Efficacy of the Serogroup B Neisseria meningitidis Vaccine (4CMenB) in Preventing Experimental Neisseria gonorrhoeae Urethral Infection: A Double-Blind Randomized Controlled Human Challenge Study Protocol

IntroductionRates of sexually transmitted infections are on the rise globally, including those caused by Neisseria gonorrhoeae. Retrospective analyses across clinical settings around the world have indicated that rates of gonorrhea declined following mass vaccination campaigns vaccines made with outer membrane vesicles (OMV) from Neisseria meningitidis serogroup B, a pathogen closely related to N. gonorrhoeae. The US FDA-approved N. meningitidis serogroup B vaccine (4CMenB) contains N. meningitidis OMV and five recombinant protein components: fHbp (factor H-binding protein), NHBA (Neisserial heparin-binding antigen), NadA (Neisseria adhesin A), and the fusion partners GNA2091 and GNA1030 (genome-derived neisserial antigens used to stabilize fHbp and NHBA, respectively); N. gonorrhoeae encodes homologs of fHbp, NHBA, GNA2091, and GNA1030, but not NadA. Humans and mice immunized with 4CMenB have been shown to develop antibodies directed against N. gonorrhoeae antigens, and 4CMenB immunized mice exhibit enhanced N. gonorrhoeae clearance in a vaginal-infection model vs. mock immunized mice. Collectively, these data led to the hypothesis that immunization with 4CMenB may provide cross-protection against N. gonorrhoeae. There is a unique and time-sensitive opportunity to test the effectiveness of this vaccine in preventing N. gonorrhoeae using the human male urethral challenge model. MethodsThis is a double-blind randomized controlled trial testing the efficacy of the FDA-approved 4CMenB vaccine in preventing experimental N. gonorrhoeae infection. Our research team is currently the only in the world to utilize the established controlled human infection model to study N. gonorrhoeae in its natural human host. Males aged >18 and <36 years with no medical contraindication to 4CMenB administration, no contraindication to intraurethral challenge with N. gonorrhoeae, and who are willing and able to consent and participate in the study will be enrolled in this study. Participants who complete both immunization and N. gonorrhoeae challenge phases will be included in the primary endpoint analyses of N. gonorrhoeae infection in each study group to determine the efficacy of standard immunization with 4CMenB in preventing experimental gonococcal infection. The secondary objective is to determine whether 4CMenB vaccinations change or delay the onset of urethritis symptoms. EthicsAll participants enrolled in the study provided informed consent twice. This study has been reviewed and approved by the University of North Carolina at Chapel Hill Institutional review Board (#21-0498). Data collection for this study is ongoing. Trial registrationClinicalTrials.gov Identifier: NCT05294588 Article summaryThe paper presents the protocol for a double-blind randomized controlled human challenge study designed to evaluate the efficacy of the FDA-approved Serogroup B Neisseria meningitidis vaccine (4CMenB) in preventing experimental Neisseria gonorrhoeae urethral infection in men. This research addresses the urgent global public health threat posed by rising gonorrhea incidence and accelerating antimicrobial resistance (AMR), which highlights the critical need for vaccines. The study is motivated by retrospective analyses from clinical settings globally, which indicated that mass vaccination campaigns using N. meningitidis outer membrane vesicle (OMV) vaccines, including 4CMenB, correlated with a decline in symptomatic gonorrhea rates, with an estimated protective effect in the range of 30-40%. This observed cross-protection is biologically plausible because N. gonorrhoeae encodes homologs of several key protein components contained in the 4CMenB vaccine. The primary objective of the randomized trial is to formally determine the efficacy of standard 4CMenB immunization in preventing the acquisition of N. gonorrhoeae infection, defined by positive NAAT or culture. A secondary objective is to determine if 4CMenB immunization changes or delays the onset of urethritis symptoms. The study enrolls men aged 18 to 36 years who are randomized to receive two doses of either 4CMenB (experimental arm) or two doses of irrelevant FDA-approved control vaccines (quadrivalent influenza and tetanus/diphtheria). The investigation utilizes the controlled human infection model (CHIM) of gonorrhea, which is uniquely employed by the research team. This approach is justified by its safety record (over 30 years of safe use at UNC) and its superior statistical power compared to observational studies, allowing the trial to detect moderate vaccine efficacy with a much smaller number of participants. This CHIM design will not only deliver a direct efficacy estimate but also generate high-value mechanistic data by permitting detailed investigation of early infection events and immune correlates of protection in the natural human host.