Declining gonococcal cephalosporin susceptibility has raised the possibility of untreatable gonorrhea in the future (1, 2). New approaches, such as vaccination, are needed as long-term strategies for gonorrhea prevention and control (3). Outer membrane vesicle (OMV) serogroup B meningococcal (MenB) vaccines, which prevent disease caused by Neisseria meningitidis serogroup B (NmB), have shown some cross-protection against gonorrhea (3). Reports from Cuba, Norway, and Canada showed reductions in gonorrhea rates after mass OMV MenB vaccination campaigns (4–6). Three studies that used STI and OMV MenB vaccine surveillance data from New Zealand, Australia, and the United States showed that OMV MenB vaccines were 30–40% effective against gonorrhea (7–9). This cross-protection may be attributed to the high genetic and antigenic homology (80–90%) between N. meningitidis and N. gonorrhoeae (10).

MenB-4C (Bexsero^®, GSK) is the OMV MenB vaccine currently licensed for use against NmB in the United States (11). MenB-4C is composed of two meningococcal OMV proteins (Porins A and B) and three recombinant meningococcal antigens (Neisserial heparin binding antigen [NHBA], Neisseria adhesin A, and factor H binding protein [fHBP]) (12). Meningococcal OMV proteins and NHBA are conserved and surface-exposed in N. gonorrhoeae, suggesting that MenB-4C vaccine-induced antibodies may recognize gonococcal antigenic proteins (10, 13). Murine models have shown that MenB-4C vaccine-induced antibodies cross-reacted with gonococcal antigenic surface proteins and accelerated genital gonococcal clearance (14). Additionally, MenB-4C vaccination produces antibodies in humans that recognize gonococcal antigenic proteins (10). The possible effectiveness of MenB-4C against gonorrhea was supported by a recent U.S.-based study using STI and MenB-4C vaccine surveillance data that demonstrated MenB-4C vaccination effectiveness of 40% against gonorrhea compared to chlamydia (8).

Because the OMV MenB vaccine effectiveness studies against gonorrhea were based on observational data from New Zealand, Australia, and the United States (7–9) and not randomized clinical trials (RCTs), it is theoretically possible that these studies may have been confounded by the healthy vaccinee bias, which may overestimate vaccine effectiveness (15). The healthy vaccinee bias suggests that persons who adopt a preventive behavior (e.g., vaccination) may be more likely to adopt preventive or healthy behaviors and be in better overall health than unvaccinated persons (16). For example, an observational study evaluating vaccine effectiveness against an STI such as gonorrhea without accounting for related STI preventative behaviors may overestimate vaccine effectiveness among vaccinated persons.

Whether the healthy vaccinee bias may have influenced prior observational studies of OMV MenB vaccines can be explored by estimating the effectiveness of MenB-FHbp vaccine (Trumenba^®, Pfizer). The Advisory Committee on Immunization Practices has recommended vaccination with a serogroup B meningococcal series for adolescents and young adults aged 16–23 years based on shared clinical decision-making to provide short-term protection against serogroup B meningococcal disease (11). MenB-4C and MenB-FHbp are the two MenB vaccines licensed for use in the U.S. MenB-FHbp has the same clinical indication and recommendation as MenB-4C (10) but is not an OMV vaccine (17) and is not thought to be protective against gonorrhea (18, 19). MenB-FHbp contains recombinant fHBP (17). The gonococcal homolog of fHBP is not surface expressed and does not bind Factor H, a protein vital to gonococcal immune evasion (18, 19). If studies of MenB-4C vaccine effectiveness have been impacted by the healthy vaccinee bias, vaccines such as MenB-FHbp, which do not have an anti-gonococcal effect, would likely also demonstrate a protective effect in observational studies. An observed absence of a protective effect of Men-FHbp would in turn support the validity of the prior observational studies of OMV vaccines and MenB-4C. The objective of this analysis was to assess the effectiveness of MenB-FHBP vaccine against gonorrhea compared to chlamydia among 16–23-year-old persons diagnosed with gonorrhea or chlamydia in New York City or Philadelphia.

Of 96,235 eligible persons aged 16–23 years with a diagnosis of gonorrhea or chlamydia during 1/1/16–12/31/2018, most were female (66.3%) and non-Hispanic Black (56.2%); however, race/ethnicity data were missing for 34.5% of persons (Table 1). Overall, 1.6% were vaccinated with MenB-FHbp. Among 134,983 STI cases recorded among 96,235 persons, 87.1% were chlamydial mono-infections and 12.9% were gonococcal mono-infections. MenB-FHbp vaccination was not significantly associated with gonococcal mono-infections (UPR=0.89, 95% CI=0.76–1.06) in bivariate analysis (Table 2). After adjusting for race/ethnicity, gender, and jurisdiction, no association between MenB-FHbp vaccination and gonococcal mono-infections was observed (APR=0.97, 95% CI=0.79–1.19).

MenB-FHbp vaccination was not protective against gonorrhea in adjusted and unadjusted analyses. This finding suggests that the healthy vaccinee bias was unlikely to have confounded the effectiveness of MenB-4C and other OMV MenB vaccines against gonorrhea as seen in prior observational studies. Rather, the high genetic similarities between gonococcal and meningococcal OMV proteins and NHBA and the anti-gonococcal antibodies that MenB-4C vaccines produce may explain the reduced gonococcal risk in vaccinated persons (10, 14). Data from population-level studies and immune responses in murine models (4–8, 14) provide evidence to support RCTs that evaluate the efficacy of MenB-4C vaccine against gonorrhea. Ongoing RCTs in populations with elevated incident gonorrhea rates will provide efficacy data critical to understanding anatomic-site specific MenB-4C vaccine efficacy (21, 22) and mechanism of vaccine-induced anti-gonococcal immune responses (22, 23).

There are limitations to this analysis. Because we did not systematically screen persons at all potentially infected anatomic sites, but relied on surveillance data, misclassification bias is possible as infections might have been acquired before vaccination but detected after vaccination. There may also have been missed, incomplete, or incorrect matches between the STI surveillance registry and the immunization information system. Although, the small prevalence of vaccinated persons (1.6%) in this sample may have also reduced the power to detect a difference, we do not think this is the case because of the biological plausibility of MenB-4C vaccine effectiveness against gonorrhea and the growing body of vaccine effectiveness from various studies (8, 9). We defined vaccination as receipt of ≥1 MenB-FHbp dose which may explain the lack of observed MenB-FHbp effectiveness. However, a single MenB-4C dose was still effective against gonococcal mono-infection (8). Approximately one-third of responses for the race variable was missing and so the association with gonococcal mono-infection should be interpreted with caution.

In conclusion, the absence of observed effectiveness of MenB-FHb against gonococcal mono-infection supports the validity of the prior observational studies demonstrating modest effectiveness of OMV MenB vaccines against gonorrhea. RCTs examining the protective effect of MenB-4C vaccines against gonorrhea are essential to understanding its feasibility and prospect as an effective vaccine against gonorrhea.