A retrospective case-control study, published online in The Lancet on July 10, 2017, reported that MeNZB–a group B meningococcal vaccine–was effective for preventing gonorrhea acquisition. The vaccine was administered to about 1 million adolescents in New Zealand between 2004 and 2006, and gonorrhea cases fell 31% in those vaccinated compared to unvaccinated controls. The exact mechanisms by which MeNZB, which contains outer membrane vesicles (OMVs) from Neisseria meningitidis group B strain NZ98/254, provided cross-protection against gonorrhea remain to be elucidated.
Gonorrhea is a sexually transmitted infection (STI) caused by the bacterium Neisseria gonorrhoeae, a close relative of N. meningitidis with 80-90% genetic homology. The WHO estimates that approximately 78 million new cases of gonorrhea occur annually, half of which are in low- and middle-income countries. Untreated infection can lead to complications, such as pelvic inflammatory disease, infertility and ectopic pregnancy in women, and urethritis and infertility in men. Gonorrhea also increases the risk of acquiring and transmitting HIV.
Since the first introduction of antibiotics for gonorrhea treatment in the mid-1930s, the bacterium has demonstrated a remarkable ability to develop resistance to antibiotics through a variety of mechanisms, due to its natural competence in DNA exchange. Some countries have reported cases of gonorrhea that are resistant to all known antibiotics. On July 7, 2017, the WHO issued a warning of the rise in untreatable antibiotic-resistant gonorrhea, and called for new drugs to be developed. A dedicated section on gonorrhea at the subsequent STI & HIV World Congress (July 9-12, 2017, Rio de Janeiro, Brazil) also focused on antibiotic resistance and ways to mitigate the problem, in light of potential threats of super-gonococcal strains untreatable by existing antibiotics. During the Congress, The Lancet Infectious Diseases launched its Commission on STIs, which stated that ultimately, a gonococcal vaccine might be the only sustainable solution for gonorrhea control.
Like N. meningitides, N. gonorrhoeae only infects humans, with no known animal or environmental reservoir. Female mice, which are only transiently susceptible to N. gonorrhoeae infection during proestrus, are the most commonly used animal model to study gonococcal pathogenesis and as a challenge model in gonococcal vaccine research. The bacterium possesses multiple virulence factors that help it adhere to and invade host epithelial cells, as well as evade host immune defenses through its highly variable surface antigens. This may explain why repeat infection is very common as the body fails to build an effective adaptive immune response. Upon exposure to N. gonorrhoeae through sexual contact, an estimated 30% of men and 80% of women can become infected, while asymptomatic infection can occur in 10% of infected men and 80% of infected women. Many factors are at play, including host vaginal microbiota, which can contribute to the differences in gonococcal infectivity and pathogenesis. Knowledge of host immune correlates of protection against gonorrhea is severely lacking, which hampers vaccine development.
Two gonococcal vaccines made it to clinical trials a few decades ago, a killed whole cell vaccine and a purified pilin vaccine. The failure of both vaccines has discouraged academic researchers and the pharmaceutical industry alike from investing many resources into this area. But with the looming threat of untreatable super-gonorrhea and the positive findings from The Lancet’s MeNZB study, a renewed interest in gonococcal vaccine development is expected. Although the MeNZB vaccine is currently no longer available, two other group B meningococcal vaccines have been approved–4CMenB and rLP2086. 4CMenB consists of three recombinant antigens identified by reverse vaccinology–NadA, FHbp (factor H-binding protein) and NHBA (neisserial heparin-binding antigen)–which are formulated with the OMVs that were used in MeNZB. rLP2086 is a bivalent vaccine containing recombinant FHbp subfamilies A and B. Whether or not any of these meningococcal vaccines can provide cross-protection against gonorrhea remains to be seen.
It has taken four decades of active research and diverse approaches for the two meningococcal vaccines 4CMenB and rLP2086 to reach market approval in 2014. For a gonococcal vaccine to be a success, concerted efforts are required from all stakeholders, from molecular biologists, microbiologists and immunologists, to clinical trialists and funding bodies. Many unanswered questions remain with regards to the mechanisms of immune responses to N. gonorrhoeae in male versus female genital tracts. Is humoral (antibody) more crucial than T-cell-mediated immunity? What is the importance of innate immunity? As an STI vaccine, would mucosal vaccination be a better route than injection? Is systemic IgG more desirable than local secretory IgA? Which antigens are more conserved and suitable as vaccine epitopes? In clinical trials, what should we measure as biomarkers for vaccine efficacy?
As in the case of group B meningococcal vaccines, rational vaccine design using genomics and proteomics can help pinpoint the most promising gonococcal antigens or antigen combinations. The lack of suitable animal models can drive alternative approaches to create innovative models for pre-clinical screening of vaccine candidates. Funding from governmental bodies into this area can incentivize the pharmaceutical industry to participate. Finally, findings from clinical trials should feed new insights back to basic researchers to further refine their vaccine designs, and a good example is The Lancet’s retrospective MeNZB study in which potentially protective immune markers against gonorrhea may be identified and validated in a prospective study. At EBioMedicine, let us celebrate the upcoming World Sexual Health Day on September 4, 2017, by congratulating the efforts and dedication from our researchers at every step of the journey to develop a gonococcal vaccine.
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