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Review
. 2024 Oct 16;230(4):e758-e767.
doi: 10.1093/infdis/jiae289.

Urgent Need to Understand and Prevent Gonococcal Infection: From the Laboratory to Real-World Context

Yara Ruiz García  1 , Jeanne Marrazzo  2 , Federico Martinón-Torres  3   4   5 , Kimberly Workowski  6 , Giulia Giordano  7 , Mariagrazia Pizza  7 , Woo-Yun Sohn  8
Affiliations
Review

Urgent Need to Understand and Prevent Gonococcal Infection: From the Laboratory to Real-World Context

Yara Ruiz García et al. J Infect Dis. .

Abstract

Neisseria gonorrhoeae is widespread globally. Primary prevention is unsuccessful and antimicrobial resistance threatens optimal management. There is no specific vaccine and natural infection studies show that N gonorrhoeae can avoid and suppress immune responses. In addition to extensive variation in expression and specificity of many gonococcal surface antigens, it induces a robust inflammatory response through the Th17 pathway with a large influx of neutrophils and inflammatory cytokines but evades macrophages. The Th1- and Th2-mediated response is suppressed, resulting in low, short-lived antibody titers. Real-world evidence suggests that gonorrhea cases are reduced among recipients of Neisseria meningitidis group B vaccines containing outer membrane vesicles (OMVs). Although the first randomized trial of an OMV-containing MenB vaccine against N gonorrhoeae infection did not show statistically significant vaccine efficacy, ongoing trials might shed further light. Several candidate vaccine antigens for a gonococcal-specific vaccine are being evaluated preclinically but only one has reached clinical trials.

Keywords: Neisseria gonorrhoeae; Neisseria meningitidis; gonorrhea; immunology; vaccine.

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Conflict of interest statement

Potential conflicts of interest. Y. R. G., G. G., and W-Y. S. are employed by GSK and hold shares in GSK. M. P. was employed by GSK at the time of the study, holds shares in GSK, and is now Visiting Professor at Imperial College London. J. M. reported payment to her institution from the National Institutes of Health (NIH) for conduct of phase 2 trial of Bexsero (a trademark owned by or licensed to GSK) in prevention of gonorrhea. F. M-T. has received honoraria from GSK, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. F. M-T. has also acted as principal investigator in randomized controlled trials of the above-mentioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. K. W. reported payment from NIH for the conduct of a Bexsero clinical trial. The authors declare no other financial and non-financial relationships and activities. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Important antigens on the surface of Neisseria gonorrhoeae. Abbreviations: LOS, lipooligosaccharide; NHBA, neisserial heparin binding antigen; Opa, opacity protein; Por, porin.
Figure 2.
Figure 2.
Current evidence for meningococcal group B outer membrane vesicle vaccines against Neisseria gonorrhoeae. Data from [31–38, 44]. Abbreviations: CI, confidence interval; GC, gonococcal; HIV, human immunodeficiency virus; MSM, men who have sex with men; VE*, vaccine effectiveness (observational study); VE#, vaccine efficacy (clinical trial).
Figure 3.
Figure 3.
Ongoing clinical trials of 4CMenB vaccine against gonorrhea. *Study timelines subject to change. Abbreviations: ACTRN, Australian Clinical Trials Registration Number; GBM+, gay bisexual men+ (men [cisgender and transgender], transgender women, and nonbinary people who have sex with men); IgG, immunoglobulin G; IMD, invasive meningococcal disease; KEMRI, Kenya Medical Research Institute; MSM, men who have sex with men; NCT, National Clinical Trial; NIAID, National Institute of Allergy and Infectious Diseases; NT, Northern Territory; OMV, outer membrane vesicle; RCT, randomized controlled trial.
Figure 4.
Figure 4.
Homology of 4CMenB components to Neisseria gonorrhoeae proteins. From Semchenko et al [48]. *fHbp is not expressed on the gonococcal surface; NadA is missing in gonococcus. Abbreviations: %ID, percent identity; ABC, ATP-binding cassette; AhpC, alkyl hydroperoxide reductase C; FbpA, ferric binding protein A; fHbp, factor H binding protein; FkpA, FKBP-type peptidyl-prolyl cis-trans isomerase; FrpB, Fe-regulated protein B; LbpA, lactoferrin binding protein A; LptD, lipopolysaccharide-assembly protein; LysM, lysin motif; MafA, multiple adhesin family A; MtrE, outer membrane efflux protein; NadA, Neisseria adhesin A; NHBA, neisserial heparin binding antigen; NMB, Neisseria meningitidis strain MC58; NspA, Neisseria gonorrhoeae surface protein A; OMP, outer membrane protein; OMV, outer membrane vesicle; OpcA, opacity protein A; PilQ, pili-associated protein Q; PorA, porin, serosubtype P1.4; PorB, porin, major OMP PIB; RmpM, reduction modifiable protein M; Tbp1, transferrin binding protein 1; Tfp, type IV pili; TSA, thiol-specific antioxidant.
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