Abstract
There is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero®) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. High titers of serum IgG1 and IgG2a and vaginal IgG1 that cross-reacted with Ng OMVs were induced by vaccination via either the subcutaneous or intraperitoneal routes, and a 4-fold increase in the serum bactericidal50 titers was detected against the challenge strain. Antibodies from vaccinated mice recognized several surface proteins in a diverse collection of Ng strains, including PilQ, BamA, MtrE, PorB, and Opa, and 4CMenB-induced antibodies bound PilQ and MtrE in native form on the surface of viable bacteria. In contrast, the antibodies were only cross-reactive against lipooligosaccharide species from a few Ng strains. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against Ng and implicate several Ng surface antigens as potentially protective targets. This work also validates the murine infection model as a relevant experimental system for investigating mechanisms of vaccine-mediated protection against gonorrhea.
Author summary Over 78 million Neisseria gonorrhoeae (Ng) infections occur globally each year and control of gonorrhea through vaccination is challenged by a lack of strong evidence that immunity to gonorrhea is possible. This contention was recently challenged by epidemiological evidence suggesting that an outer membrane vesicle (OMV) vaccine from the related species Neisseria meningitidis (Nm) protected humans against gonorrhea. Here we provide experimental evidence in support of this hypothesis by demonstrating that a licensed, modified version of this Nm OMV-based vaccine accelerates clearance of Ng in a mouse infection model. These results confirm the possibility cross-species protection and are important in that they support the biological feasibility of vaccine-induced immunity against gonorrhea. We also showed that several Ng outer membrane proteins are recognized by antisera from vaccinated mice that may be protective targets of the vaccine. Additionally, our demonstration that a vaccine that may reduce the risk of gonorrhea in humans protects mice against Ng, a highly host-restricted pathogen, validates the mouse model as a potentially useful tool for examining mechanisms of protection, which could be exploited in the development of other candidate gonorrhea vaccines.
