We conducted a systematic literature search to identify peer-reviewed manuscripts that evaluated the effectiveness of MenB-4C vaccine against gonorrhea. A CDC librarian conducted a search of multiple electronic databases (PubMed, Medline, Embase, Global Health, Scopus, Google Scholar, CINAHL, and Cochrane Library) using the following search terms: (“MenB-4C” OR “4CMenB” OR “meningococcal vaccine” OR “outer membrane vesicle vaccine” OR “OMV vaccine” OR “Bexsero^®”), AND (“gonorrhea” OR “gonorrhoea” OR “Neisseria gonorrhoeae” OR “N. gonorrhoeae”) AND (“vaccine effectiveness” OR “effectiveness”) AND (“sexually transmitted diseases” OR “sexually transmitted Infections” OR “STD” OR “STI”).

We limited eligible manuscripts to those that 1) were published from January 1, 2013 (year MenB-4C was first licensed and approved anywhere in the world) to July 12, 2024, 2) reported estimates of MenB-4C vaccine effectiveness against gonorrhea, 3) were published in English, and 4) published in a peer-reviewed journal. We also reviewed the reference list of eligible articles to identify other eligible manuscripts that our literature search may have missed. We excluded data that were reported in abstracts, posters, conference proceedings, dissertations, books, modeling studies, meta-analyses, or from preclinical trials. All included studies were assessed for methodological quality and risk of bias using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, Quality Assessment Tool of Case-Control Studies, and the Quality Assessment of Controlled Intervention Studies by the National Heart, Lung, and Blood Institute [18].

Two reviewers (W.E.A and E.G) independently reviewed eligible studies. Disagreements were resolved by discussion. We coded data from each eligible study by study site/jurisdiction, sample size, study design, study period, data source, inclusion criteria, unit of statistical analysis (infection-level or person-level), MenB-4C vaccine effectiveness or vaccine efficacy estimate ([1-effect size measure] x 100) and 95% confidence intervals (CI) against gonorrhea and gonorrhea/chlamydia co-infection, intervention group (MenB-4C) and comparison/reference group (unvaccinated or a non-OMV-based vaccine), and reference group for gonorrhea. Estimates of effect size measure with a 95% confidence interval that did not include 1.0 were considered statistically significant. This systematic review and its findings were presented according to the PRISMA checklist (a reporting checklist for evaluating systematic reviews) (Supplementary Material Figure S1) [19].

We conducted a meta-analysis to estimate pooled MenB-4C vaccine effectiveness (≥1 dose of MenB-4C vaccine) against gonorrhea using the DerSimonian-Laird random-effects model [20]. We reported the tau², Q-test, and the I² statistic to assess study heterogeneity. Egger’s test was used to assess publication bias [21]. We did not generate funnel plots because of the limitations of this technique in assessing publication bias with a small study sample (<10 studies) [22]. Because of the inherent differences in observational studies and randomized clinical trials (RCT) as well as the potentially underpowered sample size of the RCT included in this meta-analysis [17], we conducted a sensitivity analysis where we estimated pooled MenB-4C vaccine effectiveness using only estimates from observational studies. All analyses were conducted in Stata 18 statistical software [23]. This meta-analysis was reported according to the MOOSE checklist (a reporting checklist for meta-analyses of observational studies in epidemiology) (Supplementary Material Figure S2) [24]. This study was not reviewed by the Institutional Review Board of the CDC because it was a systematic review and meta-analysis of published studies.

A total of 365 articles were identified by searching Medline, Embase, Global Health, CINAHL, and Scopus databases (Figure 1). After excluding 183 duplicate entries, we identified 162 unique references. We screened all 162 articles based on title and abstract and identified 13 articles. The full text of the thirteen articles were assessed for eligibility. Eight articles met the inclusion criteria [10–17] (Figure 1). Five articles were excluded because they did not report vaccine effectiveness estimates or reported effectiveness of a non-OMV-based MenB vaccine against gonorrhea. We reviewed the reference list of all eight eligible articles and did not identify additional articles eligible for inclusion in this systematic review. All eligible articles were published during 2022–2024.

Of the eight eligible studies, four studies analyzed data from jurisdictions in the United States (New York City and Philadelphia; Southern California; Oregon; and Northern California) [10–13]; two from South Australia, Australia [14, 15]; one from Milan, Italy [16]; and one from Paris, France [17] (Table 1). The data sources used in the eight studies included linked STI surveillance and immunization information system records [10, 12, 14, 15], electronic health records [11, 13, 16], and a RCT [17]. The unit of analysis of vaccine effectiveness was person-level for five studies [11, 12, 14–16] and infection-level for three studies [10, 13, 17].

The study design, data sources, and analytical samples differed between included studies (Table 1). Abara et al. (2022) conducted a retrospective cohort study that used STI surveillance data from New York City and Philadelphia to link gonorrhea and chlamydia cases and MenB-4C vaccination status (two-dose, one-dose, and unvaccinated) among persons aged 16–23 years-old and compared gonorrhea prevalence by vaccination group [10]. Bruxvoort et al. employed a matched case-control design to compare gonorrhea incidence rates among recipients of MenB-4C vaccine and recipients of MenACWY vaccine (a polysaccharide conjugate meningococcal vaccine targeting meningococcal serogroups A, C,W, and Y), aged 15–30 years, using electronic health record data from Kaiser Permanente Southern California [11]. Robison et al. conducted a case-control study to compare gonorrhea prevalence among recipients of MenB-4C vaccine and MenB-FHbp vaccine (a non-OMV-based serogroup B meningococcal vaccine), aged 18–29 years, following a serogroup B meningococcal disease outbreak at two universities in Oregon, USA [12]. Abara et al. (2024) conducted a retrospective cohort study that used electronic health records from Kaiser Permanente Northern California to compare gonorrhea prevalence among MenB-4C vaccinated persons and unvaccinated persons, aged 15–30 years [13].

Wang et al. conducted two case-control studies that used surveillance data from South Australia to assess the effectiveness of MenB-4C vaccine against gonorrhea in two studies [14, 15]. The first study (Wang et al., 2022) used surveillance data from adolescents and adults with a gonorrhea or chlamydia diagnosis who were born between February 1, 1998–February 1, 2005, and had a disease notification date between February 1, 2019–January 31, 2021 [14]. The second study (Wang et al., 2023) also used surveillance data from South Australian adolescents and adults with a gonorrhea or chlamydia diagnosis who were born between January 31, 1998–April 30, 2006, and a disease notification date between February 1, 2019–January 31, 2021 [15]. Eligible gonorrhea and chlamydia case records were linked to MenB-4C vaccination records in both studies. Both case-control studies compared the odds of gonorrhea diagnosis in MenB-4C vaccinated persons and unvaccinated persons [14, 15].

Raccagni et al. conducted a case-control study that used electronic health record data of Italian MSM, ≥18 years, living with HIV and in HIV care, and with a diagnosis of gonorrhea, chlamydia, syphilis, or anal human papilloma virus between July 2016–February 2021 [16]. Raccagni et al. linked STI records and MenB-4C vaccination records, and compared the odds of gonorrhea in MenB-4C vaccinated persons to unvaccinated persons to estimate MenB-4C vaccine effectiveness [16]. Molina et al. conducted a RCT that included MSM, ≥18 years, using HIV pre-exposure prophylaxis (PrEP), with a history of bacterial STIs (chlamydia, gonorrhea, or syphilis) in the past 12 months, and who were enrolled in the ANRS PREVENIR study cohort (a cohort of MSM using tenofovir and emtricitabine for HIV prevention) [17, 25]. They compared the risk of a first episode of gonorrhea among MenB-4C vaccinated persons to unvaccinated persons [17].

For all studies, gonococcal cases (the outcome of interest) were identified by a positive gonorrhea nucleic-acid amplification test (NAAT) or positive N. gonorrhoeae culture of urethral, rectal, or pharyngeal specimens. Four studies evaluated MenB-4C vaccine effectiveness against gonococcal mono-infection and gonorrhea/chlamydia co-infection [10, 13–15]. The RCT study reported efficacy estimates of MenB-4C against gonorrhea at anatomic-specific sites (urethra, rectum, and pharynx) [17]. No observational study examined anatomic-site vaccine effectiveness of MenB-4C against gonorrhea. Eligible studies reported various effect size measures to assess the effectiveness of MenB-4C vaccine against gonorrhea including odds ratio [12, 14–16], prevalence ratio [10, 13], or hazard ratio [11, 17].

Chlamydia was the reference group for gonorrhea in four studies [10, 13–15]. One study used a diagnosis of chlamydia, syphilis, or anal human papilloma virus as its reference group [16] (Table 1). Six studies incorporated a window period to allow for an optimal immune response to develop post-vaccination [10, 11, 13–15, 17]. STI diagnoses that occurred after this window period were considered to have occurred after vaccination. The post-vaccination window period was ≥14 days in three studies [13–15], and ≥30 days [10], ≥31 days [11], or ≥1 month [17]. Two studies did not report a post-vaccination window period [11, 12].

Estimates of MenB-4C vaccine effectiveness against gonorrhea ranged from 23–47% from seven observational studies (Table 1). Three U.S. studies reported MenB-4C vaccine effectiveness (≥1 MenB-4C vaccine dose) estimates of 23% [13], 46% [11], and 47% [12] against gonorrhea among adolescents and young adults, aged 15–30 years .Two studies from South Australia demonstrated that two MenB-4C vaccine doses were 32–33% effective against gonorrhea in adolescents and young adults, aged 15–25 years old [14, 15]. Two doses of MenB-4C were 44% effective against gonorrhea in a study of Italian MSM living with HIV, aged ≥18-years-old, and in HIV care [16]. One study evaluated the dose-dependent association between MenB-4C vaccination and gonorrhea [10]. Compared to being unvaccinated, two doses of MenB-4C vaccine were 40% effective against gonorrhea and one dose was 26% effective. Data from the RCT did not show any efficacy of MenB-4C vaccine against gonorrhea [17].

Pooled vaccine effectiveness against gonorrhea after receipt of ≥1 MenB-4C dose was 32.4% (95% CI=26.2–38.7) (Figure 2) based on nine estimates from eight studies [10–17]. Egger’s test showed no publication bias (t-value of Egger’s test=1.14, P=0.290 and there was no study heterogeneity (Q(8)=6.65, P=0.575, tau²=0.00, I²=0.00%) . In the sensitivity analysis where we excluded the RCT [17] and only included eight effectiveness estimates from seven observational studies [10–16], pooled vaccine effectiveness against gonorrhea after receipt of ≥1 MenB-4C dose was 33.5% (95% CI=26.9–40.1) (Figure 3). Egger’s test showed no publication bias (t-value of Egger’s test=1.32, P=0.235 and there was no study heterogeneity (Q(7)=5.55, P=0.593, tau²=0.00, I²=0.00%) .

Four studies assessed MenB-4C vaccine effectiveness against gonococcal mono-infections [10, 13–15] (Table 1). Two doses of MenB-4C vaccine were 31.6% [14] and 28.3% [15] effective against gonococcal mono-infections according to two studies by Wang et al [14, 15]. Abara et al. (2022) demonstrated that two doses and one dose of MenB-4C were 40% and 26% effective against gonococcal mono-infection, respectively [10]. Another study by Abara et al. (2024) showed that ≥1 dose of MenB-4C was 23% effective against gonococcal mono-infections [13].

Four studies presented results of MenB-4C vaccine effectiveness against gonorrhea/chlamydia co-infection [10, 13–15] (Table 1). Two South Australian studies showed that two doses of MenB-4C were 32.7% and 44.7% effective against gonorrhea/chlamydia co-infection [14, 15]. Two U.S. studies concluded that MenB-4C was not effective against gonorrhea/chlamydia co-infection [10, 13].

Wang et al. assessed the duration of protection of two doses of MenB-4C vaccine against gonorrhea by comparing the effectiveness of two doses of MenB-4C vaccine against gonorrhea within 6–36 months post-vaccination and >36 months post-vaccination [14] (Table 1). Effectiveness of two doses of MenB-4C against gonorrhea within 6–36 months post-vaccination (34.9%) was significantly higher than the effectiveness estimate >36 months post-vaccination (23.2%). Abara et al. [10] and Raccagni et al. [16] did not explicitly assess the duration of protection, however, the median duration of follow-up after vaccination, in both studies, were 3.1 years (37 months) and 3.8 years (45 months) with an observed two-dose vaccine effectiveness of 40% and 44%, respectively.

A risk of bias assessment was done for the case-control (Supplementary Material Table S1), cohort (Supplementary Material Table S2), and RCT studies (Supplementary Material Table S3) included in this systematic review. All studies included in this systematic review were of good quality. A sample size justification was not provided in any of the case-control or cohort studies [10–16]. However, the large analytical sample size of these studies (range=1,051–109,737) mitigated any concerns that these studies were underpowered to detect a difference in gonorrhea risk by MenB-4C vaccination status. A sample size justification for the RCT was provided [17]. However, enrollment in the RCT was prematurely discontinued based on results from an interim analysis that were later found to have used incomplete data. Because of this, the investigators suggest that the final analytical sample size may not have been sufficiently powered to detect moderate vaccine efficacy [17].

Gonorrhea and chlamydia can be asymptomatic and may not be detected without routine screening [26]. The RCT was the only study that employed routine screening to ascertain gonorrhea diagnoses. Because the cohort and case-control studies did not report routine gonorrhea or chlamydia screening before MenB-4C vaccination, misclassification bias is possible: infections might have been acquired before vaccination but detected only after vaccination. This may have decreased the observed estimate of vaccine effectiveness. Additionally, five studies assessed gonorrhea and chlamydia diagnosis at a single time point (person-level analysis) rather than at multiple time points (infection-level analysis). Estimating vaccine effectiveness by assessing gonorrhea or chlamydia at one time point and assigning case or reference group categorization based on this time point may have inadvertently missed subsequent gonorrhea or chlamydia diagnoses and introduced bias into the analysis. However, estimates of effectiveness from the studies that assessed MenB-4C vaccination status and gonorrhea diagnoses at a single time point are comparable to those that included diagnoses at multiple time points, suggesting that this type of bias is potentially minimal.