Table 1.

Gaps in knowledge and data and research needs for gonococcal vaccine development.

Area	Data gap or research need	Notes and additional considerations
Obtaining better epidemiologic data regarding Neisseria gonorrhoeae (Ng) infection, disease, antimicrobial resistance (AMR), and natural history
Infection	•Improve global and regional estimates of Ng infection •Obtain prevalence and incidence data regarding Ng infection from more settings and populations •Evaluate overlap of Ng infection epidemiology with that of meningococcal serogroup B infection and introduction of meningococcal B vaccines across countries	•Development and validation of cheap, feasible Ng diagnostic tests is crucial for obtaining better data, especially for low- and middle-income countries (LMICs) [84] •Conduct strategically determined, additional prevalence studies in selected LMIC areas where most data are being imputed •The World Health Organization (WHO) has published a standard protocol for conducting gonorrhoea prevalence surveys in antenatal settings [85] •Use of existing Ng infection data from clinical trials (e.g., HIV prevention, human papillomavirus (HPV) vaccine, maternal studies) should be explored
Disease	•Improve global and regional estimates of Ng-associated clinical and disease outcomes •Obtain prevalence and incidence data regarding Ng-associated disease from more settings and populations, particularly in LMICs •Determine attributable fractions of such outcomes as PID and tubal factor infertility (TFI) caused by gonorrhoea	•Outcomes can include urethral discharge, pelvic inflammatory disease (PID), infertility, ectopic pregnancy, chronic pelvic pain, adverse birth outcomes, ophthalmia neonatorum and other eye disease, Ng-associated HIV infection, and other outcomes (e.g., epididymitis, proctitis, disseminated gonococcal infection, or male infertility) •Systematic reviews can be conducted first to summarize what is currently known about overall disease burden (e.g., all infertility or all TFI), about Ng-associated disease burden (e.g., Ng-associated PID and infertility), and about the methods used for attributing etiology to Ng (e.g., Ng serologic tests) •Updated etiologic studies of PID using cervical testing and of the proportion of infertility that is tubal factor [34], are needed in diverse settings •Improved methods for measuring upper-genital tract disease (e.g., biomarkers, radiology, or case definitions) and for measuring past Ng infection (e.g., improved serologic tests) would be valuable •Explore potential data sources regarding gonorrhoea-associated adverse pregnancy outcomes
AMR	•Obtain more globally representative assessments of Ng AMR, transmission, and clinical treatment failures •Determine trends in Ng AMR in more settings and among more populations	•Increase number of countries testing gonococcal isolates for AMR and reporting through WHO’s Gonococcal Antimicrobial Surveillance Programme (GASP) [2] •Improved diagnostic tests, including rapid tests for Ng AMR would aid evaluation •Systems are needed for identifying and reporting clinical treatment failures for gonorrhoea and other key AMR metrics (e.g., sentinel surveillance sites in LMIC settings)
Natural history and transmission	•Improve understanding of the proportion, predictors, and timing of Ng cervical infections ascending to the upper-genital tract, causing PID and resulting in long-term sequelae •Gain insight into the factors associated with acquisition, transmission, and duration of infection, including at multiple anatomical sites	•Innovative, ethical study designs are needed for assessing the natural history of Ng infection •Explore study designs used for understanding chlamydia natural history and their role in evaluating gonorrhoea (e.g., evaluating rates of PID in the interval between testing and treatment [86] or using serial specimens from existing prospective studies) •Couples studies might help researchers understand transmission from different anatomical sites and other factors like bacterial load
Modelling gonococcal infection, disease, AMR, economic burden, and theoretical vaccine impact and cost-effectiveness
Overall	•Review and summarize the models that have been published, are ongoing, or are planned •Determine priority data needs for robust modelling •Prioritize and coordinate modelling efforts across groups, initiatives, and interventions	•Modelling efforts related to gonorrhoea across different initiatives (e.g., AMR) and interventions (e.g., new antibiotic development) will need to be coordinated to increase model efficiency and utility •Strengthened data on burden of infection, disease, AMR, transmission, and natural history is important for all models •Consensus regarding a plausible range of important model assumptions will be valuable •Model comparisons can strengthen robustness of conclusions from modelling studies
Models of Ng infection, disease, AMR, and economic burden	•Develop dynamic models of Ng infection, disease, and AMR in varied settings •Estimate global and regional economic burden of Ng infection and disease •Predict future trends in Ng infection, disease, AMR, and costs	•Improve data for modelling inputs and assumptions, including information about key populations and sexual networks •Modelling can be difficult for low prevalence infections with heterogenous distribution within the population •Predictions of the effect of increasing AMR on infection and disease incidence and on costs can help refine the value of a vaccine
Vaccine impact models	•Model the potential effectiveness of a future Ng vaccine in the context of the observed epidemiology and disease burden in different settings •Model potential vaccine impact against different assumptions and scenarios	•How to value AMR, a vaccine’s potential effect on AMR, and a vaccine’s impact in the context of AMR will be key to understanding overall vaccine impact and value •Understanding vaccine impact considering different target populations, immunization strategies, and efficacies can guide PPCs in addition to value propositions •Models should consider both high-income countries (HICs) and LMIC settings •Will be important to include alternative interventions (e.g., new antibiotics) in models
Cost-effectiveness models	•Model the potential cost-effectiveness of a future Ng vaccine given the observed and predicted health and economic burden in different settings •Model potential cost-effectiveness against different assumptions and scenarios	•Systematic reviews can assess what is known about gonorrhoea health care–seeking and –usage, and costs of care and treatment, for both infection and disease •Work will be needed to refine estimates of disability adjusted life-years and quality adjusted life-years considering all Ng outcomes •Cost-effectiveness analyses can guide preferred product characteristics (PPCs) in addition to value assessments
Advancing basic science, translational, immunobiologic, and clinical research
Experimental systems	•Refine animal models and in vitro systems to expand the range of features of human infections that can be studied and to enable vaccine candidate assessment •Explore and optimize use of controlled human infection models (CHIMs) to study Ng immune responses and vaccine efficacy	•Continued understanding of complex Ng immunobiology can lead to new target antigens, novel adjuvant, or delivery systems •Improved preclinical systems for evaluating vaccine candidates can facilitate entry into clinical evaluation •Better data about pathogenesis and immunity in human infections can be compared with animal models to refine them •Current CHIMs exist only for male urethral infection, but could be developed for others (e.g., postmenopausal women)
Antigen discovery and vaccinology	•Continue to take advantage of new technologies to screen for new antigenic targets and define the most promising list of candidates [7], [44], [45], [56] •Further define mechanisms of immunity and immune evasion, which could help in developing adjuvants and delivery platforms for Ng vaccines •Evaluate vaccine candidates in preclinical models or CHIMs	•Evaluation of vaccine candidates is challenging, given that no established surrogate markers or correlates of protection against Ng exist •Given antigenic variability of Ng, a combination of antigens might be needed to provide broad protection against different Ng strains •Findings related to meningococcal outer membrane vesicle (OMV) vaccines and possible cross-protection for Ng can provide direction for vaccine development
Translational, immunobiologic, and clinical studies	•Conduct studies to obtain better data on human immune responses to Ng infection, including prospective evaluations of responses associated with reinfection •Evaluate the effect of licensed meningococcal serogroup B OMV vaccines on Ng acquisition •Evaluate the effect of coinfections, the microbiome, and hormonal status on Ng infection, disease, and immune response •Better understand the role of oropharyngeal and rectal infection in Ng transmission and promotion of AMR •Facilitate progression of promising preclinical candidates into clinical evaluation as soon as possible	•Clinical studies are needed to examine host factors and immune responses during Ng infection, and those predicting the likelihood of infection, reinfection, or ascension to the upper-genital tract •Innovative studies can be modelled on those conducted for chlamydia (e.g., studies reporting that clearance of infection between testing and treatment is linked with reduced risk for repeat infection) [87] •People with an increased risk for complicated Ng disease from complement disorders can provide clues to correlates of risk and protection [88] •Efficacy of meningococcal serogroup B vaccines ideally will be evaluated through clinical trials specifically designed for examining efficacy against Ng infection or disease acquisition; prospective observational studies as the vaccines are rolled out in new areas can also add insight •Couples studies might be useful for evaluating transmission and factors associated with transmission •Correlates of protection might be difficult to identify but would be highly useful; although not essential for vaccine development and licensing, they can make bridging studies easier
Encouraging investment and planning for policy and implementation decisions in advance
Value assessment and PPCs	•Consolidate data on burden of disease, economic burden, and vaccine impact and cost-effectiveness •Understand drivers of gonococcal vaccine development and who the main stakeholders are •Obtain country-level input regarding the potential value of Ng vaccines and features of a vaccine that would be essential and those that would be desirable in different settings	•Improving the quantity and quality of underlying disease data is crucial for developing the vaccine value assessment and PPCs •Considering the interests and needs of different stakeholders is vital (e.g., WHO’s Strategic Advisory Group of Experts, Gavi, the Vaccine Alliance, funders, vaccine developers, national policymakers, health care providers, individuals at risk, parents, and civil society) •Value-of-vaccines assessments consider more than just health benefits and can also include broader societal and public value
Acceptability and implementation	•Evaluate the level of awareness and knowledge about gonorrhoea and Ng AMR and risk perception among young people and their parents, health care providers, and policymakers •Obtain country-level information regarding the likely acceptability of and demand for Ng vaccines from a broad range of countries •Evaluate the potential acceptability of Ng vaccines and potential barriers to acceptance or uptake by individuals and communities for different populations and settings •Assess the potential delivery systems for gonococcal vaccines for different target populations in varied health care systems	•Increasing awareness of Ng AMR and treatment failures can affect both awareness and demand for Ng vaccines •Understanding potential acceptability of Ng vaccines and how they would be used, including country-level input, early in vaccine development can help guide development of vaccines that are suited for global use and able to be implemented more quickly upon licensure and pre-qualification