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.

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

BACKGROUND: Treatment 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 %). METHODS: We 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. RESULTS: The 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. CONCLUSION: Provision 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.

Postoperative HbA1c Level as a Predictor of Rotator Cuff Integrity After Arthroscopic Rotator Cuff Repair in Patients With Type 2 Diabetes.

Background: In patients with type 2 diabetes mellitus (DM), preoperative glycosylated hemoglobin (HbA1c) is associated with outcomes after arthroscopic rotator cuff repair (ARCR); however, the relationship between outcomes and postoperative serum glycosylated hemoglobin (HbA1c) after ARCR has not been investigated. Purpose: To evaluate outcomes after ARCR in patients (1) with and without DM and (2) with DM according to their pre- and postoperative HbA1c levels. Study Design: Cohort study; Level of evidence, 3. Method: Included in this study were 148 patients without DM and 35 patients with type 2 DM who underwent ARCR between January 1, 2017, and December 31, 2019. Clinical and radiological outcomes were evaluated preoperatively and at the latest clinical follow-up. Postoperative magnetic resonance imaging was performed after 12 months. In patients with type 2 DM, HbA1c levels were evaluated preoperatively as well as 6 and 12 months postoperatively; patients with an HbA1c level of ≥7% were defined as having uncontrolled DM. Multivariate logistic regression analyses were performed to determine the factors for retears after ARCR. Results: The retear rates after ARCR were 22.9% (8/35) and 16.9% (25/148) in patients with and without DM, respectively. The retear rates were significantly higher in the 6-month postoperative uncontrolled DM group than in the controlled DM and non-DM groups (50% vs 8.7% and 16.8%; P < .05). The odds ratio for retears in the postoperative uncontrolled DM group was 5.555 (P =0.01) compared with the non-DM group. Among the patients with DM, in the uncontrolled DM group, 6-month postoperative hyperglycemia was superior in accuracy, sensitivity, and specificity for predicting retears after ARCR than preoperative hyperglycemia (77.1% vs 62.9%, 75% vs 37.5%, and 77.8% vs 70.4%, respectively). Conclusion: This study demonstrated the association between uncontrolled postoperative DM and an increased risk of retears compared with no DM or controlled DM. Furthermore, postoperative HbA1c values were correlated more closely with the risk of retears than preoperative HbA1c values.

Incidence and risk factors for syphilis infection among men who have sex with men: A cohort study from an urban sexual health clinic in Jakarta, Indonesia.

Objective: Syphilis infection remains a significant health issue among marginalised populations in Indonesia, in particular among men who have sex with men (MSM), in whom there are limited studies from Indonesia exploring risk factors associated with STI acquisition.Our study aimed to identify risk factors of syphilis infection among MSM attending large sexual health clinic in Jakarta. Methods: We conducted a retrospective cohort analysis using patient records (MSM aged 18 years or older) period Jan 2018-Dec 2019. We used Cox regression to identify risk factors associated with syphilis incidence. Results: Study population were 2912 MSM tested for syphilis, 473 (16.2%) were diagnosed with syphilis on their first visit; early syphilis (415; 14%) and latent syphilis (58, 2%). Among the cohort of 2439 MSM who tested negative at baseline, 40 MSM were identified with a new positive syphilis result during 2 years follow up. Risk factors remaining significantly associated with syphilis incidence included having STI symptom at 1st visit (aHR, 2.8; 95% CI, 1.38-5.65), and HIV-infection (aHR 4.53; 95% CI 2.24 - 9.17).Syphilis incidence rate was 8.19 (95% CI 6.01-11.16) per 100 PYFU. Conclusions: Syphilis infection at baseline and incidence was high among MSM attending this large clinic in Jakarta. Integrated and accessible syphilis prevention and detection coupled with HIV services are needed, with a special focus on high-risk individuals.

Impact of Testing Strategies to Combat a Major Syphilis Outbreak Among Australian Aboriginal and Torres Strait Islander Peoples: A Mathematical Modeling Study.

Background: A syphilis outbreak among Australian Aboriginal and Torres Strait Islander people (respectfully referred to as Aboriginal) has resulted in almost 4000 notifications by 2020, with several congenital syphilis cases and infant deaths. Outbreak control efforts became coordinated under a National enhanced test and treat response in 2017. We evaluated the impact of these efforts and of expansion of testing interventions on syphilis prevalence. Methods: We developed an individual-based mathematical model of infectious syphilis transmission among young heterosexual Aboriginal people aged 15-34 years living in and moving between regional and remote areas, and we assessed the impact of existing and hypothetical outbreak control responses on syphilis prevalence. Results: The increased testing coverage achieved through the response (from 18% to 39% over 2011-2020) could stabilize the epidemic from 2021. To return to pre-outbreak prevalence (<0.24%) by 2025, testing coverage must reach 60%. The addition of annual community-wide screening, where 30% of youth in communities are tested over 6 weeks, would reduce prevalence to the pre-outbreak level within 4 years. If testing coverage had been scaled-up to 60% at the start of outbreak in mid-2011, the outbreak would have been mitigated. Conclusions: Our results suggest that to control the syphilis outbreak, the response needs to be delivered to enable the maximum coverage of testing to be reached in the shortest time to reduce the prevalence to pre-outbreak levels. Reduction could be hastened with community-wide screening at similar time periods across all communities together with increases in annual testing coverage.

Intensified partner notification and repeat testing can improve the effectiveness of screening in reducing Chlamydia trachomatis prevalence: a mathematical modelling study.

BACKGROUND: The Australian Chlamydia Control Effectiveness Pilot (ACCEPt) was a cluster randomised controlled trial designed to assess the effectiveness of annual chlamydia testing through general practice in Australia. The trial showed that testing rates increased among sexually active men and women aged 16-29 years, but after 3 years the estimated chlamydia prevalence did not differ between intervention and control communities. We developed a mathematical model to estimate the potential longer-term impact of chlamydia testing on prevalence in the general population. METHODS: We developed an individual-based model to simulate the transmission of Chlamydia trachomatis in a heterosexual population, calibrated to ACCEPt data. A proportion of the modelled population were tested for chlamydia and treated annually at coverage achieved in the control and intervention arms of ACCEPt. We estimated the reduction in chlamydia prevalence achieved by increasing retesting and by treating the partners of infected individuals up to 9 years after introduction of the intervention. RESULTS: Increasing the testing coverage in the general Australian heterosexual population to the level achieved in the ACCEPt intervention arm resulted in reduction in the population-level prevalence of chlamydia from 4.6% to 2.7% in those aged 16-29 years old after 10 years (a relative reduction of 41%). The prevalence reduces to 2.2% if the proportion retested within 4 months of treatment is doubled from the rate achieved in the ACCEPt intervention arm (a relative reduction of 52%), and to 1.9% if the partner treatment rate is increased from 30%, as assumed in the base case, to 50% (a relative reduction of 59%). CONCLUSION: A reduction in C. trachomatis prevalence could be achieved if the level of testing as observed in the ACCEPt intervention arm can be maintained at a population level. More substantial reductions can be achieved with intensified case management comprising retesting of those treated and treatment of partners of infected individuals.

A Gonococcal Vaccine Has the Potential to Rapidly Reduce the Incidence of Neisseria gonorrhoeae Infection Among Urban Men Who Have Sex With Men.

BACKGROUND: A gonococcal vaccine is urgently needed due to increasing gonorrhea incidence and emerging multidrug-resistant gonococcal strains worldwide. Men who have sex with men (MSM) have among the highest incidences of gonorrhea and may be a key target population for vaccination when available. METHODS: An individual-based, anatomical site-specific mathematical model was used to simulate Neisseria gonorrhoeae transmission in a population of 10 000 MSM. The impact of vaccination on gonorrhea prevalence was assessed. RESULTS: With a gonococcal vaccine of 100% or 50% protective efficacy, gonorrhea prevalence could be reduced by 94% or 62%, respectively, within 2 years if 30% of MSM are vaccinated on presentation for sexually transmitted infection (STI) testing. Elimination of gonorrhea is possible within 8 years with vaccines of ≥ 50% efficacy lasting 2 years, providing a booster vaccination is available every 3 years on average. A vaccine's impact may be reduced if it is not effective at all anatomical sites. CONCLUSIONS: Our study indicates that with a vaccine of modest efficacy and an immunization strategy that targets MSM presenting for STI screening, the prevalence of gonorrhea in this population could be rapidly and substantially reduced.

Modelling response strategies for controlling gonorrhoea outbreaks in men who have sex with men in Australia.

The ability to treat gonorrhoea with current first-line drugs is threatened by the global spread of extensively drug resistant (XDR) Neisseria gonorrhoeae (NG) strains. In Australia, urban transmission is high among men who have sex with men (MSM) and importation of an XDR NG strain in this population could result in an epidemic that would be difficult and costly to control. An individual-based, anatomical site-specific mathematical model of NG transmission among Australian MSM was developed and used to evaluate the potential for elimination of an imported NG strain under a range of case-based and population-based test-and-treat strategies. When initiated upon detection of the imported strain, these strategies enhance the probability of elimination and reduce the outbreak size compared with current practice (current testing levels and no contact tracing). The most effective strategies combine testing targeted at regular and casual partners with increased rates of population testing. However, even with the most effective strategies, outbreaks can persist for up to 2 years post-detection. Our simulations suggest that local elimination of imported NG strains can be achieved with high probability using combined case-based and population-based test-and-treat strategies. These strategies may be an effective means of preserving current treatments in the event of wider XDR NG emergence.

Modelling testing and response strategies for COVID-19 outbreaks in remote Australian Aboriginal communities.

BACKGROUND: Remote Australian Aboriginal and Torres Strait Islander communities have potential to be severely impacted by COVID-19, with multiple factors predisposing to increased transmission and disease severity. Our modelling aims to inform optimal public health responses. METHODS: An individual-based simulation model represented SARS-CoV2 transmission in communities ranging from 100 to 3500 people, comprised of large, interconnected households. A range of strategies for case finding, quarantining of contacts, testing, and lockdown were examined, following the silent introduction of a case. RESULTS: Multiple secondary infections are likely present by the time the first case is identified. Quarantine of close contacts, defined by extended household membership, can reduce peak infection prevalence from 60 to 70% to around 10%, but subsequent waves may occur when community mixing resumes. Exit testing significantly reduces ongoing transmission. Concurrent lockdown of non-quarantined households for 14 days is highly effective for epidemic control and reduces overall testing requirements; peak prevalence of the initial outbreak can be constrained to less than 5%, and the final community attack rate to less than 10% in modelled scenarios. Lockdown also mitigates the effect of a delay in the initial response. Compliance with lockdown must be at least 80-90%, however, or epidemic control will be lost. CONCLUSIONS: A SARS-CoV-2 outbreak will spread rapidly in remote communities. Prompt case detection with quarantining of extended-household contacts and a 14 day lockdown for all other residents, combined with exit testing for all, is the most effective strategy for rapid containment. Compliance is crucial, underscoring the need for community supported, culturally sensitive responses.

Supplemental Trichomonas vaginalis testing is required to maintain control following a transition from Pap smear to HPV DNA testing for cervical screening: a mathematical modelling study.

OBJECTIVES: Using mathematical modelling, we have previously shown that the prevalence of infection with Trichomonas vaginalis (TV) is likely to increase in the general population in Australia with the transition from Pap smear-based cervical screening to human papillomavirus (HPV) DNA testing. Here we use the existing model to estimate the level of supplemental testing required to maintain TV control. METHODS: A compartmental mathematical model describing the transmission of TV in the general heterosexual population in Australia was used to evaluate the impact of a range of screening scenarios on TV prevalence over time following the transition to HPV DNA testing for cervical screening. Scenarios considered were the inclusion of a TV test with the HPV test and the addition of TV testing to routine chlamydia testing conducted in primary care. RESULTS: Our modelling suggests that with sufficient coverage, inclusion of TV testing with routine chlamydia screening in general practice, TV prevalence can be reduced over time, but at the current reported coverage will gradually increase following the transition to HPV testing. Inclusion of TV testing with HPV testing in the cervical screening programme is preferable to no supplemental testing but is considerably less effective in controlling TV. CONCLUSIONS: These findings support the inclusion of TV testing with routine chlamydia testing of young people.