Summary
Gonorrhoea, a sexual transmitted infection, is a global problem disproportionately affecting women and infants in LMICs. Complications include pelvic inflammatory disease, ectopic pregnancy, infertility and infant blindness. The problem is exacerbated by increasing resistance to antibiotics which threatens to make gonorrhoea untreatable. There is no licensed gonococcal vaccine. However, a retrospective study of the MenZB meningococcal outer membrane vesicle (OMV) vaccine in New Zealand estimated 31% effectiveness against gonorrhoea. Gonococcus is closely related to meningococcus. We hypothesise that OMV produced from gonococcus instead of meningococcus will better protect against gonorrhoea than MenZB. We have genetically modified a circulating gonococcal strain to produce a gonococcal OMV-based candidate vaccine. This can induce an immune response in mice. We need to understand whether this or a similar candidate OMV vaccine can confer protection.
To test our hypothesis, we will evaluate gonococcal OMVs in the mouse gonorrhoea model. To maximise our chance of success, we will engineer a meningococcal and second gonococcal strain to produce two further OMV vaccine candidates replicating our vaccine design. All three OMV vaccines will be characterised and tested in the mouse gonorrhoea model compared with Bexsero, the commercial four-component meningococcal vaccine which contains MenZB OMVs. If one of our OMV candidate vaccines accelerates clearance of gonococcal infection in mice, this will support advancing the vaccine into clinical development and testing in humans. Finally, we will explore the immunological mechanisms behind the action of the OMV candidates, to help identify correlates of protection that will be valuable for clinical development.
Project outcomes
Background: Neisseria gonorrhoeae (gonococcus) causes 87 million cases of gonorrhea annually with women in low- and middle-income countries disproportionately affected. Rapid emergence of multi-drug resistant gonococcus threatens to make these infections untreatable. The need for a gonococcal vaccine is pressing, but none is available. A retrospective study in New Zealand with Neisseria meningitidis (meningococcus) group B vaccine MeNZB found 31% protection against gonorrhea. MeNZB consists of detergent-extracted outer membrane vesicles (dOMV) and is a components of GSK’s Bexsero (4CMenB) meningococcal group B vaccine.
Aim/Methods: We hypothesised that a gonococcal OMV-based vaccine will have greater efficacy against gonorrhea than a meningococcal OMV-based vaccine. We developed native OMV (NOMV) candidate gonococcal vaccines from recent Chilean gonococcal strain GC_0817560 and laboratory gonococcal strain FA1090. lpxL1 and rmp genes were deleted to reduce reactogenicity, minimize production of potentially unprotective antibodies and increase NOMV yield. NOMV were harvested from bacterial cultures by filtration and ultracentrifugation, characterised for physical properties and formulated with aluminum hydroxide to give candidates dmGC_0817560 NOMV and dmFA1090 NOMV. Immunogenicity and ability to accelerate clearance of FA1090 gonococcal infection compared with Bexsero following parental administration was assessed in the vaginal colonization model in estradiol-treated BALB/c mice.
Results: Deletion of lpxL1 from GC_0817560 and FA1090 resulted in a pentacylated form of lipid A that induced a marked reduction in IL-6 release from human PBMCs, while deletion of rmp further reduced IL-6 release and resulted in increased NOMV yield. dmGC_0817560 NOMV and dmFA1090 NOMV induced gonococcal specific serum and vaginal mucosal IgG and IgA antibodies and gonococcal-specific Th1/Th17 CD4+ T-cell responses. Gonococcal NOMV accelerated clearance of FA1090 from estradiol-treated BALB/c mice significantly faster than Bexsero (P<0.0001). There was no significant difference in clearance of FA1090 by dmGC_0817560 NOMV and dmFA1090 NOMV.
Conclusion: We have demonstrated that candidate gonococcal OMV-based vaccines can clear both homologous and heterologous gonococcal infection in the mouse vaginal gonorrhea model more quickly than meningococcal-vesicle-containing vaccine Bexsero. dmGC_0817560 NOMV represents a promising candidate for further development as a vaccine against gonorrhea.
Professor Calman MacLennan
MRC Senior Clinical Fellow
Jenner Investigator and Group Leader
Jenner Institute, University of Oxford (UK)
Collaborators:
Professor Sanjay Ram, University of Massachusetts Medical School (USA)
Dr Paula Freixeiro, Jenner Institute, University of Oxford (UK)
Dr Christine Rollier, Oxford Vaccine Group, University of Oxford (UK)
Dr Robert W. Kaminski, Walter Reed Army Institute of Research (WRAIR) (USA)
Dr Sinead Delany-Moretlwe, University of the Witwatersrand (South Africa)