(C) PLOS One
This story was originally published by PLOS One and is unaltered.
 . . . . . . . . . .



Potential public health impacts of gonorrhea vaccination programmes under declining incidences: A modeling study [1]

['Lin Geng', 'Lee Kong Chian School Of Medicine', 'Nanyang Technological University', 'Singapore', 'Lilith K. Whittles', 'Department Of Infectious Disease Epidemiology', 'Imperial College London', 'London', 'United Kingdom', 'Borame L. Dickens']

Date: 2025-02 

Abstract Background Gonorrhea is the second most common sexually transmitted disease notified in Singapore in 2023. Evidence suggests that the 4CMenB vaccine designed to protect against Neisseria meningitidis infection may offer partial cross-protection against gonorrhea. This generated interest in using 4CMenB for the purpose of staving gonorrhea transmission. We explored the efficacy of potential gonorrhea vaccination strategies in the context of historically declining gonorrhea incidence. Methods and findings We employed an integrated transmission-dynamic model, calibrated using Bayesian methods to local surveillance data to understand the potential public health impact of 4CMenB in reducing gonorrhea acquisition and transmission in men who have sex with men (MSM) in Singapore. We explored the efficacy of implementing six vaccination programmes: (1) offering vaccination to all male adolescents in schools (vaccination before entry [VbE]), (2) offering vaccination to individuals attending sexual health clinics for testing (vaccination on attendance [VoA]), (3) offering vaccination to individuals attending sexual health clinics and who were diagnosed with gonorrhea (vaccination on diagnosis [VoD]), or (4) vaccination according to risk (VaR), by offering vaccination to patients who were diagnosed with gonorrhea plus individuals who tested negative, but report having more than five sexual partners per year. We further examined how altering (5) VoA and (6) VoD strategies changed if the strategies only targeted high risk groups (VoA(H),VoD(H)). We assessed efficacy by examining vaccination impact relative to no vaccination and when behavioral parameters were held constant. We further ascertained the effects of varying vaccine uptake (10%, 33%, 100%), vaccine efficacy (22%, 31%, 47%), and duration of protection (1.5, 4, 7.5 years) on the effectiveness of each vaccination strategy. For a hypothetical 10-year vaccination programme, VbE had 14.18% of MSM gonorrhea cases averted over the time the programme was implemented. VoA had the highest protective impact on the MSM population with 40.26% averted cases (95% credible interval (CrI): 18.32%−52.57%), but required more vaccine doses than any other strategy. VoD had a smaller impact (12.04% averted cases (95% CrI: 7.12%−15.00%)), but was three times more efficient than VoA in terms of averted cases per dose. VoA(H) and VoD(H) improved the efficiency of VoA and VoD strategies by increasing averted cases per dose to 0.22 and 0.24 respectively, but conferred similar protective effects as VoA (VoA(H): 40.10% averted cases (95% CrI: 18.14%−52.55%)) and VoD (VoD(H): 12.04% averted cases (95% CrI: 7.12%−15.00%)), respectively. VaR (40.10% averted cases (95% CrI: 18.14%−52.55%)) had almost the same impact as VoA, but was more efficient by requiring administration of fewer doses than VoA, with 0.21 (95% CrI: 0.12–0.27) averted cases per dose. Sensitivity analyses indicated that VaR had the greatest public health impact with the highest number of averted cases per dose for vaccines of any efficacy or duration of protection (or both), although VoD and VoD(H) saved more vaccine resource and had the highest number averted MSM cases per dose for highly protective vaccines of long protection. Conclusions Vaccination of MSM against gonorrhea, according to risk in sexual health clinics in Singapore, can be considered to reduce gonorrhea acquisition and transmission. Development of gonorrhea-specific vaccines which focuses on protective efficacy and the implementation of efficient vaccination programmes can maximize public health impact.

Author summary This article explores the efficacy of potential gonorrhea vaccination strategies in the context of historically declining gonorrhea incidence, using an integrated transmission-dynamic model, calibrated using Bayesian methods to local surveillance data

Vaccination of high risk groups was projected to have the greatest public health impact with the highest number of averted cases per dose for vaccines of any efficacy or duration of protection (or both), but vaccination after diagnoses, or vaccination after diagnoses in high-risk group individuals saved more vaccine resource and had the highest number of averted cases per dose for highly protective vaccines of long protection. Gonorrhea-specific vaccines may confer greater public health impacts by maximizing efficacy over the duration of protection under modeled vaccination programmes.

What do these findings mean? Vaccination of MSM against gonorrhea according to risk in sexual health clinics can be potentially efficient and confer high public health impacts, in settings of declining gonorrhea incidence, such as Singapore.

Citation: Geng L, Whittles LK, Dickens BL, Chio MTW, Chen Y, Tan RKJ, et al. (2025) Potential public health impacts of gonorrhea vaccination programmes under declining incidences: A modeling study. PLoS Med 22(2): e1004521. https://doi.org/10.1371/journal.pmed.1004521 Received: August 5, 2024; Accepted: January 7, 2025; Published: February 7, 2025 Copyright: © 2025 Geng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All code and data used for this research can be accessed at https://github.com/lineliott/gonovaxSG/. Funding: This work was supported by Nanyang Technological University, Singapore—Imperial Research Collaboration Fund (INCF-2023-007 to JTL and AG). LJT is Assistant Professor at Nanyang Technological University. AG is Professor and LKW is Lecturer at Imperial College London. The funders had other role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: CrI, credible interval; DSC, department of sexually transmitted infections control; MSM, men who have sex with men; OMVs, outer membrane vesicles; STIs, sexually transmitted infections; VaR, vaccination according to risk; VbE, vaccination before entry; VoA, vaccination on attendance; VoD, vaccination on diagnosis

Introduction Neisseria gonorrhoeae, a bacterial pathogen, is primarily transmitted through unprotected vaginal, anal, or oral intercourse. The infection typically affects the mucosal epithelium of male urogenital tracts, the rectum, pharynx, or conjunctiva, manifesting with inflammation, discharge, and a burning sensation during urination [1]. Among them, most male urogenital infections are symptomatic while rectal and pharyngeal infections are asymptomatic [1,2]. According to the Department of Sexually Transmitted Infections Control (DSC), Singapore, the majority of men who have sex with men (MSM) gonorrhea cases have single site infections at urethra, but up to 6% have 2 or 3 sites infections with the majority being asymptomatic (pharynx and rectal). Globally, gonorrhea ranks among the top five most frequently reported curable sexually transmitted infections (STIs) and causes significant public health burdens [1]. While gonorrhea incidence has moderated during the COVID-19 pandemic, which may be due to reductions in sexual contacts during lockdowns/stay-at-home orders and/or reduced testing, evidence showed that gonorrhea transmission may be surpassing pre-COVID-19 levels, due to relaxation of non-pharmaceutical measures motivated by COVID-19 [3]. However, in Singapore, low but persistent gonorrhea incidence has been reported over the last few decades, with a historical decline in incidence reported in the 2000s [4]. Yet, gonorrhea remains one of the top STIs diagnosed in MSM at the DSC clinic in 2023. The disease presents a challenge due to the ability of N. gonorrhoeae to evade the host’s immune response, complicating pharmaceutical prevention strategies. Therefore, the primary approach to mitigating gonorrhea involves antibiotic therapy for infected individuals. However, antimicrobial resistance in N. gonorrhoeae has historically existed and has escalated globally [2], and the first local case of resistance was reported in 2018 [5]. Since then, the local antibiogram of gonorrhea cultures has been closely monitored for decreased susceptibility and resistance to the recommended antibiotics, but to date, few resistant strains have been diagnosed in Singapore. However, as there are limited antibiotics to target gonorrhea, the exploration of more sustainable interventions such as vaccination for public health preparedness remains crucial [6]. The interest in vaccine prevention against N. gonorrhoeae arose from observations of declining gonorrhea incidence with the use of the MenB (one type of meningococcal serogroups) outer membrane vesicles (OMVs) vaccine in Norway [7] and Cuba [8,9], which were used to protect against meningococcal disease caused by meningococcal group B bacteria. These observations suggested that meningitis prevention might also protect against gonorrhea. A retrospective observational case-control study confirmed that the Neisseria meningitidis serogroup B OMV vaccine (MeNZB [GSK]) provided a 31% (95% credible interval (CrI) 21–39) efficacy against gonorrhea with a 3-dose program [10]. Subsequent studies provided further genetic evidence that the anti-gonococcal antibodies induced by MeNZB can offer additional cross-protection against gonorrhea [11]. Furthermore, studies from the United States, Canada, and Australia have reported that 4CMenB, an alternative vaccine option for gonorrhea, can be more effective than MeNZB, with efficacies ranging between 33% and 46% [12]. However, a recent study suggested a more conservative, statistically insignificant 22% efficacy of 4CMenB vaccine in gonorrhea prevention, which may be due to an underpowered sample size [13]. Prior modeling work has also highlighted the potential cost-effectiveness of introducing the 4CMenB vaccine in the United Kingdom through various uptake strategies, advocating for vaccination according to risk (VaR) among the MSM population. This approach is projected to avert an average of 110,200 cases (95% CrI 36,500–223,600) over 10 years in the study setting [14]. However, further analysis suggested that pessimistic vaccine sentiments may attenuate the benefits of these vaccination programmes [15]. Nevertheless, current work has focused on high and/or increasing transmission settings for gonorrhea. In contrast, Singapore’s epidemiology presents a unique opportunity to assess the population health impacts of gonorrhea vaccination programmes in the context of historically declining incidence over the past 2 decades. While the previous climate of criminalized same-sex relationships has hindered the gathering of statistics in MSM populations, decriminalization also provided a rare opportunity to study and prevent STIs in a group that has been disproportionately affected globally. In this study, we aimed to guide potential public health decisions regarding the implementation of different gonorrhea vaccination programmes. We sought to devise and compare alternative, pragmatic approaches to implementing vaccination within sexual health clinics or educational institutions, in terms of their public health impact and efficiency. To do so, we used a high-resolution compartmental model of gonorrhea and utilized a Bayesian evidence synthesis framework to characterize the transmission dynamics of gonorrhea. This was calibrated using three different case-time series of gonorrhea incidence among MSM from 2004 to 2018. We examined how the impact of vaccination programs over 2024–2034 depends on vaccine-specific factors, such as uptake, efficacy, and duration of protection, as well as different epidemic trajectories.

Discussion We calibrated a transmission model of gonorrhea to explore the population health impacts of potential vaccination strategies over a 10-year period. Over 2024–2034, we found that strategies which targeted MSM on diagnoses (VoD, VoD(H)) were highly efficient in terms of number of averted cases per dose, but had less population health impact, compared to vaccination of MSM on attendance (VoA), in terms of the total number of averted cases. While these results highlighted certain trade-offs between population health impact and efficiency among vaccination strategies, we found that vaccination based on both attendance and only offering vaccines to high-risk groups or vaccination by targeting those at risk (VoA[H], VaR) can confer both the benefits of having a large number of averted cases and preserve acceptable efficiency with an estimated 0.22 (95% CrI: 0.09–0.29) averted cases per dose. This suggested that impact and efficiency gains were mainly conferred from targeting MSM with a high number of sexual partners. From an implementation standpoint, VaR may be the most practical strategy as high sexual activity MSM diagnosed with gonorrhea may not disclose partnership numbers, and may be classed as MSM at low risk and not be vaccinated under VoA(H). Conversely, these same individuals would be eligible under VaR. Increasing vaccine uptake also conferred greater public health impact for all strategies in terms of the percentage of cases averted (Fig 4), but higher vaccine uptake was estimated to reduce the efficiency of all strategies in terms of number of averted cases per dose. Specifically, as uptake rates increased, sensitivity analyses revealed that there was always a corresponding increase in the percentage of averted cases, but was accompanied by a corresponding decline in the efficiency of the programme (in terms of averted cases per dose). However, VoD and VoD[H] showed minimal declines in efficiency even as uptake rates increased, which may be due to administration of vaccines in MSM who are at high risk even at high uptake rates. In contrast, VoA, VoA[H], and VaR demonstrated that higher uptake rates significantly reduced the efficiency of the programmes, in terms of averted cases per dose. Our work corroborates with literature on the potential public health benefits of vaccination programmes of STIs. Gonorrhea vaccination in settings of increasing incidence were projected to be cost-effective when administered according to risk in sexual health clinics [14]. Pre-emptive vaccination was expected to reduce the likelihood of mpox outbreaks in the same study setting, especially in targeting of dense and well-connected sexual contact networks [21]. Whereas vaccination for human papillomavirus could reduce the risk of cervical cancer with increasing improvement in equality in cervical cancer incidence in the future [22]. A key strength of our analysis was that we calibrated our transmission-dynamic model to three separate case series and used Bayesian methods to account for uncertainty in epidemiological parameters. Our simulation framework directly captured the uncertainty in these parameters, including those that characterize heterogeneities and changes in sexual behavior and testing, by using a large number of parameters drawn from the posterior distribution of data to simulate future changes in gonorrhea transmission in different vaccination programme scenarios. As the future transmission trajectory of gonorrhea is unknown, we considered alternative trajectories, such as assuming constant rates of transmission, or declining rates of transmission for 2024–2034 (See S1 Text, Section 5). We reported conservative estimates given constant rates of transmission and presented the alternative scenario in the S1 Text. We incorporated various hypothetical vaccine profiles as the vaccine efficacy and protection of duration of potential gonorrhea vaccines is currently uncertain. Our simulations also comprised vaccination programmes that can be implemented in a real-world setting, such as through sexual health clinics or schools, which further highlighted the applicability of our simulations. There are certain limitations to this research study. In our exploration of the public health impacts of these vaccination programmes, we did not study the cost-effectiveness of these strategies, which departed from prior modeling work done in settings of historical increasing incidence [14], due to the lack of publicly available cost data on gonorrhea treatment in the local context. We did not calibrate our model to actual gonorrhea incidence in MSM populations, as these were not available. Instead, we calibrated our model to three alternative epidemiological time series which could realistically proxy epidemiological patterns in MSM populations across the years—across these different scenarios, we found that our results on vaccination programme impact and efficiency did not vary significantly. Certain parameters employed for model calibration also relied on information from other study settings, such as the natural recovery rate, and the proportion of asymptomatic infections, although there should be no major location-specific differences in these parameters. We also characterized the change in transmission probability over the observation period using a linear function, or assumed that they were constant in the future. Our exploration included an alternative exponentially decaying functional form to characterize changes in transmission probabilities, but this did not fit to observed historical trends appropriately. Additionally, we excluded data from 2019 and 2020 from model calibration, as non-pharmaceutical measures motivated by COVID-19 may have exogenous impacts on gonorrhea transmission, which cannot be captured by our model [14]. Future work should consider explicitly accounting for these factors and incorporate more recent, local epidemiological information on gonorrhea transmission. There was also a lack of community sexual behavior data, such as information on sexual networks, to characterize behaviors and proportions of key at-risk populations in the study setting. Hence, it was difficult to parameterize changes in sexual behaviors after vaccination over study period. We relied on survey data from a UK MSM demographic survey to parameterize screening rates in high/low sexual activity groups in Singapore, and explored the impact of different screening and sexual behavior parameters in sensitivity analysis. However, due to recent legislative changes in decriminalizing sex between consenting adult males in the study setting, the practicality of collecting such data in the study setting is increased, and future work should seek to ascertain potential vaccination programme effectiveness using more accurate local data, as well as understand the impact of vaccination on sexual behaviors. We hypothesize that vaccination may be accompanied by higher risk activities due to an assumption of efficacious vaccine-mediated protection, and thereby modulate the public health impact of vaccination programmes. Our analysis may also require constant updates in conjunction with rapidly developing literature surrounding the protective efficacy of 4CMenB against gonorrhea infection. The most recent systematic review reported a pooled efficacy of 32.4% [23], a finding that supported the parameters used in our primary analysis. However, a more recent retrospective cohort study reported a 23% protective effectiveness against gonorrhea [24], highlighting heterogeneities in published estimates. We also presented a simplified analysis of vaccination programmes, where protective efficacies and duration were identical for both the primary/secondary dose and the booster dose. However, this biased our estimates of public health impact conservatively as protective efficacies should be higher when protection is conferred under the booster dose. Our model only incorporated high/low risk sexual activity groups, but assumed homogeneity in behaviors within each group. Proximal factors, such as past sexual history, unprotected sexual behavior, or substance use were also not accounted for due to lack of available granular data. Therefore, estimation of the force of infection were coarsened to either of high/low risk population subgroups. Potentially important population subgroups, such as superspreaders, were not accounted for. Higher efficiency vaccination strategies, such as targeting those at very high risk, were therefore not explored, as parameters for these population subgroups were not available for model calibration and scenario analysis. The main study results were also based on a constant population size over time, but shifts in age distribution and migration may influence our results. A decreasing population size over time would lead to a gradual depletion of susceptibles and lead to gradually lower raw public health impacts for the vaccination programmes, and vice versa, for an increasing population size. However, data on the future population age structure and numbers over the next 10–20 years is currently not available and these scenarios were precluded from our modeling study. As our output was primarily focused on projecting the potential future impacts of the vaccination programmes, it was difficult to forecast and incorporate changes in public health campaigns, changes in healthcare access, or risk perception, which may influence screening rates over the future 10–20-year time horizon. We therefore relied on a constant, risk-group-specific screening rate for these projections. Hypothetically, increases in screening rates due to intensified public health campaigns may increase the public health impacts of strategies such as VoA and VoD, by provision of vaccination to more individuals attending sexual health clinics. Combining modeled vaccination programmes with alternative public health strategies may also amplify the public health impact of the vaccination programmes. These scenarios can be explored in future studies. Utilization of rapid test kits and intensified outreach can enhance the uptake rate of vaccination programmes in at-risk populations. Mitigation of potential stigma towards gonorrhea through intensified outreach, and increasing diagnosis rates in asymptomatics by roll-out of rapid test can facilitate timely vaccination and testing, and potentially enhance the impact of gonnorhea vaccination programmes. Lastly, our study did not consider sentiments on vaccination, which was previously found to downwardly influence the public health impact of vaccination programmes [15].

Conclusions Vaccination of MSM against gonorrhea, according to risk or on diagnoses in sexual health clinics in Singapore, with the 4CMenB vaccine can be considered. Development of gonorrhea-specific vaccines should prioritize maximizing vaccine efficacy over duration of protection.

[END]
---
[1] Url: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004521

Published and (C) by PLOS One
Content appears here under this condition or license: Creative Commons - Attribution BY 4.0.

via Magical.Fish Gopher News Feeds:
gopher://magical.fish/1/feeds/news/plosone/