show synergistic activity in complement-dependent bacterial killing. This review summarizes published and unpublished data and provides evidence of the added value of multicomponent vaccines. EXPERT OPINION: The ability of 4CMenB vaccine to elicit antibodies targeting multiple surface-exposed antigens is corroborated by the recent data on real-world evidences. Bactericidal activity is generally mediated by antibodies that bind to antigens highly expressed on the bacterial surface and immunologically related. However, simultaneous binding of antibodies to various surface-exposed antigens can overcome the threshold density of antigen-antibody complexes needed for complement activation. The data discussed in this review highlight the interplay between antibodies targeting major and minor antigens and their effect on functionality. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers of studies with original data mentioned in the article: NCT00937521, NCT00433914, NCT02140762, and NCT02285777.

Strategies to Tackle Antimicrobial Resistance: The Example of Escherichia coli and Pseudomonas aeruginosa.

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.