4CMenB journey to the 10-year anniversary and beyond

ABSTRACT

The 4-component meningococcal serogroup B (MenB) vaccine, 4CMenB, the first broadly protective, protein-based MenB vaccine to be licensed, is now registered in more than 50 countries worldwide. Real-world evidence (RWE) from the last decade confirms its effectiveness and impact, with infant immunization programs showing vaccine effectiveness of 71–95% against invasive MenB disease and cross-protection against non-B serogroups, including a 69% decrease in serogroup W cases in 4CMenB-eligible cohorts in England. RWE from different countries also demonstrates the potential for additional moderate protection against gonorrhea in adolescents. The real-world safety profile of 4CMenB is consistent with prelicensure reports. Use of the endogenous complement human serum bactericidal antibody (enc-hSBA) assay against 110 MenB strains may enable assessment of the immunological effectiveness of multicomponent MenB vaccines in clinical trial settings. Equitable access to 4CMenB vaccination is required to better protect all age groups, including older adults, and vulnerable groups through comprehensive immunization policies.

Plain Language Summary

Invasive meningococcal disease, caused by the bacterium Neisseria meningitidis(meningococcus), is rare but often devastating and can be deadly. Effective vaccines are available, including vaccines against meningococcal serogroup B disease. In 2013, the 4-component meningococcal serogroup B vaccine, 4CMenB, became the first broadly protective, protein-based vaccine against serogroup B to be licensed, with the second (bivalent vaccine, MenB-FHbp) licensed the following year. 4CMenB is now registered in more than 50 countries, in the majority, for infants and all age groups. In the US, it is approved for individuals aged 10–25 years. Evidence from immunization programs in the last decade, comparing vaccinated and unvaccinated individuals and the same population before and after vaccination, confirms the effectiveness and positive impact of 4CMenB against serogroup B disease. This also demonstrates that 4CMenB can provide protection against invasive diseases caused by other meningococcal serogroups. Furthermore, N. meningitidis is closely related to the bacterium that causes gonorrhea, N. gonorrhoeae, and emerging real-world evidence suggests that 4CMenB provides additional moderate protection against gonococcal disease. The safety of 4CMenB when given to large numbers of infants, children, adolescents, and adults is consistent with the 4CMenB safety profile reported before licensure.

For the future, it would be beneficial to address differences among national guidelines for the recommended administration of 4CMenB, particularly where there is supportive epidemiological evidence but no equitable access to vaccination. New assays for assessing the potential effectiveness of meningococcal serogroup B vaccines in clinical trials are also required because serogroup B strains circulating in the population are extremely diverse across different countries.

GRAPHICAL ABSTRACT

KEYWORDS:

• 4CMenB
• Bexsero
• cross-protection
• effectiveness
• impact
• Neisseria meningitidis
• Neisseria gonorrhoeae
• real-world evidence
• safety
• serogroup B

Introduction

Invasive meningococcal disease (IMD) is unpredictable and life-threatening, and is associated with long-term physical, neurological, psychological, and behavioral complications.^1,2 Most cases are caused by six meningococcal serogroups (A, B, C, W, Y, and X) and effective vaccines are available to prevent IMD caused by the five most common serogroups: vaccines that target the polysaccharide capsule of meningococcal serogroups A, C, W, and Y (MenACWY), and protein-based vaccines against meningococcal serogroup B (MenB).³ Additionally, a pentavalent MenABCWY vaccine was licensed recently⁴ and another is in phase 3 clinical development,⁵ with a Biologics License Application accepted for filing. The development of a MenACWYX vaccine is also at an advanced stage.⁶

Protein-based MenB vaccines were developed because the MenB polysaccharide is poorly immunogenic and has the potential to induce autoimmune antibodies.⁷ The first protein-based MenB vaccines, VA-MENGOC-BC (Finlay Institute; Cuba), MenBvac (Norwegian Institute of Public Health; Norway), and MeNZB (Novartis; New Zealand), were based on outer membrane vesicles (OMV) and ‘tailor-made’ for specific strains, but these lacked broad protective activity against diverse, heterologous MenB strains.⁸ The first broad-spectrum protein-based MenB vaccine, 4CMenB (Bexsero, GSK), was licensed in 2013 after over 20 years of research and development, for individuals aged 2 months or older.^9–11 This was followed the next year by the licensure of the bivalent vaccine, MenB-FHbp (Trumenba, Pfizer) for individuals aged 10–25 years.¹² 4CMenB includes three recombinant protein antigens, Neisseria adhesin A (NadA), neisserial heparin-binding antigen (NHBA), and factor H binding protein (fHbp), plus detergent-extracted OMV from an epidemic strain collected in New Zealand, containing Porin A (PorA P1.4) as the main immunodominant antigen.^13,14

In this narrative review, we chart the 10-year journey since 4CMenB licensure in Europe, including recommendations for its administration in different countries worldwide and accumulating real-world evidence (RWE) on its impact and effectiveness against IMD and its safety profile. Emerging evidence on the potential for protection against non-MenB disease and Neisseria gonorrhoeae is also discussed, as well as the need for improved access to MenB vaccination. Finally, we examine methods that have been used to evaluate multicomponent MenB vaccines before the availability of RWE, and describe a new assay (the endogenous complement human serum bactericidal antibody assay, enc-hSBA assay) for the assessment of the immunological effectiveness of new and existing multicomponent MenB vaccines in clinical trial settings.

A set of audio slides and a graphical abstract linked to this review article can be found at https://www.tandfonline.com/doi/full/10.1080/21645515.2024.2357924.

Evolution of 4CMenB national approvals and recommendations

As IMD is unpredictable and uncommon,^3,15-17 the efficacy of meningococcal vaccines cannot be determined with sufficient statistical power via conventional placebo-controlled clinical endpoint trials. The initial licensure of MenB vaccines therefore relied on demonstrations of safety and immunogenicity, derived by human serum bactericidal antibody (hSBA) assay on a small number of vaccine antigen-specific indicator MenB strains.¹⁸ These data, combined with Meningococcal Antigen Typing System (MATS) estimations of vaccine coverage,¹⁹ provided the basis for the licensure of 4CMenB in the European Union (EU) in 2013 as a three-dose series plus booster dose (3 + 1) schedule for individuals from the age of 2 months (Figure 1). In 2020, the EU recommendations were updated to include a two-dose series plus booster dose (2 + 1) schedule from the age of 2 months,¹¹ following demonstrations of similar immunogenicity, antibody persistence, and safety profiles with either a 2 + 1 or 3 + 1 vaccination schedule^20,21 and no evidence for a difference in MenB strain coverage.²²

Figure 1. Road map leading to the regulatory approval and distribution of 4CMenB in more than 50 countries worldwide^9–11 and to the inclusion of 4CMenB in national and regional immunization programs since initial registration.

*Adolescents/young adults (age 15–24 years) who wish to be vaccinated. 4CMenB, 4-component MenB vaccine; EU, European Union; MenB, meningococcal serogroup B; NIP, national immunization program; RIP, regional immunization program; SCDM, shared clinical decision-making; SmPC, summary of product characteristics; UK, United Kingdom; US, United States.

National and regional MenB vaccination policies are generally driven by the local epidemiology of MenB disease and local recommending bodies. 4CMenB is registered in more than 50 countries worldwide and, to date, 4CMenB is included in the national infant immunization program of 16 (Figure 1): Andorra,²³ Chile,²⁴ Czechia,^25,26 France,²⁷ Ireland,²⁸ Italy,²⁹ Lithuania,^30,31 Malta,³² New Zealand,³³ Portugal,^34,35 San Marino,³⁶ Spain,^37,38 the United Kingdom (UK),^39,40 and, most recently, Germany,⁴¹ Luxembourg,⁴² and Switzerland.⁴³ 4CMenB is also included in a national immunization program for adolescents (aged 14–15 years) in Czechia^25,26 and Switzerland (aged 11–15 years, with catch-up until age 20 years),⁴³ and adolescents/young adults (aged 13–25 years) in close-living situations in New Zealand.³³ 4CMenB has been recommended recently for vaccination of adolescents/young adults (aged 15–24 years) in France, who wish to be vaccinated.⁴⁴ In the United States (US), the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices recommends 4CMenB, given as two doses at least 1 month apart, for adolescents and young adults aged 16–23 years on the basis of shared clinical decision-making.^45,46 In 2018–2019, a regional immunization program for children younger than 4 years and adolescents (15–20 years) was introduced in South Australia,⁴⁷ and this program is ongoing for infants and adolescents aged 15–16 years.⁴⁸ In 2024, this was joined by a funded MenB immunization program in Queensland, Australia, for infants, children aged 13–23 months (catch-up vaccination), and adolescents aged 15–19 years.⁴⁹ In Italy, in addition to the national infant program, a regional adolescent immunization program is recommended and funded for adolescents aged 11–18 years based on the decision of individual regions.²⁹ In Canada, a regional adolescent immunization program was introduced in 2023 in the provinces of Prince Edward Island and Nova Scotia.^50,51

National guidelines vary for the coadministration of 4CMenB with routine childhood vaccines and for antipyretic prophylaxis^52,53 (Figure 2). Of the countries that include 4CMenB in their national infant immunization program, 10 recommend coadministration (for at least one primary dose) with routine childhood vaccines and six recommend antipyretic prophylaxis with paracetamol (Figure 2).^{23,24,27-38,40-43,54,55} Few countries recommend immunization against five meningococcal serogroups in the same age group. Most of the 16 countries with national infant 4CMenB immunization programs recommend MenACWY vaccine administration to adolescents or young adults, but only four (Czechia, France, Chile, and Malta) recommend MenACWY vaccination of young children.^{24,25,32,44,56} Both MenB and MenACWY vaccination of adolescents is recommended in Czechia,^25,26 Switzerland,⁴³ France,⁴⁴ the US,⁴⁵ South Australia and Queensland, Australia,^48,49 three regions of Italy (Puglia, Calabria, and Sicily; in Sicily, MenB vaccination up to age 12 years),^57–59 and Prince Edward Island and Nova Scotia in Canada.^51,60 Concomitant administration of 4CMenB with MenACWY enables broad IMD protection against five meningococcal serogroups; no immunological interference is detected when both vaccines are administered to infants, adolescents, or adults at the same vaccination visit, and there is no notable increase in reactogenicity compared to separate administration of the vaccines.^61–63

Figure 2. Recommendations in 16 national immunization programs for the coadministration (co-adm) of routine childhood vaccines with 4CMenB and the use of prophylactic paracetamol (known as acetaminophen in the United States).^52,53

4CMenB, 4-component MenB vaccine; UK, United Kingdom.

Real world effectiveness and impact against MenB disease

Post-licensure data that have accumulated over the last 10 years provide evidence of the real-world effectiveness and impact of 4CMenB against MenB disease. Recent reviews of these data are available;^53,64-66 a summary is provided here, along with the latest RWE.

Real-world effectiveness data are available from four European countries (the UK, Italy, Spain, and Portugal), the US, Canada, and South Australia (Figure 3(a)). In September 2015, the UK became the first country to include 4CMenB in a national infant immunization program³⁹ and outcomes data are available from up to 5 years of implementation of two-dose priming in infancy and a booster dose at 12 months of age.^65,67–69 Evaluation of the effect of vaccination on MenB disease incidence during the first 3 years of the program (September 2015 to August 2018) in England showed a 75% decrease in incidence among the age groups that were fully eligible for vaccination, with 63 observed cases versus 253 expected cases (incidence rate ratio [IRR] 0.25; 95% confidence interval [CI]: 0.19–0.36), and vaccine protection lasting for at least 2 years after the 2 + 1 regimen.⁶⁷ Over 3 years, there were 169 MenB disease cases in the vaccine eligible cohorts, and it was estimated that a further 277 cases (95% CI: 236–323) were prevented, representing one case avoided every 4 days. Further reductions in MenB disease in children younger than 5 years in England were also reported in the fourth year of the immunization program.⁶⁵ Another analysis of MenB disease cases in England between September 2015 and March 2021 also found a sharp decline among vaccine-eligible children younger than 5 years, from the pre-vaccine average of 328 cases per year (2010–2015) to 148 cases per year after 4CMenB implementation, a significant decline of 55% (p < .0001).⁶⁹

Figure 3. Real-world evidence of the effectiveness, impact, and safety of 4CMenB.

A. Vaccine effectiveness and vaccine impact against invasive meningococcal serogroup B (MenB) disease.

B. Safety profile of 4CMenB.

C. Effectiveness against non-B meningococcal disease and gonococcal disease.

4CMenB, 4-component MenB vaccine; AE, adverse event; AEFI, AE following immunization; aIRR, adjusted IRR; CI, confidence interval; IMD, invasive meningococcal disease; IRR, incidence rate ratio; MenACWY, meningococcal serogroup ACWY vaccine; MenB, meningococcal serogroup B; MenB-FHbp, MenB-factor H binding protein vaccine; MenW, meningococcal serogroup W; MSM, men who have sex with men; NIP, national immunization program; OMV, outer membrane vesicles; OR, odds ratio; PLWH, people living with HIV; RIP, regional immunization program; SAE, serious AE; SLSJ, Saguenay-Lac-Saint-Jean; SmPC, summary of product characteristics; UK, United Kingdom; US, United States; VE, vaccine effectiveness.

Evidence of persistent protection following 4CMenB vaccination is also available from Canada, where a mass vaccination campaign was launched in 2014 to control a long-lasting MenB disease outbreak in the Saguenay-Lac-Saint-Jean (SLSJ) region of Quebec.⁷⁰ By the end of the campaign in 2014, 83% of residents aged between 2 months and 20 years (approximately 59,500 individuals) had been vaccinated. In the four-year post-campaign period, there was a 96% decrease in incidence of MenB disease in the target age group, from 11.4/100,000 person-years in 2006–2014 to 0.4/100,000 person-years in 2014–2018 (p < .0001). No MenB disease cases were reported in the target age group between May 2014 and the end of 2016.⁷¹ The MenB disease rate in 2014–2018 was 0.51/100,000 person-years in vaccinated persons (one case) and 2.45/100,000 in unvaccinated persons (one case), resulting in vaccine effectiveness of 79%, with a large 95% CI (−231% to 99%).⁷⁰ Outbreak control data are also reported from the US, where 4CMenB was used to control MenB disease outbreaks among college students, two in 2013–2014⁷² and one in 2016.⁷³ Following two vaccine doses administered at least 1 month apart, no additional cases of MenB-related disease were reported among individuals vaccinated during the three immunization campaigns.

In Italy, when 4CMenB was introduced in the national infant immunization program in 2017 as a 3 + 1 schedule starting at 2 months of age,²⁹ two regions had already introduced publicly-funded infant immunization programs: Tuscany, where vaccination started in 2014 using a 3 + 1 schedule from 2 months of age, and Veneto, where vaccination began in 2015 with a 2 + 1 schedule from 7 months of age.⁷⁴ Vaccine effectiveness against MenB disease was 93.6% (95% CI: 55.4–99.1) in Tuscany in 2014–2018 and 91.0% (59.9–97.9) in Veneto in 2015–2018. The overall impact of 4CMenB vaccination, estimated from pre- and post-vaccine incidence rates of MenB disease in all children aged 0–5 years, was 68% in Tuscany and 31% in Veneto, suggesting a greater impact of vaccination when the immunization program was started in younger infants.⁷⁴ More recently, 4CMenB vaccine effectiveness against MenB disease in fully immunized children in three Italian regions (Tuscany, Veneto, and Piedmont) was found to be 94.9% (95% CI: 83.1–98.4) by a screening method and 91.7% (24.4–98.6) in six regions (Tuscany, Veneto, Piedmont, Apulia, Liguria, and Sicily) by a case-control method.⁷⁵ Almost 20% of the cases in unvaccinated children were among infants too young to be vaccinated, suggesting earlier vaccination may prevent more MenB disease cases.

The results of case-control studies in Portugal and Spain, made possible through the widespread use of the vaccine in the private market following scientific society recommendations, provide further evidence of the real-world effectiveness of 4CMenB.^76,77 In Portugal, analysis of MenB cases presenting in 2014–2019 at 31 pediatric services showed that vaccination with 4CMenB was significantly less likely among children and adolescents who developed MenB disease than in matched controls, with an odds ratio of 0.21 (95% CI: 0.08–0.55), corresponding to vaccine effectiveness of 79%.⁷⁶ In Spain, a nationwide matched case-control study of the effectiveness of 4CMenB in children younger than 5 years found the effectiveness of complete vaccination (at least two 4CMenB doses) was 71% (95% CI: 45–85) against MenB disease.⁷⁷

Various analyses have been conducted of the success of the infant, child, and adolescent 4CMenB vaccination program in South Australia, where the number of MenB disease cases had increased by an average of 10% per year from 2003 to 2016, peaking at 10 cases in 2015.⁷⁸ An observational time series analysis assessed vaccine impact among adolescents aged 16–19 years in 237 senior schools randomized to the 4CMenB immunization program in 2017 (intervention) or 2018 (control).⁷⁸ The number of MenB disease cases fell to five in 2017–2018 and one in 2018–2019 (Figure 4), showing persistent protection, and comparing the 14-year pre-vaccine period with the 2-year post-vaccine period (2017–2019) showed an overall 71% (95% CI: 15–90, p = .02) reduction in number of MenB disease cases in adolescents. Another analysis reported no cases of MenB disease in the trial population in 2017–2018 and afterward in 2019, as compared with 12 cases among students aged 15–18 years in the pre-vaccine period, 2015–2016.⁷⁹ Evaluation 2 years after implementation of the program showed 100% vaccine effectiveness against MenB disease in adolescents and young adults, since no cases were reported after implementation, and vaccine effectiveness in children of 94.2% (95% CI: 36.6–99.5) using a screening method and 94.7% (40.3–99.5) by case-control method.⁸⁰ Moreover, 3 years after implementation, reductions in MenB disease incidence were 63.1% (95% CI: 29.0–80.9) in infants and 78.5% (33.0–93.1) in adolescents, and vaccine effectiveness against MenB disease was 90.7% (6.9–99.1) for the childhood program and 83.5% (0–98.2) for the adolescent program.⁸¹

Figure 4. Observed and projected serogroup B invasive disease cases in South Australia before (2003–2016) and after 4CMenB vaccination of students aged 16–19 years as part of the ‘B part of It’ program.⁷⁸

4CMenB, 4-component MenB vaccine; CI, confidence interval; MenB, meningococcal serogroup B; PI, predicted interval.

Real world safety of 4CMenB in different settings

In the clinical development studies, involving more than 6000 participants, 4CMenB had an acceptable safety and tolerability profile in infants, toddlers, adolescents, and adults.⁸² The most common local and systemic adverse events (AEs) in infants and children were injection site reactions, fever, and irritability, while in adolescents and adults, malaise, and headache were most frequently reported.

The safety observations in infants were generally similar to those reported following other routine infant vaccines, such as combined diphtheria-tetanus-acellular pertussis (DTaP), inactivated poliomyelitis (IPV), Haemophilus influenzae type b (Hib), hepatitis B (HBV), and pneumococcal conjugate (PCV) vaccines.⁸³ Coadministration of 4CMenB with routine childhood vaccines was however more reactogenic than routine vaccines administered alone.^82,83 In one study of 1885 infants, fever was observed after 26–41% of 4CMenB doses when administered alone, 23–36% after routine vaccines given alone, and 51–61% after 4CMenB and routine vaccines administered together.⁸⁴ The incidence of fever following 4CMenB was low in adolescents and adults.^82,83 Antipyretic prophylaxis with paracetamol can improve the tolerability of 4CMenB. A randomized controlled trial of infants given 4CMenB with routine vaccines (DTaP-HBV-IPV/Hib and PCV) reported lower rates of fever (defined as ≥ 39.0°C) and solicited local AEs in infants given three doses of prophylactic paracetamol (one dose at the time of vaccination and two doses at intervals of 4–6 h) compared with those receiving the same vaccinations without paracetamol, without affecting the immunogenicity of any of the 4CMenB or routine vaccine antigens.⁸⁵ Antipyretic prophylaxis and advising parents on the appropriate management of fever after vaccination also substantially reduced reports of fever requiring medical attention.^85–87

A decade of active and passive safety reporting in different age groups in conjunction with 4CMenB immunization campaigns or outbreak control provides additional valuable safety experience (Figure 3b). This includes further evidence on the effectiveness of antipyretic prophylaxis from the 4CMenB vaccination campaign in Quebec (SLSJ region),⁸⁸ with the finding that at least two doses of paracetamol reduced the odds of fever after each 4CMenB dose by more than half (odds ratio 0.28 to 0.40) among children younger than 2 years old. In the UK, a retrospective case note review of hospitalized preterm infants showed implementation of prophylactic paracetamol reduced the risk of fever and AEs to levels seen before the introduction of 4CMenB into the national immunization program.⁸⁹

Other surveillance studies describe the characteristics of AEs reported following mass immunization. Suspected AEs from the 21-month period after 4CMenB implementation in the UK infant immunization program were examined in a prospective surveillance study.⁹⁰ During this time, approximately 1.29 million children aged 2–18 months were vaccinated and around 3 million doses of 4CMenB were administered. Of 902 reports of suspected AEs received via the UK Yellow Card Scheme, 41% were related to local reactions and 40% to fever, with no significant safety concerns and no reduction in compliance with doses of other routine vaccinations. Further examination of UK safety data after 4CMenB vaccination of 107,231 children aged 1–18 months in 2015–2018 detected few cases of specific safety outcomes (seizures, febrile seizures, and Kawasaki disease), although there was an increased risk of seizures (adjusted IRR 1.43; 95% CI: 1.02–2.02) and febrile seizures (1.72; 1.08–2.75).⁹¹ Since 93% of 4CMenB doses were administered on the same day as other routine vaccines in the national immunization schedule, it was not possible to attribute this finding to a specific vaccine.

Post-marketing surveillance data for Italy in 2017 (2161 suspected AEs following immunization [AEFI]) and Germany in 2013 to 2016 (1960 AEFI) indicated no safety concerns with 4CMenB and a safety profile consistent with that described in the vaccine’s summary of product characteristics.^92,93 In South Australia, the safety profile of 4CMenB was examined as part of the immunization program in adolescents in relation to AEs reported via the South Australian Vaccine Safety Surveillance System, a spontaneous reporting system for AEFI.^94,95 Following 58,637 doses of 4CMenB administered to 30,522 students (median age, 16 years), 193 AEFI were reported in 187 students, giving an AEFI reporting rate of 0.33% (95% CI: 0.28–0.38), or 329 AEFI per 100,000 doses. Almost all students (166 of 169) who were contactable for AEFI follow-up reported resolution of the AE. The most common AEFI were injection site reactions, headache, and nausea.⁹⁴ The rate of AEFI reporting was therefore low in adolescents, but was higher than the rate reported nationally in individuals aged 7–17 years via passive reporting following 4CMenB use in the private market; in 2020, following 40,888 4CMenB doses, there were 39 AEFI, translating into an AEFI reporting rate of 95.4 per 100,000 doses in Australia.⁹⁶ Overall, 4CMenB was well tolerated with no unexpected safety issues.

4CMenB safety surveillance data gathered in conjunction with MenB disease outbreak control in France, the US, and Canada^88,97,98 are in line with AEFI reporting in funded or private immunization programs. No new safety concerns were reported and AEFI were consistent with those reported in the 4CMenB clinical trials before licensure. In Canada, as part of the immunization campaign of individuals aged 2 months to 20 years in Quebec (SLSJ region), an active surveillance questionnaire was issued to vaccinated individuals or their parents 7 days after each vaccine dose and 6 months after the last dose.⁹⁹ Of 154 reported serious AEs that were eligible for further analysis, the most frequent were respiratory problems (34%) and other infections (25%) that were considered as expected for the age group. Three cases of nephrotic syndrome were diagnosed in the 6-month period after the second 4CMenB dose and an additional case was identified by hospitalization database review in children aged 2–5 years. This potential signal was evaluated in the larger cohort of vaccinated children in England, which found no evidence of an increased risk of nephrotic syndrome,¹⁰⁰ suggesting the cases observed in Quebec may have occurred by chance.⁶⁴ Another study of a national healthcare database in England also found no increased risk of Kawasaki disease associated with 4CMenB administration in infants or toddlers.¹⁰¹

Safety data are available from the US from 4CMenB vaccination campaigns that began before 4CMenB licensure, under a CDC sponsored Investigational New Drug protocol, to control two MenB outbreaks on college campuses.⁹⁷ Following vaccination of 15,236 individuals and administration of 28,229 4CMenB doses, the rate of reported serious AEs was 3.3 per 1000 vaccinated individuals, and a causal relationship with 4CMenB was reported for two serious AEs (rhabdomyolysis and anaphylaxis; both individuals recovered fully). Overall, the study found an acceptable safety profile for the continued use of 4CMenB.

Protection beyond MenB disease: non-B serogroups and N. gonorrhoeae

Antigenic components of 4CMenB can also be expressed in non-B meningococcal strains and in other pathogenic Neisseria species, including N. gonorrhoeae strains. Furthermore, 4CMenB has been shown to elicit immune responses against both non-B strains and gonococcal strains, demonstrating the potential for protection beyond MenB disease.¹⁰²

The hSBA assay of serogroups C, W, and Y invasive disease isolates from England and Wales, France, Germany, and Brazil showed that, of 147 non-B isolates, 109 were killed (hSBA titer ≥ 4) by sera from infants immunized with 4CMenB, resulting in overall coverage of 74%, with 64% of MenC, 80% of MenW, and 94% of MenY isolates killed, versus only 14% of isolates killed by pooled pre-immune sera.¹⁰³ Testing this non-B isolate panel with adolescent post-vaccination sera also showed 4CMenB cross-reactivity, with 62% of 147 isolates killed; 55% of MenC, 74% of MenW, and 66% of MenY isolates versus 7.5% of isolates killed by pre-immune sera.¹⁰⁴ Moreover, a study of MenX isolates found evidence of 4CMenB coverage for nine isolates from several countries in Africa but not for two unrelated MenX isolates from France.¹⁰⁵

The first RWE of 4CMenB protection against MenW disease came from England following implementation of the 4CMenB infant immunization program and an emergency MenACWY program for adolescents, which started in 2015 to control an outbreak of MenW disease.¹⁰⁶ MenW cases were compared in the 4 years before and 4 years after implementation of both vaccines, using Poisson modeling to estimate direct protection offered by the infant 4CMenB program and the indirect impact of the adolescent MenACWY program in children eligible for 4CMenB but not MenACWY. This showed 69% (adjusted IRR 0.31; 95% CI: 0.20–0.67) fewer MenW cases than predicted in children eligible for 4CMenB, regardless of vaccination status, with 4CMenB directly preventing 98 cases (95% CI: 34–201). Further RWE of an effect against non-B serogroups comes from an analysis in Spain, in which 243 (79.4%) of 306 IMD cases in children younger than 5 years were MenB, 20 (6.6%) were MenW, five (1.6%) were MenC, and seven (2.3%) were MenY, with the remainder caused by non-groupable meningococcal strains or the serogroup could not be identified.⁷⁷ Vaccine effectiveness of two 4CMenB doses was 76% (95% CI: 57–87) against IMD caused by any serogroup and 92% (28–99) against non-MenB disease, demonstrating effectiveness against serogroup B and non-serogroup B meningococci.

The potential for 4CMenB effectiveness against gonorrhea was indicated by the presence in N. gonorrhoeae isolates of a highly conserved gene for the surface-exposed antigen NHBA, the finding that three NHBA variants, which account for 82% of gonococcal strains, each share 67% identity to NHBA peptide 2 included in 4CMenB, and the recognition of gonococcal NHBA by antibodies induced by 4CMenB.^107,108 Accessory proteins may also contribute to this potential, given the high level of sequence identity between 4CMenB OMV proteins and N. gonorrhoeae homologs, and recognition of gonococcal OMV proteins by 4CMenB-induced antibodies.¹⁰⁸ Furthermore, results from retrospective analyses conducted in New Zealand on individuals immunized with the MenB OMV vaccine, MeNZB, showed 31% vaccine effectiveness against gonorrhea¹⁰⁹ and 24% vaccine effectiveness against hospitalization caused by gonorrhea.¹¹⁰ These observations have particular importance given the long-term consequences of gonococcal infection, especially when left undiagnosed due to asymptomatic infection, which occurs more frequently in women than in men.¹¹¹ Moreover, there is no effective vaccine against gonorrhea and antibiotic-resistant gonococcal strains present a global threat.¹¹²

Various studies to investigate the potential for 4CMenB protection against N. gonorrhoeae infection are ongoing or have been completed,^{80,81,113–127} as summarized in Figure 5. Encouraging results have been reported in populations vaccinated with 4CMenB in Quebec (SLSJ region),¹¹⁹ the US (New York City, Philadelphia, Southern California, and Oregon),^115,116,118 South Australia,^80,81 and Italy¹²¹ (Figure 3(c)). An estimated risk reduction for N. gonorrhoeae infection of 59% (95% CI: −22 to 84; p = .1) was reported in conjunction with the 4CMenB immunization campaign in Quebec, with a reported decrease in cases among 14–20 year-olds and an increase in older, unvaccinated individuals.¹¹⁹ A retrospective observational study of surveillance and immunization registry records for individuals aged 16–23 years in New York City and Philadelphia found that two-dose 4CMenB had 40% (95% CI: 23–53) effectiveness against gonorrhea compared to no vaccination and after adjusting for gender, race, and jurisdiction.¹¹⁸ Furthermore, when the methods in this study were replicated in a second study of the effectiveness of MenB-FHbp, a non-OMV vaccine, against gonorrhea, vaccine effectiveness was 3%, suggesting the results of the original study were unlikely to be confounded by healthy vaccinee bias.¹²⁸ In Southern California, a study of 6641 4CMenB recipients matched to 26,471 MenACWY recipients found that gonorrhea rates were 46% lower among recipients of 4CMenB versus MenACWY, while chlamydia rates were similar.¹¹⁶ Moreover, a recent case-control analysis examined gonorrhea prevalence following MenB vaccination campaigns with 4CMenB and MenB-FHbp prompted by university outbreaks in Oregon in 2015 and 2016.¹¹⁵ Comparison of 15,760 recipients of 4CMenB with 15,212 recipients of non-OMV-based MenB-FHbp showed a lower gonorrhea prevalence in the 4CMenB group (24 versus 44 cases), with 47% (95% CI: 13–68) effectiveness with 4CMenB among those aged 18–29 years and 59% (95% CI: 20–79) effectiveness for those aged 18–19 years. Another case-control analysis, conducted in South Australia, reported 33.2% (95% CI: 15.9–47.0) effectiveness of two-dose 4CMenB against gonorrhea in adolescents and young adults, using age-matched individuals with chlamydia infection as controls, during 3 years of program implementation.^80,81 In Italy, an unmatched case-control study of 1051 men who have sex with men (MSM) living with HIV, reported an adjusted effectiveness estimate with 4CMenB of 44% (95% CI: 9–65; p = .02) against gonorrhea, with a median follow-up of 3.8 years.¹²¹ Additionally, results were presented recently from the first phase 3 randomized study to evaluate 4CMenB against gonorrhea in MSM.^127,129 The DOXYVAC trial in France assessed 4CMenB and doxycycline post-exposure prophylaxis in MSM on HIV pre-exposure prophylaxis. The patients had a median age of 40 years, median 10 sexual partners in the previous 3 months, and 98% had a history of sexually-transmitted infection in the last 12 months.¹²⁷ The incidence of a first episode of gonorrhea was 58.3 and 77.1 per 100 person-years in the 4CMenB and no vaccine arms, respectively. Overall, the results were inconclusive, with vaccine efficacy against gonorrhea infection not meeting statistical significance (22%; 95% CI: −1 to 40; p = .06), although some benefits could not be ruled out.¹²⁹ The study had been discontinued due to the Data and Safety Monitoring Board’s recommendation to stop enrollment, based on interim analysis results that were later modified post audit. Two additional studies are completed, with final results pending: the phase 4 N. gonorrhoeae immune response study in North Carolina, US,¹¹³ and the BexKPK gonococcal vaccine study in Kenya.¹²²

Figure 5. Ongoing and completed studies on the potential for 4CMenB to protect against Neisseria gonorrhoeae infection.

* Figure 3c presents real-world evidence of the effectiveness and impact of 4CMenB in completed studies.

†Study supported by GSK.

^‡Vaccine efficacy 22% (95% CI: -1–40) against gonorrhea infection. Results inconclusive; some benefits could not be ruled out.

4CMenB, 4-component MenB vaccine; ANRS, National French Agency for Research on AIDS; CDC, Centers for Disease Control and Prevention; MSM, men who have sex with men; MSSS, Ministry of Health and Social Services, Quebec; N, number of enrolled participants (actual number for completed studies; planned number for ongoing studies); NIAID, National Institute of Allergy and Infectious Diseases; PrEP, pre-exposure prophylaxis; RCT, randomized controlled trial; SA, South Australia; SLSJ, Saguenay-Lac-Saint-Jean; STI, sexually transmitted infection; US, United States.

According to two modeling studies, modest vaccine effectiveness against gonorrhea could result in a reduction in gonorrhea prevalence that has a meaningful public health impact.^130,131 A heterosexual N. gonorrhoeae transmission model showed that a vaccine with an efficacy of 30% or greater and 2-year duration of protection could reduce gonorrhea prevalence in the US by more than 10%,¹³¹ fitting with the 10% goal set by the US Department of Health and Human Services for reducing gonorrhea rates in male adolescents and young men.¹³² The potential public health impact of adolescent 4CMenB vaccination on N. gonorrhoeae infection in England found that a national adolescent immunization program for a vaccine with 31% efficacy, 6 years’ duration of protection, and 85% uptake could avert 50,000 gonococcal infections over 10 years, equivalent to 10% of heterosexual infections.¹³⁰ Vaccine impact was predicted to increase over time with catch-up and booster vaccination.

The need for improved access to MenB vaccination among all age and at-risk groups

Epidemiological data, mostly generated in Europe and North America, show the incidence of IMD is highest in children younger than 5 years, with a second peak in adolescents and young adults, and a third in older adults.^133,134 For 4CMenB, the most common age-based recommendation is for infant immunization.⁵³ As highlighted earlier, adolescent 4CMenB immunization is recommended in few countries (Figure 1). In Czechia, the adolescent recommendation is for those aged 14–15 years,^25,26 in Switzerland, 11–15 year-olds (with catch-up until age 20 years),⁴³ in France, 15–24 year-olds who wish to be vaccinated,⁴⁴ while in New Zealand, it is for adolescents/young adults in close-living situations.^33,53 South Australia and Queensland, Australia, have immunization programs for infants and adolescents,^47–49 and a regional adolescent program exists in Italy alongside the national infant immunization program.²⁹ Canada has a regional adolescent immunization program,^50,51 and in the US, 4CMenB is recommended at age 16–23 years, on the basis of shared clinical decision-making.^45,46

Immunization of adolescents and young adults is supported by RWE of the effectiveness of adolescent vaccination from the South Australia 4CMenB immunization program, which showed a sharp decline in MenB disease cases in the region (Figure 4) and no cases in 4CMenB-vaccinated adolescents,⁷⁸ and from outbreak control data from US colleges,^72,73 where no additional cases of MenB disease were found among immunized individuals. Furthermore, immune responses persist after 4CMenB vaccination in both early childhood and adolescence. Studies show seroprotective hSBA titers are maintained against at least one vaccine antigen for 24 to 36 months by 76–100% of children after priming in infancy, and by 84–100% of children after priming in the second year of life.¹³⁵ Among adolescents or young adults, antibody persistence extended 7.5 years after primary vaccination in a variety of settings,¹³⁵ so 4CMenB vaccination at 16–18 years of age may protect adolescents and young adults during a peak period for IMD.¹³⁶ Booster vaccination induces robust anamnestic responses in all age groups.¹³⁵ This suggests prior vaccination may provide residual antibody protection in outbreak settings, with a single booster dose administered to adolescents or young adults likely to provide protective immunity faster than a two-dose series given to vaccine-naïve individuals. The future immunization strategy for this age group should therefore include both vaccine-naïve individuals and boosting those primed in infancy.

There is also a strong argument for considering the inclusion of older adults in MenB immunization programs. Data from Europe and North America show older adults generally have higher case fatality rates with IMD than younger adults, adolescents, and children, which is probably linked to underlying comorbidities.¹³⁷ IMD in this age group is associated with atypical symptoms that may be misdiagnosed, and with a high healthcare burden and economic cost.⁵⁶ In addition, the incidence of IMD in older adults appears to be increasing, which may be due to a combination of waning immunity, immune senescence, and the success of meningococcal immunization programs in younger age groups.^56,137

Other populations at increased risk of IMD include individuals with immune system disorders, such as functional or anatomic asplenia and complement deficiency, and those living with HIV.^138–140 MSM in outbreak settings and MSM with HIV are also reported to be at increased risk of IMD.^138–142 The risk of IMD in populations with immune system disorders is considerably higher than for healthy persons; for example, up to 10,000-fold higher for individuals with complement deficiencies and up to 23-fold higher for those living with HIV.^45,143 One study conducted in England found the relative risk of IMD in people living with HIV was 4.5 that in people without HIV, and the risk of MenB disease in individuals living with HIV was higher in the 16–24 years age group than in older age groups.¹⁴³ Despite this, meningococcal vaccination coverage in these at-risk populations is low. Data available from the US show uptake rates of MenACWY and MenB vaccination of only 4.6% and 2.2%, respectively, among patients with complement deficiencies,¹⁴⁴ and 28.1% and 9.7%, respectively, among those with asplenia.¹⁴⁵ Another US study found that, among people living with HIV, 16.3% received a MenACWY vaccine dose in the two years after diagnosis in 2019–2022.¹⁴⁶ In Australia, MenB vaccination coverage for people medically at risk of IMD was 12.1% in 2019,¹⁴⁷ and in Norway, two doses of MenACWY vaccine and MenB vaccine were received by, respectively, 4.2% and 8.0% of splenectomized patients up to 2020.¹⁴⁸

Individuals at high risk of IMD because of underlying medical conditions are usually included in national or regional recommendations for 4CMenB vaccination. The immunogenicity and safety of 4CMenB has been demonstrated in several studies of special populations including children and adolescents with complement deficiencies, asplenia, or splenic dysfunction,^149,150 adults vaccinated from 6 months after allogeneic hematopoietic cell transplantation,¹⁵¹ and individuals living with HIV.^152,153 The safety profile of 4CMenB in individuals aged 2–17 years with underlying conditions was comparable to that in healthy controls.¹⁴⁹ In this group, immune responses tended to be lower in complement-deficient individuals with terminal chain complement deficiency or those on eculizumab treatment;¹⁴⁹ several case reports of vaccine failures also suggest a reduced ability of meningococcal immunization to protect against IMD in eculizumab-treated immunocompromised patients.^45,149,154 In the study of people living with HIV, participants received two doses a month apart of 4CMenB co-administered with the licensed MenACWY-CRM vaccine (MenACWY conjugated to nontoxic mutant of diphtheria toxin; Menveo, GSK).¹⁵² One month after two vaccine doses, at least 98% of the participants achieved protective antibody titers for each MenB indicator strain and at least 94% achieved protective titers against serogroups A, C, W, and Y, and the safety profile of vaccine co-administration was acceptable.

In countries or regions where epidemiological evidence indicates a need for improved control of MenB disease, better MenB vaccination coverage is warranted in all age groups, including adolescents/young adults and older adults, those with underlying medical conditions, and people living with HIV. This would be consistent with the road map introduced by the World Health Organization (WHO) for defeating meningitis by 2030, specifically reduction of vaccine-preventable bacterial meningitis cases by 50% and deaths by 70%, with equal access to locally relevant meningococcal disease vaccination programs for all those at risk, driven by the national or regional epidemiology of IMD and with adequate funding in place.¹⁵⁵ Non-funded access to MenB vaccination promotes a socioeconomic disparity between those who have the ability to pay for the vaccine and those who do not but are at risk of IMD because of age, low socioeconomic status, or underlying medical condition.^156,157 In 2022, France became the first country to introduce 4CMenB in the national immunization program for equity reasons.^27,156,158 Similarly, the stated aim of the Queensland MenB Vaccination Program, initiated in 2024, is to “remove financial barriers to vaccination, improve vaccine uptake, and improve the protection that MenB vaccination provides against meningococcal disease.”⁴⁹

Evaluating multicomponent MenB vaccines before the RWE era

The true population effectiveness of MenB vaccines can only be confirmed through RWE of clinical outcomes, as demonstrated for 4CMenB. Before vaccine licensure, and before RWE is generated, reliable and accurate in vitro methods are required for assessing the performance of multicomponent MenB vaccines in clinical trial settings.

The traditional hSBA assay measures antigen-specific responses to vaccination but this method is not useful for predicting MenB vaccine strain coverage at a population level due to broad diversity in different MenB vaccine antigens in circulating strains,^159–161 requiring many MenB strains to be tested. In this scenario, the amount of serum needed from vaccinated individuals is likely to be challenging, especially for young children. Methods were therefore developed for predicting 4CMenB strain coverage on genetically diverse MenB strains, including MATS,^162,163 which correlates with killing in the hSBA assay, and the genotyping tool, genetic MATS (gMATS), which is based on the correlation between antigen genotypes and MATS outcome.¹⁶⁴ MATS point estimates generated using panels of epidemiologically-representative MenB strains predicted 4CMenB strain coverage of between 66% and 91% in various countries (Figure 6).^68,164-176 gMATS, which can be performed using genome sequencing data from cultivable and non-cultivable clinical isolates, predicted 58–89% 4CMenB coverage of MenB strain panels from 11 European countries, Canada, US, and Australia.^{164,169,176-179}

Figure 6. Potential coverage of 4CMenB against MenB strains circulating worldwide, as predicted by Meningococcal Antigen Typing System (MATS).

4CMenB, 4-component meningococcal serogroup B vaccine; CI, confidence interval; Eng/Wal/NI, England, Wales, and Northern Ireland; MenB, meningococcal serogroup B; US, United States.

MATS and gMATS provide conservative predictions of 4CMenB strain coverage, as indicated by MenB strains that were not predicted to be covered by MATS or gMATS but were found to be killed by hSBA assay using sera from vaccinated individuals.^{159,180–182} This is likely to be because, like the traditional hSBA assay, MATS, and gMATS do not account for a potential synergistic immunogenic effect of antibodies induced by two or more vaccine components, i.e. simultaneous binding of antibodies to multiple antigens leading to bactericidal killing, or the contribution to protection of OMV components other than PorA.¹⁸³ Also, gMATS cannot provide data for MenB isolates harboring new antigen-encoding alleles.

More recently, the enc-hSBA assay has been developed to complement immunogenicity results obtained with the traditional hSBA assay, enabling a more complete assessment of the performance of 4CMenB in clinical trials. The enc-hSBA assay uses endogenous complement present in each vaccinated person’s serum to provide a measure of the killing activity of vaccine-specific antibodies present in sera at a single dilution against each strain tested,^184,185 while the traditional hSBA assay uses an exogenous complement source from seronegative donors and measures vaccine-induced responses against four antigen-specific indicator strains (Figure 7). The enc-hSBA assay accounts for intersubject heterogeneity in complement-mediated bactericidal killing of MenB strains and the synergistic effects of antibodies raised by multiple MenB vaccine antigens against circulating strains with diverse genetic features.¹⁸⁴

Figure 7. Characteristics of the traditional human serum bactericidal antibody (hSBA) assay and the endogenous complement hSBA (enc-hSBA) in relation to the assessment of meningococcal serogroup B (MenB) vaccines.^{159,184–186}.

Enc-hSBA, endogenous complement hSBA; hSBA, human serum bactericidal antibody; MenB, meningococcal serogroup B.

The enc-hSBA assay was qualified using a panel of 110 invasive MenB strains and validated using four 4CMenB vaccine antigen-specific indicator strains.^19,184 The 110 strains are representative of global strain diversity, with an antigen genotype repertoire representing approximately 87–97% of strains in Europe, the US, Canada, and Australia, and 89% of MenB strains overall.¹⁸⁶ The enc-hSBA assay thereby enables the assessment of immunological vaccine effectiveness, defined as the ability of a multicomponent vaccine to induce a bactericidal immune response against a broad panel of MenB strains carrying more than one antigen, in the context of a clinical trial, in conditions that mirror real-world settings. Since the enc-hSBA assay uses the individual’s own complement, bactericidal activity might be impaired for people with certain underlying conditions or those undergoing treatment that impacts the complement system.¹⁸⁴ However, as the enc-hSBA assay is used in a clinical trial context, such individuals are likely to be balanced between randomized groups. Any limitations are also counteracted by the ability to test a large panel of MenB strains, and its highly standardized and robust methodology.¹⁸⁴

The enc-hSBA assay has demonstrated utility in clinical trial settings.^185,187 In a phase 3 trial of 4CMenB and the investigational MenABCWY vaccine (NCT04502693), the immunological vaccine effectiveness of both vaccines was assessed in adolescents and young adults.¹⁸⁸ Results from this study show immunological vaccine effectiveness of 79% and 82% following two 4CMenB doses given, respectively, 2 months and 6 months apart (calculated from the ratio between the percentages of samples lacking bactericidal activity against the 110-strain panel in 4CMenB-immunized participants versus those who received MenACWY-CRM).¹⁸⁷ This is in line with the 71% reduction in MenB disease cases observed post-licensure in adolescents in conjunction with the South Australia 4CMenB immunization program.⁷⁸

A decade of progress and future prospects

Information from surveillance systems shows that MenB is a predominant cause of IMD in Europe, North America, North Africa, Australasia, and other Asia – Pacific countries.^3,15–17 The introduction 10 years ago of 4CMenB, the first protein-based vaccine with broad effectiveness against diverse MenB strains, was therefore an important advance in the control of IMD. Large-scale use of 4CMenB immunization in the last decade in different countries, settings, and populations is providing a wealth of RWE on the impact and effectiveness of 4CMenB on IMD case numbers in the risk groups of young children and adolescents/young adults, and a safety profile consistent with prelicensure clinical study results. Moreover, its protective effects go beyond MenB disease, with coverage predicted against non-B serogroups and RWE of effectiveness against MenW disease from the UK.¹⁰⁶ N. gonorrhoeae shares homology with the components of 4CMenB vaccine (NHBA and other OMV minor proteins), and real-world data from Canada, the US, South Australia, and Italy^{80,81,115,116,118,119,121} demonstrate the potential for moderate protection with 4CMenB against gonococcal infection. This includes the first comparison of 4CMenB and non-OMV-based MenB-FHbp,¹¹⁵ which shows data aligned with growing evidence of some protection against gonorrhea with 4CMenB and the role of OMV in this effect; findings that are of great importance considering the emergence of multidrug-resistant gonococcal strains. This has been recognized in the recommendation issued recently by the New York State Department of Health AIDS Institute, which concluded that early evidence was sufficient to recommend 4CMenB to prevent gonorrhea in at-risk adults, and a similar recommendation issued by the UK Joint Committee on Vaccination and Immunization.^189,190 The inconclusive results from the first randomized clinical trial to assess the effect of 4CMenB against gonorrhea, which was discontinued before planned completion,^127,129 are inconsistent with RWE from large-scale studies. This may be due to differences in the population under assessment, such as adolescents and young adults^{80,81,115,116,118,119} versus MSM on HIV pre-exposure prophylaxis in the DOXYVAC trial.¹²⁷ The trial results are also inconsistent with those from a case-control study of over 1000 MSM living with HIV.¹²¹ Further data are awaited from other ongoing randomized controlled trials assessing the effectiveness of 4CMenB vaccination on gonorrhea.

Over the last 10 years, the number of countries that have introduced 4CMenB infant immunization programs has grown, as has the number of regional adolescent immunization programs in countries with or without infant recommendations. However, there is room for improvement to achieve the WHO goal of providing equal access to vaccines for all those at risk of meningitis in alignment with epidemiological evidence.¹⁵⁵ There is diversity among countries in age-based recommendations for meningococcal vaccination, even among neighboring countries with similar economic resources and epidemiological risk,¹⁹¹ and few countries recommend adolescent 4CMenB vaccination despite the at-risk status of this age group and RWE of 4CMenB effectiveness from South Australia.⁷⁸ Also, older adults are not yet included in the recommendations, even though this age group has the highest case fatality rate and their inclusion could reduce the burden of meningococcal disease on healthcare systems, which appears to be on the increase.^56,137 Depending on the regional or national epidemiology of IMD and disease burden, and healthcare priorities, immunization programs should, where possible, consider additional age-based risk groups, with an immunization strategy that is comprehensive for the general population and encompasses boosting those primed in infancy and vaccinating vaccine-naïve individuals. Moreover, countries should emphasize recommendations in populations at higher risk of IMD because of underlying medical conditions, such as complement deficiencies, asplenia, or splenic dysfunction, or because of treatments that inhibit complement activation, as well as people living with HIV. There is evidence of poor vaccination coverage in these groups so increased efforts are needed to address the lack of adherence to recommendations, such as educating healthcare providers, tailoring this education to specific patient populations, and clear recommendations to patients and parents through disease-awareness initiatives.^192,193

Over 100 million 4CMenB doses have been administered so far and 4CMenB is confirmed to have an acceptable tolerability profile, with no safety concerns, including when co-administered with routine infant vaccines. Co-administration of MenB vaccination with MenACWY vaccination is recommended in adolescents in a growing number of countries,^56,191 and would provide protection against the five most important meningococcal serogroups, supporting equity and safer travel. The addition of 4CMenB vaccination to adolescent MenACWY immunization programs, and for other groups at higher risk of gonorrhea infection, may also have an important long-term population impact on N. gonorrhoeae infections.¹³⁰ There is, however, a need for better awareness of the need for two vaccines against IMD among healthcare providers, parents, and patients.¹⁹²

Ongoing international studies and safety monitoring will continue to improve understanding of the benefits and risks of 4CMenB in immunization programs, outbreaks, and in specific populations. This includes continuing randomized controlled trials and observational studies in different countries on the effect of 4CMenB against gonococcal infections. Also, recent studies did not show any significant reduction of the acquisition of MenB carriage in adolescents following MenB vaccination,^83,194,195 highlighting the need to protect those at risk of IMD. However, the effect of 4CMenB against meningococcal carriage in this age group is being investigated further.^196,197

The future may include the licensure of MenB-containing combination vaccines, which requires comprehensive evaluation of vaccine performance before licensure, in clinical trials. The enc-hSBA assay has been developed to assess the ability to induce a bactericidal immune response in conditions close to real-world settings via use of endogenous complement and an epidemiologically-relevant panel of 110 diverse MenB strains representative of the meningococcal genetic landscape.¹⁸⁴ This enables an assessment of the immunological effectiveness of multicomponent MenB vaccines in randomized clinical trial settings, complementing immunogenicity data generated using the traditional hSBA assay.

In conclusion, real-world experience gained over the last decade confirms the impact, effectiveness, and safety profile of 4CMenB against invasive MenB disease and shows cross-protection against some non-B serogroups and N. gonorrhoeae infections. More countries should reinforce recommendations for vaccination and consider a broader 4CMenB immunization policy. This includes 4CMenB vaccination of older adults, and adolescents and young adults, preferably co-administered with MenACWY to protect against the five most common invasive meningococcal serogroups and may potentially provide moderate protection against gonococcal infection. Equal access to 4CMenB vaccination is warranted to better protect all age groups and vulnerable groups, given the wealth of supporting data gained from 10 years of administration to various populations across the world.

Authors’ contribution

All authors were involved in the analysis and interpretation of the relevant literature and the development of the manuscript. All authors gave final approval before submission.

Trademark statement

Bexsero and Menveo are trademarks owned by or licensed to GSK. MeNZB is a trademark of Novartis. Trumenba is a trademark of Pfizer. VA-MENGOC-BC is a trademark of Finlay Institute. MenBvac is a trademark of Norwegian Institute of Public Health.

Acknowledgments

The authors thank Business & Decision Life Sciences Medical Communication Service Center for editorial assistance and manuscript coordination, on behalf of GSK. Joanne Knowles (independent medical writer, on behalf of GSK) provided medical writing support.

Disclosure statement

VA, AM, DT, SB, and LS are employed by and hold financial equities in GSK.

RR and MP are former employees of GSK. MP is Professor at Imperial College.

FMT received honoraria from Sanofi, MSD, Moderna, GSK, Biofabri, AstraZeneca, Novavax, Janssen, and Pfizer. He also received financial support for travel and attending meetings from Pfizer, MSD, GSK, and Sanofi. He is a member of ETAGE – WHO Europe, coordinator of Spanish Pediatric Critical Trials Network, and coordinator of WHO collaborating center for vaccine safety of Santiago de Compostela. As Principal Investigator in randomized controlled trials of Ablynx, Abbot, Seqirus, Sanofi, MSD, Merck, Pfizer, Roche, Regeneron, Janssen, Medimmune, Novavax, Novartis, and GSK, he received financial support through his institution.

MKT declares that the Institut Pasteur received work contracts funded by GSK, Pfizer, and Sanofi. He also reports the patent NZ630133A “Vaccines for serogroup X meningococcus” issued with GSK.

TN declares that the University of Melbourne and Murdoch Children’s Research Institute received research grants for clinical trials from Iliad, Dynavax, Sanofi, Moderna, and CSL Seqirus. He also received personal payments for consultant fees from AstraZeneca, Pfizer, CSL Seqirus, and MSD; for participation on a Data Safety Monitoring Board or Advisory Board from Moderna, Clover, Novavax, Serum Institute of India, Technovalia, and Moderna; and support for attending meetings from MSD, GSK, and AstraZeneca. He also declares leadership or fiduciary role in another board, society, committee, or advocacy group for the mRNA Victoria Scientific Ad Board (unpaid), and for the Advances in mRNA Science Advisory Board (personal payment. Independent body but funded by an untied grant from Moderna).

RB performs contract research on behalf of UKHSA for GSK, Pfizer, and Sanofi Pasteur.

The authors declare no other financial and non-financial relationships and activities.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2357924

Additional information

Funding

GlaxoSmithKline Biologicals SA funded this literature review and took in charge all costs associated with the development and publication of this manuscript.