Neisseria gonorrhoeae (gonococcus) and Neisseria meningitidis (meningococcus) are important global pathogens causing gonorrhea and meningitis, respectively, and/or sepsis ^[1].

Neisseria meningitidis leads to an invasive meningococcal disease (IMD) that could be fatal and lead to severe morbidity, and it is widespread all over the world. It can be characterized into 12 serogroups, of which the most common are serogroups A, B, C, W135, X, and Y ^[2]. Serogroup B (MenB) has been predominant in children and young adults, and it is broadly diffused, especially in Europe. Luckily, recently protective vaccines against B serogroup have become available. In fact, according to ECDC data in Italy for Neisseria gonorrhoeae (gonococcus) reported in 2019, there were 813 confirmed cases, with a higher prevalence in the age groups of 15–24 and 25–34 years ^[3]. Meanwhile, in Italy in 2018, according to the College of Health, the number of new cases was 601 ^[4]. Due the importance of this pathogen worldwide, two protein-based vaccines, namely 4CMenB (Bexsero^®) and rLP2086 (Trumenba^®), are currently licensed for use in different countries. In other countries, the VA-MENGOC-BC vaccine is available ^[5]. Given this premise, it is extremely important to choose the right vaccine for the prevention of this condition; furthermore, considering the epidemiological data concerning this pathogen in Europe, it is essential to choose which vaccine is best for a booster dose.

N. gonorrhoeae is a significant health problem worldwide due to the rapid change in antimicrobial susceptibility with the development of antibiotic resistance to the molecules generally used for its treatment, the presence of limited studies, and the absence, to date, of an effective vaccine ^[6].

According to data from the World Health Organization (WHO), the incidence rates translate globally into 86.9 million (95% UI: 58.6–123.4 million) new gonorrhea cases in women and men aged 15–49 years ^[7]. From an epidemiological point of view, gonorrhea appears to be the second-most sexually transmitted disease, with approximately 1.6 million new gonococcal infections in the United States in 2018, especially in young adults ^[8].

Although it occurs asymptomatically in 10–50% of cases, antimicrobial resistance (AMR) in many countries has been extremely high in recent years with a lack of efficacy, not only in the current recommended treatment for gonorrhea (ceftriaxone and azithromycin), but also in penicillin, sulfonamides, tetracyclines, fluoroquinolones, and macrolides. Gonococcal infections have critical implications for reproductive, maternal, and neonatal health, including a five-fold increase in HIV transmission, infertility, and inflammation, leading to acute and chronic lower abdominal pain in women, ectopic pregnancies and maternal death, first-trimester abortions, and severe neonatal eye infections that can lead to blindness.

The financial costs of these complications are very high for both individuals and healthcare systems. Antimicrobial resistance increases this burden by prolonging the infection in more people and increasing the number of people with long-term complications. To date, prevention involves the use of prophylaxis and the avoidance of direct sexual contact ^[9], given the absence of an effective vaccine; a recent review of the literature illustrates the main scientific efforts in this regard ^[9]. At present, only two gonococcal vaccine candidates have reached the stage of human experimentation in the past. The lack of a clear correlation between protection and the absence of immunity to Ng reinfection have called into question the possibility of a gonorrhea vaccine. However, several studies have been performed in order to find the right antigens for the development of an effective vaccine.

2. Available Data on the Prevention of Gonorrhea by MenB Vaccines

2.1. Immunogenicity of Gonococcal OMVs and the 4CMenB Vaccine against Gonorrhea in Mice

Neisseria gonorrhoroeae is not an animal pathogen, but a human one, and its investigation is obtained through the use of a murine model given by the infection of the genital tracts of mice treated with estradiol. Moreover, its action, similarly to N. meningitidis, depends on the K antigen and on endotoxins (outer-membrane lipopolysaccharide). Due to these reasons, under-cited studies were performed on these premises. Leduc et al. [18]^[10] tested the hypothesis that the external-membrane-vesicle vaccine 4CMenBV (Bexsero) against Neisseria meningitidis induces cross-protection against gonorrhea in a female mouse model infected in the genital tract. They found that immunization with half the dose of the vaccine significantly accelerated clearance and reduced the bacterial load of Ng compared to the administration of a placebo. In addition, an increase in serum IgG, and in vaginal IgA and IgG, was also obtained both in the administration through the subcutaneous (SC) and intraperitoneal (IP) routes, leading to clearance within one week in the vaccinated group compared to the control group (injected with alum or PBS). This finding directly supports the evidence available today relating to cross-protection induced by vaccination with the production of protective antibodies against various surface antigens. Furthermore, they found that 4CMenB reproducibly accelerates the clearance of Ng from the murine genital tract and reduces bacterial load over time, and that complement-mediated and opsonophagocytic bacteriolysis may contribute to protection [18]^[10]. In the study of Plante et al., the intranasal administration of lithium-chloride-extracted gonococcal outer-membrane preparations to female mice (treated with estradiol to prolong infection) was performed to evaluate the impact on vaginal colonization [19]^[11]. The results were an accelerated clearance of N. gonorrhoeae compared to the control group and the detection of gonococcal-specific antibodies in the sera of the immunized mice [19]^[11]. The same results were also reported in a study investigating the intravaginal administration of gonococcal OMVs with microencapsulated interleukin-12 in female mice [20]^[12]. In summary, the demonstration that an authorized NMV OMV-based vaccine accelerates the clearance of Ng in a mouse model’s genital tract infection is direct evidence that cross-species protection can be an effective vaccine strategy for gonorrhea.

2.2. Ecological Studies

Several ecological studies have shown the protection of people immunized with OMV MenB for N. gonorrhoeae. In Norway and Cuba, a reduction in gonorrhea cases was identified after MenB OMV vaccines [20,21]^[12][13]. In Norway, the rates of gonorrhea had already reduced since the mid-1970s, during which there was a clear decline in both sexes within subjects aged 20 to 24 years. A limit of the study is the presence of behavioral factors, such as the use of condoms since the early 1990s, especially among young people [20]^[12]. In Cuba, the authors both reviewed epidemiological data for N. meningitidis and N. gonorrhoeae infections and collected serum, saliva, and oropharynx samples from high school students who had previously been vaccinated with VA-MENGOC-BC (MBV) during their infancy. They were revaccinated with a third dose during the study. The epidemiological data showed a decrease in the incidence of gonorrhea. The samples, tested by Western blot analysis, were positive with an increase in the serum responses of the anti-MBV (PL) antigens, except for the anti-PL IgA responses of saliva present only and significantly induced in the carriers. Carriers were augmented with a third dose of MBV-induced, similar anti-gonococcal responses and serum-PL saliva IgA and IgG [21]^[13]. Further epidemiological data show the influence of MBV on the incidence of gonorrhea, suggesting that the vaccines depend on the age of sexual arrival [22]^[14]. In Norway, a retrospective case-control study was conducted on patients in sexual health clinics aged 15–30 who were eligible to receive MeNZB. Cases were identified through the laboratory isolation or detection of Neisseria gonorrhoeae from a clinical specimen, while the controls were individuals with a positive chlamydia test. The estimated vaccine efficacy after adjustment for ethnicity, deprivation, geographic area, and gender was 31% (95% CI 21–39) [23]^[15]. A retrospective cohort study was conducted on a cohort of individuals born between 1984 and 1999 (n = 935,496) to estimate the efficacy of the New Zealand meningococcal B vaccine against hospitalization associated with gonorrhea. The efficacy of the vaccine (MeNZB™) against hospitalization caused by gonorrhea was estimated to be 24% (95% CI 1–42%), suggesting a significant reduction in the hospitalization rate for gonorrhea. This supports previous research, indicating a possible cross-protection of this vaccine against gonorrhea acquisition and disease in an outpatient setting [24]^[16].

2.3. Ongoing Studies Assessing Impact of 4CMenB against N. Gonorrhoeae and Real-World Studies

A phase 3, double-blinded, randomized placebo-controlled, multi-centered trial is being conducted in Australia to assess the efficacy of the 4CMenB (Bexsero^®) vaccine, in the prevention of Neisseria gonorrhoeae infection. The sample comprises people aged 18–40 years old, men, transgender women, and gay or bisexual men+, who are either HIV negative and taking pre-exposure prophylaxis [PrEP], or HIV positive with a low viral load (<200 copies/mL) and CD4 count >350 cells/cmm, who have a high N. gonorrhoeae incidence and are indicated by Australian guidelines to have regular, comprehensive sexual health screenings [25]^[17]. Another phase II multi-center study with a length of 24 months is currently being conducted in the USA and Thailand to verify the efficacy of two doses of 4CMenB in the prevention of urogenital and anorectal infections in at-risk subjects aged 18 to 50 years (n = 2200) [26]^[18]. In the USA, a phase 2 case-control clinical trial is being conducted to assess the systemic and mucosal immunogenicity of the 4CMen vaccine against Neisseria gonorrhoeae, using a placebo vaccine for comparison (arm 1 = 40 e arm 2 = 10; n = 50). The enrolment will be stratified by both sex and treatment arm, and the length of the study is estimated to be 14 months. The endpoint is to detect the rectal mucosal Immunoglobulin G (IgG) antibody response to Neisseria gonorrhoeae elicited by the 4CMenB vaccine compared with the placebo vaccine [27]^[19]. Another clinical trial to demonstrate that the meningococcal B vaccine (Bexsero^®) reduces the occurrence of the first episode of Neisseria gonorrhoeae is being made in France. Other objectives include a reduction in the occurrence of cumulative episodes of NG, first episode of anal and urinary NG, first episode of symptomatic anal and urinary NG; serum bactericidal activity against meningococcus B and gonococci; and the tolerance; prevalence, and incidence of meningococcal carrying at the pharyngeal, anal, and urinary levels, and the impact of prophylaxis on it [28]^[20]. In Australia, a study aims to evidence the impact and the effectiveness of the 4CMenB vaccine against IMD and gonorrhea in people aged 14–19 years with a target sample of 7100 participants, and the estimated completion date is 31 December 2024 [29]^[21]. One of the objectives is to implement 4CMenB immunization in young people aged 14–19 years, a second one is to evidence carriage prevalence; and finally, one is to study the vaccine effect (impact and effectiveness) against both invasive meningococcal disease (IMD) and gonorrhea using data from the above study, comparing notifications between vaccinated and unvaccinated participants [29]^[21]. Wang et al. [30]^[22] are carrying out a cohort and case-control study among patients adhering to the 4CMenB vaccination program in South Australia, obtaining data on both disease notifications and vaccination coverage. The efficacy of the vaccine was estimated by the reduction in the probability of infection using screening and case-control methods. The impact of the vaccine was estimated using incidence ratios (IRRs), obtained by comparing the number of cases in each year following the start of the vaccination program with cases in the age-equivalent cohort during the years of the pre-vaccination program. Two years after the implementation of the childhood vaccination program, the incidence of serum meningococcal disease of group B was reduced in the implementation of the program in children aged 1 to 11 months, but not the remaining ages. Meanwhile, the two-dose vaccine efficacy was estimated to be between 94.2% and 94.7% for invasive meningococcal disease B and 32% for gonorrhea [31]^[23]. Another study is being conducted in South Australia in adolescents and young adults 15–24 years of age to evaluate the effectiveness of the 4CMenB vaccination program against invasive meningococcal disease and gonorrhea through a combination of observational studies using routine surveillance and research data [31]^[23]. In a study conducted in Canada, after the vaccination of 82% of subjects between the ages of 2 months and 20 years, no cases of gonorrhea occurred among the vaccinated, while two cases were reported among those not vaccinated, obtaining a significant effect in multivariate analysis (relative risk of B-IMD: 0.22; p = 0.04) [32]^[24]. Similar values, with lower vaccination coverage, were reported in a US case-control study reporting a vaccine efficacy in protection against gonorrhea of 40% with two doses and of 26% with one dose [33]^[25]. In a matched-cohort study conducted from 2016 to 2020 [34]^[26] at Kaiser Permanente Southern California, the authors examined the association of gonorrhea and chlamydial infection between 6641 recipients of 4CMenB and 26,471 recipients of MenACWY in which their findings, during the follow-up period, showed a reduction in the incidence rates of gonorrhea by 46%, while no effect was found for Chlamydia. A bioinformatic analysis was performed to assess the similarity of MeNZB OMV and Bexsero antigens to gonococcal proteins, and it was demonstrated that Bexsero induces antibodies in humans that recognize gonococcal proteins that may provide additional cross-protection against gonorrhea [35]^[27].