Gonorrhea Vaccine Research Articles

Refinement and optimisation of Neisseria gonorrhoeae NHBA and MetQ vaccine candidates

Neisseria gonorrhoeae has a significant impact on reproductive health with an estimated 82 million new cases of infection per year worldwide. Due to the ongoing emergence of multidrug-resistant N. gonorrhoeae strains, the high number of asymptomatic cases, and the risk of disease sequelae, the development of a gonococcal vaccine is urgently needed. We have previously described two potential gonococcal vaccine antigens, cNHBA (C-terminal fragment of the Neisseria Heparin Binding Antigen) and MetQ (methionine-binding protein). This study aimed to optimise these antigens for improved immune responses and to facilitate vaccine production, by investigating cNHBA fusions with the full-length MetQ protein or N-terminal and C-terminal MetQ fragments (Met1 and Met2, respectively) adjuvanted with aluminium hydroxide. The cNHBA and MetQ fragments and fusion antigens were all immunogenic in mice, generating a predominantly IgG1 response. Antibodies mediated bacterial killing via both serum bactericidal activity (SBA) and opsonophagocytic activity (OPA), and reduced adherence to cervical and urethral epithelial cells. Among the antigen fusions tested, MetQ-cNHBA and cNHBA-Met2 generated the highest SBA, OPA and adherence blocking titres and are proposed as promising optimised antigens for N. gonorrhoeae vaccine development.

Review of mathematical models of Neisseria gonorrhoeae vaccine impact: Implications for vaccine development

An effective prophylactic vaccine for prevention of Neisseria gonorrhoeae infection would have a major impact on sexual and reproductive health worldwide. Interest in developing gonorrhoea vaccines is growing due to the reported high rates of N. gonorrhoeae infections globally, and the threat of antimicrobial resistance. Several gonorrhoea vaccine candidates are currently under evaluation and various mathematical models have been used to assess the potential population-level impact a gonorrhoea vaccine may have once available. Here we review key aspects of gonorrhoea vaccine mathematical modelling studies, including model structures, populations considered, and assumptions used as well as vaccine characteristics and implementation scenarios investigated. The predicted vaccine impact varied between studies, ranging from as little as ∼17 % reduction in N. gonorrhoeae prevalence after 30 years up to 100 % reduction after 5 years. However, all studies predicted that even a partially effective gonorrhoea vaccine could have a substantial impact in reducing N. gonorrhoeae prevalence or incidence, particularly when high coverage is achieved within either important risk groups or the overall sexually active population. As expected, higher vaccine efficacy against acquisition of N. gonorrhoeae and longer duration of protection were linked to greater reductions in infections. A vaccine that alters onward transmission could also substantially reduce infections. Several gaps and research needs have been identified by researchers in the field and via this narrative literature review. For example, future modelling to inform gonorrhoea vaccine development and implementation should consider additional populations that are at high risk of N. gonorrhoeae infection, especially in low- and middle-income settings, as well as the impact of vaccination on the potential adverse sexual and reproductive health outcomes of infection. In addition, more detailed and robust epidemiological, biological, and behavioural data is needed to enable more accurate and robust modelling of gonorrhoea vaccine impact to inform future scientific and public health decision-making.

Neisseria gonorrhoeae vaccines: a contemporary overview.

Neisseria gonorrhoeae infection is an important public health issue, with an annual global incidence of 87 million. N. gonorrhoeae infection causes significant morbidity and can have serious long-term impacts on reproductive and neonatal health and may rarely cause life-threatening disease. Global rates of N. gonorrhoeae infection have increased over the past 20 years. Importantly, rates of antimicrobial resistance to key antimicrobials also continue to increase, with the United States Centers for Disease Control and Prevention identifying drug-resistant N. gonorrhoeae as an urgent threat to public health. This review summarizes the current evidence for N. gonorrhoeae vaccines, including historical clinical trials, key N. gonorrhoeae vaccine preclinical studies, and studies of the impact of Neisseria meningitidis vaccines on N. gonorrhoeae infection. A comprehensive survey of potential vaccine antigens, including those identified through traditional vaccine immunogenicity approaches, as well as those identified using more contemporary reverse vaccinology approaches, are also described. Finally, the potential epidemiological impacts of a N. gonorrhoeae vaccine and research priorities for further vaccine development are described.

Artificial intelligence-driven reverse vaccinology for Neisseria gonorrhoeae vaccine: Prioritizing epitope-based candidates.

Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhea. The increasing prevalence of this disease worldwide, the rise of antibiotic-resistant strains, and the difficulties in treatment necessitate the development of a vaccine, highlighting the significance of preventative measures to control and eradicate the infection. Currently, there is no widely available vaccine, partly due to the bacterium's ability to evade natural immunity and the limited research investment in gonorrhea compared to other diseases. To identify distinct vaccine candidates, we chose to focus on the uncharacterized, hypothetical proteins (HPs) as our initial approach. Using the in silico method, we first carried out a comprehensive assessment of hypothetical proteins of Neisseria gonorrhoeae, encompassing assessments of physicochemical properties, cellular localization, secretary pathways, transmembrane regions, antigenicity, toxicity, and prediction of B-cell and T-cell epitopes, among other analyses. Detailed analysis of all HPs resulted in the functional annotation of twenty proteins with a great degree of confidence. Further, using the immuno-informatics approach, the prediction pipeline identified one CD8+ restricted T-cell epitope, seven linear B-cell epitopes, and seven conformational B-cell epitopes as putative epitope-based peptide vaccine candidates which certainly require further validation in laboratory settings. The study accentuates the promise of functional annotation and immuno-informatics in the systematic design of epitope-based peptide vaccines targeting Neisseria gonorrhoeae.

Public willingness to receive chlamydia, gonorrhea, syphilis, and trichomoniasis vaccines: a scoping review

BackgroundSexually transmitted infections (STIs) like chlamydia, gonorrhea, syphilis, and trichomoniasis contribute significantly to global morbidity and mortality. Researchers are pursuing vaccines for these STIs, and a clinical trial is currently underway for a chlamydia vaccine. However, there is little research available on individuals’ willingness to receive chlamydia, gonorrhea, syphilis, and trichomoniasis vaccines. The purpose of this analysis was to map the existing literature we have on individuals’ willingness to receive these bacterial/parasitic STI vaccines and understand what information on vaccine acceptability is still needed.MethodsWe searched seven databases for literature on STI vaccine acceptability, then conducted title/abstract and full-text reviews to assess eligibility. All reviews and abstractions were conducted blindly by two reviewers, with discrepancies settled by discussion or the input of a third reviewer.ResultsEight of the original 2,259 texts of interest met inclusion criteria. After data abstraction, we found that gonorrhea was the most commonly examined, followed by chlamydia and syphilis. Trichomoniasis vaccine acceptability was not reported. Most texts reported high acceptability, but there did not appear to be data describing how vaccine characteristics affect acceptability. Similarly, while the literature covers a variety of populations, most of the study populations were based out of the United States or Canada and were patrons of healthcare facilities or participants from a larger health intervention study. Therefore, more information is needed on populations outside North America, and on groups with lower healthcare access and utilization.ConclusionAs the incidence of bacterial and parasitic STIs increase, and as we grow nearer vaccines for these illnesses, understanding how likely the public is to accept and receive these vaccines is crucial to their success. While the existing literature describes STI vaccine acceptability in a variety of populations, their overall number is small. More research into STI vaccine acceptability outside of North America, and especially examining how factors like number of doses, timing, and cost influence vaccine acceptability is needed to ensure effective future vaccine rollouts.

Evaluating vaccine-elicited antibody activities against Neisseria gonorrhoeae: cross-protective responses elicited by the 4CMenB meningococcal vaccine.

The bacterial pathogen Neisseria gonorrhoeae is an urgent global health problem due to increasing numbers of infections, coupled with rampant antibiotic resistance. Vaccines against gonorrhea are being prioritized to combat drug-resistant N. gonorrhoeae. Meningococcal serogroup B vaccines such as four-component meningococcal B vaccine (4CMenB) are predicted by epidemiology studies to cross-protect individuals from natural infection with N. gonorrhoeae and elicit antibodies that cross-react with N. gonorrhoeae. Evaluation of vaccine candidates for gonorrhea requires a suite of assays for predicting efficacy in vitro and in animal models of infection, including the role of antibodies elicited by immunization. Here, we present the development and optimization of assays to evaluate antibody functionality after immunization of mice: antibody binding to intact N. gonorrhoeae, serum bactericidal activity, and opsonophagocytic killing activity using primary human neutrophils [polymorphonuclear leukocytes (PMNs)]. These assays were developed with purified antibodies against N. gonorrhoeae and used to evaluate serum from mice that were vaccinated with 4CMenB or given alum as a negative control. Results from these assays will help prioritize gonorrhea vaccine candidates for advanced preclinical to early clinical studies and will contribute to identifying correlates and mechanisms of immune protection against N. gonorrhoeae.

The potential impact of a vaccine on Neisseria gonorrhoeae prevalence among heterosexuals living in a high prevalence setting

BackgroundTreatment of Neisseria gonorrhoeae is under threat with the emergence and spread of antimicrobial resistance. Thus, there is a growing interest in the development of a gonorrhoea vaccine. We used mathematical modelling to assess the impact of a hypothetical vaccine in controlling gonorrhoea among heterosexuals living in a setting of relatively high N. gonorrhoeae prevalence (∼3 %). MethodsWe developed a mathematical model of N. gonorrhoeae transmission among 15–49-year-old heterosexuals, stratified by age and sex, and calibrated to prevalence and sexual behaviour data from South Africa as an example of a high prevalence setting for which we have data available. Using this model, we assessed the potential impact of a vaccine on N. gonorrhoeae prevalence in the entire population. We considered gonorrhoea vaccines having differing impacts on N. gonorrhoeae infection and transmission and offered to different age-groups. ResultsThe model predicts that N. gonorrhoeae prevalence can be reduced by ∼50 % in 10 years following introduction of a vaccine if annual vaccination uptake is 10 %, vaccine efficacy against acquisition of infection is 25 % and duration of protection is 5 years, with vaccination available to the entire population of 15–49-year-olds. If only 15–24-year-olds are vaccinated, the predicted reduction in prevalence in the entire population is 25 % with equivalent vaccine characteristics and uptake. Although predicted reductions in prevalence for vaccination programmes targeting only high-activity individuals and the entire population are similar over the same period, vaccinating only high-activity individuals is more efficient as the cumulative number of vaccinations needed to reduce prevalence in the entire population by 50 % is ∼3 times lower for this programme. ConclusionProvision of a gonorrhoea vaccine could lead to substantial reductions in N. gonorrhoeae prevalence in a high prevalence heterosexual setting, even with moderate annual vaccination uptake of a vaccine with partial efficacy.

An open-label randomised controlled trial evaluating the efficacy of a meningococcal serogroup B (4CMenB) vaccine on Neisseria gonorrhoeae infection in gay and bisexual men: the MenGO study protocol

BackgroundGonorrhoea is an ongoing public health concern due to its rising incidence and the emergence of antibiotic resistance. There are an estimated 82 million new Neisseria gonorrhoeae infections each year, with several populations at higher risk for gonococcal infection, including gay and bisexual men (GBM). If left untreated, infection can lead to serious morbidity including infertility, sepsis and increased risk of HIV acquisition. Development of a gonorrhoea vaccine has been challenging, however there is observational evidence that serogroup B meningococcal vaccines, used to protect against the closely related bacteria Neisseria meningitidis, could provide cross-protection against N. gonorrhoeae.MethodsThe MenGO (Meningococcal vaccine efficacy against Gonorrhoea) study is a phase III open-label randomised control trial in GBM to evaluate the efficacy of the four-component meningococcal serogroup B vaccine, 4CMenB, against gonorrhoea. A total of 130 GBM will be recruited at the Gold Coast Sexual Health Clinic, Australia, and randomised to either receive 2 doses of 4CMenB or no intervention. Participants will be followed up for 24 months with testing for N. gonorrhoeae and other sexually transmissible infections every three months. Demographics, sexual behaviour risk, antibiotic use, and blood samples for analysis of N. gonorrhoeae-specific immune responses, will be collected during the study. The primary outcome is the number of N. gonorrhoeae infections in participants over 2 years measured by nucleic acid amplification test (NAAT). Secondary outcomes are vaccine-induced N. gonorrhoeae-specific immune responses, and adverse events in trial participants.DiscussionThis trial will determine if the 4CMenB vaccine is able to reduce N. gonorrhoeae infection. If shown to be effective, 4CMenB could be used in gonococcal prevention. Analysis of 4CMenB-induced immune responses will increase understanding of the type of immune response needed to prevent N. gonorrhoeae, which may enable identification of a potential correlate of protection to aid future gonorrhoea vaccine development.Trial registrationThe trial has been registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12619001478101) on 25 October 2019.

The Impact of Educational Intervention on Willingness to Enroll in a Clinical Trial of a Gonorrhea Vaccine.

Globally, >80 million new gonorrhea infections occur annually. Here, we assessed barriers to and influences on participation in a gonorrhea clinical trial and the impact of educational intervention. The survey was fielded in the US in March 2022. Higher enrollment of Black/African Americans and younger individuals than represented in the US demographic distribution reflected the higher incidence of gonorrhea in these groups. Behavioral characteristics and baseline attitudes toward vaccination were collected. Participants were probed on their knowledge of and likelihood to enroll in general and gonorrhea vaccine trials. Participants hesitant to enroll in a gonorrhea vaccine trial were given nine bullets of basic facts about the disease and asked again to rank their likelihood to enroll. Overall, 450 individuals completed the survey. Fewer participants were willing (quite/very likely) to join a gonorrhea versus a general vaccine trial (38.2% [172/450] vs. 57.8% [260/450]). The likelihood to enroll in any vaccine trial or a gonorrhea vaccine trial was greater with higher self-declared knowledge (Spearman's ρ = 0.277 [p < 0.001] and 0.316 [p < 0.001], respectively) and baseline openness towards vaccination (p < 0.001 for both). Self-declared awareness of gonorrhea was associated with age (p = 0.001), education (p = 0.031), and ethnicity/race (p = 0.002), with older, more educated, and Black/African Americans having higher awareness. Males (p = 0.001) and those with more sexual partners (p < 0.001) were more likely to enroll in a gonorrhea vaccine trial. Educational intervention had a significant (p < 0.001) impact on hesitancy. Improvement in willingness to enroll in a gonorrhea vaccine trial was greatest in those initially marginally hesitant and lowest in those initially strongly hesitant. Basic educational intervention has the potential to improve recruitment into gonorrhea vaccine trials.

The Optimal Management of Neisseria gonorrhoeae Infections.

Neisseria gonorrhoeae is one of the most frequent etiologic agents of STDs (sexually transmitted diseases). Untreated asymptomatic gonococcal infection in women can lead to spreading of the infection in the sexually active population and could lead to late consequences, such as sterility or ectopic pregnancies. One important issue about N. gonorrhoeae is its increasing resistance to antibiotics. This paper summarized the newest molecular antimicrobial resistance (AMR) detection assays for Neisseria gonorrhoeae connected with the latest therapeutic antimicrobials and gonococcal vaccine candidates. The assays used to detect AMR varied from the classical minimal inhibitory concentration (MIC) detection to whole-genome sequencing. New drugs against multi drug resistant (MDR) N. gonorrhoeae have been proposed and were evaluated in vivo and in vitro as being efficient in decreasing the N. gonorrhoeae burden. In addition, anti-N. gonorrhoeae vaccine candidates are being researched, which have been assessed by multiple techniques. With the efforts of many researchers who are studying the detection of antimicrobial resistance in this bacterium and identifying new drugs and new vaccine candidates against it, there is hope in reducing the gonorrhea burden worldwide.

Protocol for a Scoping Review of Evidence Pertaining to Public Willingness to Receive Chlamydia, Gonorrhea, Syphilis, and Trichomoniasis Vaccines

Protocol for a Scoping Review of Evidence Pertaining to Public Willingness to Receive Chlamydia, Gonorrhea, Syphilis, and Trichomoniasis Vaccines

Factors associated with intention to receive vaccines for bacterial sexually transmitted infections among young HPV-vaccinated Canadian women.

ObjectiveThe aim of this study was to explore the acceptability of bacterial STI vaccines among young HPV-vaccinated Canadian women to inform future vaccine program implementation.MethodsA 20-item cross-sectional questionnaire was administered from June 2019 to June 2020 to HPV-vaccinated participants of the pan-Canadian QUEST cohort. Multivariable logistic regression models assessed interest in chlamydia, syphilis, and gonorrhea vaccines using a priori variables and factors significant in bivariate analysis.ResultsOf the 1092 respondents analyzed, 82% indicated interest in receiving one or more future STI vaccines. Respondents had a median age of 19.6 years (range 16.9–23.4), and 75% of respondents identified as white/European descent. In adjusted analyses, intent to engage in positive health behaviours was associated with vaccine interest for syphilis (OR = 5.76, 95% CI 4.03–8.27), chlamydia (OR = 5.27, 95% CI 3.66–7.63), and gonorrhea (OR = 5.96, 95% CI 4.15–8.60). Willingness to pay for an STI vaccine was also associated with vaccine interest for syphilis (OR = 2.02, 95% CI 1.29–3.19), chlamydia (OR = 2.41, 95% CI 1.50–3.90), and gonorrhea (OR = 2.29, 95% CI 1.44–3.63). Ever having sexual intercourse and identifying as LGBTQ were significantly associated with vaccine interest for all infections, while age and ever being immunosuppressed were not significant in any adjusted models.ConclusionFindings indicate over 80% of participants in a cohort of young HPV-vaccinated Canadian women are interested in receiving future bacterial STI vaccines. Further exploration of STI vaccine acceptability among diverse populations is required to inform future bacterial STI vaccine program implementation.Supplementary InformationThe online version contains supplementary material available at 10.17269/s41997-022-00648-2.

Feasibility of gonorrhoea vaccination among men who have sex with men in England

Feasibility of gonorrhoea vaccination among men who have sex with men in England

Public health impact and cost-effectiveness of gonorrhoea vaccination: an integrated transmission-dynamic health-economic modelling analysis

SummaryBackgroundGonorrhoea is a rapidly growing public health threat, with rising incidence and increasing drug resistance. Evidence that the MeNZB and four-component serogroup B meningococcal (4CMenB) vaccines, designed against Neisseria meningitidis, can also offer protection against gonorrhoea has created interest in using 4CMenB for this purpose and for developing gonorrhoea-specific vaccines. However, cost-effectiveness, and how the efficacy and duration of protection affect a gonorrhoea vaccine's value, have not been assessed.MethodsWe developed an integrated transmission-dynamic health-economic model, calibrated using Bayesian methods to surveillance data (from the Genitourinary Medicine Clinic Activity Dataset and the Gonococcal Resistance to Antimicrobials Surveillance Programme) on men who have sex with men (MSM) in England. We considered vaccination of MSM from the perspective of sexual health clinics, with and without vaccination offered to all adolescents in schools (vaccination before entry [VbE]), comparing three realistic approaches to targeting: vaccination on attendance (VoA) for testing; vaccination on diagnosis (VoD) with gonorrhoea; or vaccination according to risk (VaR), offered to patients diagnosed with gonorrhoea plus individuals who test negative but report having more than five sexual partners per year. For the primary analysis, vaccine impact was assessed relative to no vaccination in a conservative baseline scenario wherein time-varying behavioural parameters (sexual risk behaviour and screening rates) stabilise. To calculate the value of vaccination per dose administered, the value of vaccination was calculated by summing the averted costs of testing and treatment, and the monetary value of quality-adjusted life-year (QALY) gains with a QALY valued at £20 000. Costs were in 2018–19 GB£, and both costs and QALYs were discounted at 3·5% per year. We analysed the effects of varying vaccine uptake (0·5, 1, or 2 times HPV vaccine uptake by MSM in sexual health clinics in England), vaccine efficacy (1–100%) and duration of protection (1–20 years), and the time-horizon considered (10 years and 20 years). In addition, we calculated incremental cost-effectiveness ratios for the use of 4CMenB using assumed vaccine prices.FindingsVbE has little impact on gonorrhoea diagnoses, with only 1·7% of MSM vaccinated per year. VoA has the largest impact but requires more vaccine doses than any other strategy, whereas VoD has a moderate impact but requires many fewer doses than VoA. VaR has almost the same impact as VoA but with fewer doses administered than VoA. VaR is the most cost-effective strategy for vaccines of moderate efficacy or duration of protection (or both), although VoD is more cost-effective for very protective and long-lasting vaccines. Even under conservative assumptions (efficacy equivalent to that of MeNZB and protection lasting for 18 months after two-dose primary vaccination and 36 months after single-dose booster vaccination), 4CMenB administered under VaR would likely be cost-saving at its current National Health Service price, averting an estimated mean 110 200 cases (95% credible interval 36 500–223 600), gaining a mean 100·3 QALYs (31·0–215·8), and saving a mean £7·9 million (0·0–20·5) over 10 years. A hypothetical gonorrhoea vaccine's value is increased more by improving its efficacy than its duration of protection—eg, 30% protection lasting 2 years has a median value of £48 (22–85) per dose over 10 years; doubling efficacy increases the value to £102 (53–144) whereas doubling the duration of protection increases it to £72 (34–120).InterpretationWe recommend that vaccination of MSM against gonorrhoea according to risk in sexual health clinics in England with the 4CMenB vaccine be considered. Development of gonorrhoea-specific vaccines should prioritise maximising efficacy over duration of protection.FundingMedical Research Council (UK), National Institute for Health Research (UK).

Meningococcal Detoxified Outer Membrane Vesicle Vaccines Enhance Gonococcal Clearance in a Murine Infection Model.

Despite decades of research efforts, development of a gonorrhea vaccine has remained elusive. Epidemiological studies suggest that detoxified outer membrane vesicle (dOMV) vaccines from Neisseria meningitidis (Nm) may protect against infection with Neisseria gonorrhoeae (Ng). We recently reported that Nm dOMVs lacking the major outer membrane proteins (OMPs) PorA, PorB, and RmpM induced greater antibody cross-reactivity against heterologous Nm strains than wild-type (WT) dOMVs and may represent an improved vaccine against gonorrhea. We prepared dOMV vaccines from meningococcal strains that were sufficient or deleted for PorA, PorB, and RmpM. Vaccines were tested in a murine genital tract infection model and antisera were used to identify vaccine targets. Immunization with Nm dOMVs significantly and reproducibly enhanced gonococcal clearance for mice immunized with OMP-deficient dOMVs; significant clearance for WT dOMV-immunized mice was observed in one of two experiments. Clearance was associated with serum and vaginal anti-Nm dOMV immunoglobulin G (IgG) antibodies that cross-reacted with Ng. Serum IgG was used to identify putative Ng vaccine targets, including PilQ, MtrE, NlpD, and GuaB. Meningococcal dOMVs elicited a protective effect against experimental gonococcal infection. Recognition and identification of Ng vaccine targets by Nm dOMV-induced antibodies supports the development of a cross-protective Neisseria vaccine.

Vaccine Candidates for the Control and Prevention of the Sexually Transmitted Disease Gonorrhea.

The World Health Organization (WHO) has placed N. gonorrhoeae on the global priority list of antimicrobial resistant pathogens and is urgently seeking the development of new intervention strategies. N. gonorrhoeae causes 86.9 million cases globally per annum. The effects of gonococcal disease are seen predominantly in women and children and especially in the Australian Indigenous community. While economic modelling suggests that this infection alone may directly cost the USA health care system USD 11.0–20.6 billion, indirect costs associated with adverse disease and pregnancy outcomes, disease prevention, and productivity loss, mean that the overall effect of the disease is far greater still. In this review, we summate the current progress towards the development of a gonorrhea vaccine and describe the clinical trials being undertaken in Australia to assess the efficacy of the current formulation of Bexsero® in controlling disease.

Evaluation of Microparticulate (S)-4,5-Dihydroxy-2,3-pentanedione (DPD) as a Potential Vaccine Adjuvant.

Adjuvants potentiate the immune response against co-inoculated antigens in the vaccine formulation. Based on the mechanism of action, the adjuvants are classified as immunostimulatory adjuvants and vaccine delivery systems. (S)-4,5-Dihydroxy-2,3-pentanedione (DPD) is the precursor of bacterial quorum sensing molecule, autoinducer (AI)-2. We tested the immunogenicity and adjuvant potential of microparticulate formulation of (S)-DPD via in vitro evaluation. By formulating the microparticles of (S)-DPD, we consolidated the advantages of both the classes of adjuvants. The microparticulate (S)-DPD was tested for its immunogenicity and cytotoxicity. We further tested its adjuvant effect by combining it with particulate vaccines for measles and gonorrhea and compared the adjuvant effect observed with the microparticulate formulations of the FDA-approved adjuvants alum, MPL A®, and MF59®. Microparticulate (S)-DPD was found to be non-cytotoxic towards the antigen-presenting cells and had an adjuvant effect with microparticulate gonorrhea vaccine. Further studies with additional bacterial vaccines and the in vivo evaluation will confirm the potential of microparticulate (S)-DPD as a probable vaccine adjuvant candidate.

Experimental Urethral Infection with Neisseria gonorrhoeae.

Gonorrhea rates and antibiotic resistance are both increasing. Neisseria gonorrhoeae (Ng) is an exclusively human pathogen and is exquisitely adapted to its natural host. Ng can subvert immune responses and undergoes frequent antigenic variation, resulting in limited immunity and protection from reinfection. Previous gonococcal vaccine efforts have been largely unsuccessful, and the last vaccine to be tested in humans was more than 35years ago. Advancing technologies and the threat of untreatable gonorrhea have fueled renewed pursuit of a vaccine as a long-term sustainable solution for gonorrhea control. Despite the development of a female mouse model of genital gonococcal infection two decades ago, correlates of immunity or protection remain largely unknown, making the gonococcus a challenging vaccine target. The controlled human urethral infection model of gonorrhea (Ng CHIM) has been used to study gonococcal pathogenesis and the basis of anti-gonococcal immunity. Over 200 participants have been inoculated without serious adverse events. The Ng CHIM replicates the early natural course of urethral infection. We are now at an inflexion point to pivot the use of the model for vaccine testing to address the urgency of improved gonorrhea control. Herein we discuss the need for gonorrhea vaccines, and the advantages and limitations of the Ng CHIM in accelerating the development of gonorrhea vaccines.

Helping to develop a gonorrhoea vaccine

Helping to develop a gonorrhoea vaccine

The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae

There 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 in Neisseria 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 B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. Serum IgG and vaginal IgA and IgG that cross-reacted with Ng OMVs were induced by 4CMenB vaccination by either the subcutaneous or intraperitoneal routes. Antibodies from vaccinated mice recognized several Ng surface proteins, including PilQ, BamA, MtrE, NHBA (known to be recognized by humans), PorB, and Opa. Immune sera from both mice and humans recognized Ng PilQ and several proteins of similar apparent molecular weight, but MtrE was only recognized by mouse serum. Pooled sera from 4CMenB-immunized mice showed a 4-fold increase in serum bactericidal50 titers against the challenge strain; in contrast, no significant difference in bactericidal activity was detected when sera from 4CMenB-immunized and unimmunized subjects were compared. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against gonorrhea, and implicate several Ng surface antigens as potentially protective targets. Additionally, this study further defines the usefulness of murine infection model as a relevant experimental system for gonorrhea vaccine development.