The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection againstNeisseria gonorrhoeae
Authors: Leduc Isabelle , Connolly Kristie L. , Begum Afrin , Underwood Knashka , Rahman Nazia , Darnell Stephen , Balthazar Jacqueline T. , Shafer William M. , Macintyre Andrew N. , Sempowski Gregory D. , Jerse Ann E. 
Published: May 2020

AbstractThere 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 inNeisseria 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 BNeisseria meningitidis(Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis thatNmOMVs induce cross-protection against gonorrhea in a well-characterized female mouse model ofNggenital tract infection. We found that immunization with the licensedNmOMV-based vaccine 4CMenB (Bexsero®) significantly accelerated clearance and reduced theNgbacterial burden compared to administration of alum or PBS. High titers of serum IgG1 and IgG2a and vaginal IgG1 that cross-reacted withNgOMVs were induced by vaccination via either the subcutaneous or intraperitoneal routes, and a 4-fold increase in the serum bactericidal50titers was detected against the challenge strain. Antibodies from vaccinated mice recognized several surface proteins in a diverse collection ofNgstrains, 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 fewNgstrains. Our findings directly support epidemiological evidence thatNmOMVs confer cross-species protection againstNgand implicate severalNgsurface 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 summaryOver 78 millionNeisseria 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 speciesNeisseria meningitidis(Nm) protected humans against gonorrhea. Here we provide experimental evidence in support of this hypothesis by demonstrating that a licensed, modified version of thisNmOMV-based vaccine accelerates clearance ofNgin 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 severalNgouter 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 againstNg, 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.