4CMenB journey to the 10-year anniversary and beyond.

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.

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 10­25 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.

Cost-effectiveness of 4CMenB vaccination against gonorrhea: importance of dosing schedule, vaccine sentiment, targeting strategy, and duration of protection.

BACKGROUND: Observational evidence suggests the 4CMenB meningococcal vaccine may partially protect against gonorrhea, with one dose being two-thirds as protective as two. We examined the cost-effectiveness of vaccinating men-who-have-sex-with-men (MSM) in England, with one- or two-dose primary vaccination. METHODS: Integrated transmission-dynamic health-economic modeling explored the effects of targeting strategy, first- and second-dose uptake levels, and duration of vaccine protection, using observational estimates of vaccine protection. RESULTS: Vaccination with one or two primary doses is always cost-saving, irrespective of uptake, although vaccine sentiment is an important determinant of impact and cost-effectiveness. The most impactful and cost-effective targeting is offering "Vaccination-according-to-Risk" (VaR), to all patients with gonorrhea plus those reporting high numbers of sexual partners. If VaR is not feasible to implement then the more-restrictive strategy of "Vaccination-on-Diagnosis" (VoD) with gonorrhea is cost-effective, but much less impactful. Under conservative assumptions, VaR(2-dose) saves £7.62M(95%CrI:1.15-17.52) and gains 81.41(28.67-164.23) QALYs over 10 years; VoD(2-dose) saves £3.40M(0.48-7.71) and gains 41.26(17.52-78.25) QALYs versus no vaccination. Optimistic versus pessimistic vaccine-sentiment assumptions increase net benefits by ∼30%(VoD) or ∼60%(VaR). CONCLUSIONS: At UK costs, targeted 4CMenB vaccination of MSM gains QALYs and is cost-saving at any uptake level. Promoting uptake maximizes benefits and is an important role for behavioral science.

Exploiting Real-Time Genomic Surveillance Data To Assess 4CMenB Meningococcal Vaccine Performance in Scotland, 2015 to 2022.

The United Kingdom implemented the first national infant immunization schedule for the meningococcal vaccine 4CMenB (Bexsero) in September 2015, targeting serogroup B invasive meningococcal disease (IMD). Bexsero contains four variable subcapsular proteins, and postimplementation IMD surveillance was necessary, as nonhomologous protein variants can evade Bexsero-elicited protection. We investigated postimplementation IMD cases reported in Scotland from 1 September 2015 to 30 June 2022. Patient demographics and vaccination status were combined with genotypic data from the causative meningococci, which were used to assess vaccine coverage with the meningococcal deduced vaccine antigen reactivity (MenDeVAR) index. Eighty-two serogroup B IMD cases occurred in children >5 years of age, 48 (58.5%) of which were in unvaccinated children and 34 (41%) of which were in children who had received ≥1 Bexsero dose. Fifteen of the 34 vaccinated children had received one dose, 17 had received two doses, and two had received three doses. For 39 cases, meningococcal sequence data were available, enabling MenDeVAR index deductions of vaccine-preventable (M-VP) and non-vaccine-preventable (M-NVP) meningococci. Notably, none of the 19 of the children immunized ≥2 times had IMD caused by M-VP meningococci, with 2 cases of NVP meningococci, and no deduction possible for 17. Among the 15 children partially vaccinated according to schedule (1 dose), 7 were infected by M-VP meningococci and 2 with M-NVP meningococci, with 6 for which deductions were not possible. Of the unvaccinated children with IMD, 40/48 were ineligible for vaccination and 20/48 had IMD caused by M-VP meningococci, with deductions not being possible for 14 meningococci. IMPORTANCE This study demonstrates the value of postimplementation genomic surveillance of vaccine-preventable pathogens in providing information on real-world vaccine performance. The data are consistent with 2 and 3 doses of Bexsero, delivered according to schedule, providing good protection against invasive disease caused by meningococci deduced from genomic data to be vaccine preventable. Single doses provide poorer protection to infants. In practical terms, these data can provide public health reassurance when vaccinated individuals develop IMD with non-vaccine-preventable variants. They further indicate that additional testing is needed on variants for which no immunological data exist to improve estimates of protection, although these data suggest that the uncharacterized variants are unlikely to be covered by Bexsero. Finally, the confirmation that incomplete or absent doses in infancy lead to reduced protection supports public health and general practitioners in promoting vaccination according to schedule.

An open-label randomised controlled trial evaluating the efficacy of a meningococcal serogroup B (4CMenB) vaccine on Neisseria gonorrhoeae infection in gay and bisexual men: the MenGO study protocol.

BACKGROUND: Gonorrhoea is an ongoing public health concern due to its rising incidence and the emergence of antibiotic resistance. There are an estimated 82 million new Neisseria gonorrhoeae infections each year, with several populations at higher risk for gonococcal infection, including gay and bisexual men (GBM). If left untreated, infection can lead to serious morbidity including infertility, sepsis and increased risk of HIV acquisition. Development of a gonorrhoea vaccine has been challenging, however there is observational evidence that serogroup B meningococcal vaccines, used to protect against the closely related bacteria Neisseria meningitidis, could provide cross-protection against N. gonorrhoeae. METHODS: The MenGO (Meningococcal vaccine efficacy against Gonorrhoea) study is a phase III open-label randomised control trial in GBM to evaluate the efficacy of the four-component meningococcal serogroup B vaccine, 4CMenB, against gonorrhoea. A total of 130 GBM will be recruited at the Gold Coast Sexual Health Clinic, Australia, and randomised to either receive 2 doses of 4CMenB or no intervention. Participants will be followed up for 24 months with testing for N. gonorrhoeae and other sexually transmissible infections every three months. Demographics, sexual behaviour risk, antibiotic use, and blood samples for analysis of N. gonorrhoeae-specific immune responses, will be collected during the study. The primary outcome is the number of N. gonorrhoeae infections in participants over 2 years measured by nucleic acid amplification test (NAAT). Secondary outcomes are vaccine-induced N. gonorrhoeae-specific immune responses, and adverse events in trial participants. DISCUSSION: This trial will determine if the 4CMenB vaccine is able to reduce N. gonorrhoeae infection. If shown to be effective, 4CMenB could be used in gonococcal prevention. Analysis of 4CMenB-induced immune responses will increase understanding of the type of immune response needed to prevent N. gonorrhoeae, which may enable identification of a potential correlate of protection to aid future gonorrhoea vaccine development. TRIAL REGISTRATION: The trial has been registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12619001478101) on 25 October 2019.

Product review on the IMD serogroup B vaccine Bexsero®.

Bexsero® is a multicomponent vaccine composed of four major proteins of Neisseria meningitidis: the fHbp, NHBA, NadA and PorA. This vaccine was licensed against invasive meningococcal disease (IMD) due to serogroup B isolates. When administered alone, Bexsero® showed a safety profile similar to other childhood vaccines. It provides an excellent immunogenicity but that requires booster doses in infants and young children. Although the vaccine does not seem to impact on acquisition of carriage of serogroup B isolates, it confers protection against isolates of serogroup B harboring distinct but cross-reactive variants of fHbp, NadA and NHBA. Primary vaccination schemes in infancy underwent a rapid increase after a toddler booster suggesting an anamnestic response and the establishment of a memory response. As Bexsero® targets sub-capsular proteins that can be conserved regardless the capsule, the vaccine can be effective against non-B isolates such as isolates of serogroups W and X.

4CMenB vaccine and its role in preventing transmission and inducing herd immunity.

INTRODUCTION: Vaccination is the most effective method of protecting people from invasive meningococcal disease (IMD). Of all the capsular groups, B is the most common cause of invasive meningococcal disease in many parts of the world. Despite this, adolescent meningococcal B vaccine programs have not been implemented globally, partly due to the lack of evidence for herd immunity afforded by meningococcal B vaccines. AREAS COVERED: This review aims to synthesize the available evidence on recombinant 4 CMenB vaccines' ability to reduce pharyngeal carriage and therefore provide indirect (herd) immunity against IMD. EXPERT OPINION: There is some evidence that the 4CMenB vaccine may induce cross-protection against non-B carriage of meningococci. However, the overall body of evidence does not support a clinically significant reduction in carriage of disease-associated or group B meningococci following 4CMenB vaccination. No additional cost-benefit from herd immunity effects should be included when modeling the cost-effectiveness of 4CMenB vaccine programs against group B IMD. 4CMenB immunization programs should focus on direct (individual) protection for groups at greatest risk of meningococcal disease. Future meningococcal B and combination vaccines being developed should consider the impact of the vaccine on carriage as part of their clinical evaluation.

A re-assessment of 4CMenB vaccine effectiveness against serogroup B invasive meningococcal disease in England based on an incidence model.

BACKGROUND: The four-component serogroup B meningococcal 4CMenB vaccine (Bexsero, GSK) has been routinely given to all infants in the United Kingdom at 2, 4 and 12 months of age since September 2015. After 3 years, Public Health England (PHE) reported a 75% [95% confidence interval 64%; 81%] reduction in the incidence of serogroup B invasive meningococcal disease (IMD) in age groups eligible to be fully vaccinated. In contrast, vaccine effectiveness (VE) evaluated in the same immunization program applying the screening method was not statistically significant. We re-analyzed the data using an incidence model. METHODS: Aggregate data-stratified by age, year and doses received-were provided by PHE: serogroup B IMD case counts for the entire population of England (years 2011-2018) and 4CMenB vaccine uptake in infants. We combined uptake with national population estimates to obtain counts of vaccinated and unvaccinated person-time by age and time. We re-estimated VE comparing incidence rates in vaccinated and non-vaccinated subjects using a Bayesian Poisson model for case counts with person-time data as an offset. The model was adjusted for age, time and number of doses received. RESULTS: The incidence model showed that cases decreased until 2013-2014, followed by an increasing trend that continued in the non-vaccinated population during the immunization program. VE in fully vaccinated subjects (three doses) was 80.1% [95% Bayesian credible interval (BCI): 70.3%; 86.7%]. After a single dose, VE was 33.5% [12.4%; 49.7%]95%BCI and after two doses, 78.7% [71.5%; 84.5%]95%BCI. We estimated that vaccination averted 312 cases [252; 368]95%BCI between 2015 and 2018. VE was in line with the previously reported incidence reduction. CONCLUSIONS: Our estimates of VE had higher precision than previous estimates based on the screening method, which were statistically not significant, and in line with the 75% incidence reduction previously reported by PHE. When disease incidence is low and vaccine uptake is high, the screening method applied to cases exclusively from the population eligible for vaccination may not be precise enough and may produce misleading point-estimates. Precise and accurate VE estimates are fundamental to inform public health decision making. VE assessment can be enhanced using models that leverage data on subjects not eligible for vaccination.

Factor H binding protein (fHbp)-mediated differential complement resistance of a serogroup C Neisseria meningitidis isolate from cerebrospinal fluid of a patient with invasive meningococcal disease.

During an outbreak of invasive meningococcal disease (IMD) at the University of Southampton, UK, in 1997, two Neisseria meningitidis serogroup C isolates were retrieved from a student ('Case'), who died of IMD, and a close contact ('Carrier') who, after mouth-to-mouth resuscitation on the deceased, did not contract the disease. Genomic comparison of the isolates demonstrated extensive nucleotide sequence identity, with differences identified in eight genes. Here, comparative proteomics was used to measure differential protein expression between the isolates and investigate whether the differences contributed to the clinical outcomes. A total of six proteins were differentially expressed: four proteins (methylcitrate synthase, PrpC; hypothetical integral membrane protein, Imp; fructose-1,6-bisphosphate aldolase, Fba; aldehyde dehydrogenase A, AldA) were upregulated in the Case isolate, while one protein (Type IV pilus-associated protein, PilC2) was downregulated. Peptides for factor H binding protein (fHbp), a major virulence factor and antigenic protein, were only detected in the Case, with a single base deletion (ΔT366) in the Carrier fHbp causing lack of its expression. Expression of fHbp resulted in an increased resistance of the Case isolate to complement-mediated killing in serum. Complementation of fHbp expression in the Carrier increased its serum resistance by approximately 8-fold. Moreover, a higher serum bactericidal antibody titre was seen for the Case isolate when using sera from mice immunized with Bexsero (GlaxoSmithKline), a vaccine containing fHbp as an antigenic component. This study highlights the role of fHbp in the differential complement resistance of the Case and the Carrier isolates. Expression of fHbp in the Case resulted in its increased survival in serum, possibly leading to active proliferation of the bacteria in blood and death of the student through IMD. Moreover, enhanced killing of the Case isolate by sera raised against an fHbp-containing vaccine, Bexsero, underlines the role and importance of fHbp in infection and immunity.

Strain coverage of Bexsero vaccine assessed by whole-genome sequencing over a cohort of invasive meningococci of serogroups B and W isolated in Switzerland.

Invasive meningococcal disease (IMD), caused by Neisseria meningitidis (Nm) strains, is a life-threatening but vaccine-preventable condition. Bexsero is a four-component vaccine that offers broad protection against Nm of serogroup B (NmB), particularly common in Europe. In Switzerland, Bexsero has not yet been licensed and no information is available concerning the predicted vaccine coverage on isolates of circulating Nm. We performed genotyping of Bexsero antigen loci by whole-genome sequencing (WGS) on 104 NmB collected in Switzerland in the 2010-2015 period. We searched for antigen variants previously defined as predictors of strain coverage and estimated that 50% of IMD NmB strains were potentially covered by the vaccine. Clonal complexes (cc) 32, 41/44 and 269, considered the best covered lineages, were further sub-typed according to Bexsero Antigen Sequence Type (BAST) scheme. We also genotyped by WGS 40 Nm of serogroup W (NmW) collected in the country between 2010 and 2016. NmW cc22 isolates appeared to be covered by the vaccine, which was not the case for cc11 isolates, whose incidence has recently increased in Switzerland and all over Europe. Our work underlines the benefit of using WGS for surveillance of vaccine antigen variant distribution in local Nm population and taking proper measures to prevent the spread of NmB.

High genomic-based predicted strain coverage among invasive meningococcal isolates when combining Bexsero and Trumenba vaccines.

Two protein-based vaccines (Bexsero® and Trumenba®) are licensed for invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B (MenB). The aim of this study was to evaluate the possible protection of these vaccines, based on the genomic profiles of IMD isolates. All invasive meningococcal isolates in Sweden during 2014-2018 (n = 242) were analyzed with the vaccine coverage scheme available at the PubMLST database. The overall estimated genomic strain coverage among the Swedish invasive meningococcal isolates was 55% for Bexsero and 57% for Trumenba (p = 0.714). The estimated serogroup-specific coverage for Bexsero respectively Trumenba was: MenB; 67% and 90% (p < 0.05), MenW; 93% and 4% (p < 0.05), MenC; 87% and 30% (p < 0.05) and MenY; 1% and 96% (p < 0.05). With the combination of the two vaccines, the potential genomic-based strain coverage was 95%, indicating a possible additive effect of combining Bexsero and Trumenba, which, however, needs to be confirmed by analysis of phenotypic antigen expression.

Characteristics of YouTube videos about the meningococcal B vaccine (4CMenB).

YouTube has become a large source of health information, and it has the capacity to influence users: for instance, regarding their vaccination habits. The aim of our study was to analyze the characteristics of the videos published on YouTube about the meningococcal B vaccine (4CMenB, Bexsero®). A search was made on YouTube using the keyword "Bexsero." The association between the authorship of videos (health professionals or others) and the rest of the variables (tone of the message and vaccination recommendations, among others) was evaluated using the Chi-square test. In total, 77 videos were analyzed; 74% supported the use of the vaccine, and the most frequently mentioned vaccination recommendations were in epidemic outbreaks (28.6%) and in children (18.2%). Depending on the type of authorship, significant differences were observed regarding the tone of the message and the frequency with which the videos discussed effectiveness, dosage, adverse effects, and vaccination recommendations. There is a difficulty in obtaining information on vaccination recommendations. Recommendations are very diverse since there is a great heterogeneity in the official recommendations for the use of this vaccine, depending on the country the information is from.

Genetic variability of Polish serogroup B meningococci (2010-2016) including the 4CMenB vaccine component genes.

Neisseria meningitidis serogroup B (MenB) has recently become the major cause of invasive meningococcal disease in Poland. Therefore, the purpose of this study was to characterize MenB isolates, responsible for invasive meningococcal disease in 2010-2016, by MLST and sequencing of genes encoding proteins used as 4CMenB vaccine antigens. Two methods of coverage estimation were performed: extrapolation of MATS results of Polish meningococci 2010-2011 (exMATS) and gMATS, which combines genotyping and MATS results. Among 662 isolates 20 clonal complexes (CC) were detected, of which the most frequent were CC32, CC41/44 and CC18, accounting for 31.9%, 16.5% and 12.7%, respectively. A total of 111 combinations of PorA variable regions (VR1/VR2) were found, with P1.7,16 (15.0%) and P1.22,14 (13.6%) being prevalent. Vaccine variant VR2:4 was detected in 7.3% of isolates, mainly representing CC41/44 and non-assigned CC. Eighty five fHbp alleles encoding 74 peptide subvariants were revealed. Subvariant 1.1, a component of 4CMenB, was prevalent (24.2%) and found generally in CC32. Typing of the nhba gene revealed 102 alleles encoding 87 peptides. The most frequent was peptide 3 (22.4%), whereas vaccine peptide 2 was detected in 9.8%, mostly among CC41/44. The nadA gene was detected in 34.0% of isolates and the most prevalent was peptide 1 (variant NadA-1; 71.6%), found almost exclusively in CC32 meningococci. Vaccine peptide 8 (variant NadA-2/3) was identified once. Consequently, 292 completed BAST profiles were revealed. Regarding vaccine coverage, 39.7% of isolates had at least one 4CMenB vaccine variant, but according to exMATS and gMATS the coverage was 83.3% and 86.6%, respectively. In conclusion, Polish MenB (2010-2016) was highly diverse according to MLST and gene alleles encoding 4CMenB vaccine antigens. Some correlations between clonal complexes and variants of examined proteins/BAST profiles were revealed and a high coverage of 4CMenB vaccine was estimated.

Measurement of surface protein antigens, PorA and PorB, in Bexsero vaccine using quantitative mass spectrometry.

Bexsero is a multivalent vaccine containing outer membrane vesicles (OMV) derived from Neisseria meningitidis group B strain NZ98/254 and three recombinant meningococcal proteins, Neisserial adhesin A, Heparin binding antigen and factor H binding protein. OMV production relies on the growth of large-scale cultures of N. meningitidis under controlled conditions. Changes to environmental factors, such as temperature, pH, nutrient availability and trace elements, can impact the growth rate of the meningococcus. Furthermore outer membrane expression levels vary in response to the environmental milieu, thus any changes in environmental conditions can result in changes in OMV protein content. This makes consistent production of OMVs challenging and the ability to measure the protein content of the final product is desirable to ensure product quality. The aim of this work was to develop a mass spectrometry (MS) method for measuring the porin proteins and to evaluate this approach for assessing the batch consistency of Bexsero vaccine. Using isotope dilution MS, we measured the PorA and PorB content in 75 lots of Bexsero vaccine. PorA ranged from 4.0 to 5.95 µg/dose with an average of 4.8 µg/dose. PorB ranged from 5.4 to 8.7 µg/dose with an average of 6.5 µg/dose. This is the first description of the quantitative characterisation of adjuvanted Bexsero vaccine drug product at the final stage of the production process, once the aluminium adjuvanted vaccine has been packaged into syringes, to assess manufacturing consistency. The significance of our findings to quality control in the future is discussed.

Genetic Similarity of Gonococcal Homologs to Meningococcal Outer Membrane Proteins of Serogroup B Vaccine.

The human pathogens Neisseria gonorrhoeae and Neisseria meningitidis share high genome identity. Retrospective analysis of surveillance data from New Zealand indicates the potential cross-protective effect of outer membrane vesicle (OMV) meningococcal serogroup B vaccine (MeNZB) against N. gonorrhoeae A licensed OMV-based MenB vaccine, MenB-4C, consists of a recombinant FHbp, NhbA, NadA, and the MeNZB OMV. Previous work has identified several abundantly expressed outer membrane proteins (OMPs) as major components of the MenB-4C OMV with high sequence similarity between N. gonorrhoeae and N. meningitidis, suggesting a mechanism for cross-protection. To build off these findings, we performed comparative genomic analysis on 970 recent N. gonorrhoeae isolates collected through a U.S surveillance system against N. meningitidis serogroup B (NmB) reference sequences. We identified 1,525 proteins that were common to both Neisseria species, of which 57 proteins were predicted to be OMPs using in silico methods. Among the MenB-4C antigens, NhbA showed moderate sequence identity (73%) to the respective gonococcal homolog, was highly conserved within N. gonorrhoeae, and was predicted to be surface expressed. In contrast, the gonococcal FHbp was predicted not to be surface expressed, while NadA was absent in all N. gonorrhoeae isolates. Our work confirmed recent observations (E. A. Semchenko, A. Tan, R. Borrow, and K. L. Seib, Clin Infect Dis, 2018, https://doi.org/10.1093/cid/ciy1061) and describes homologous OMPs from a large panel of epidemiologically relevant N. gonorrhoeae strains in the United States against NmB reference strains. Based on our results, we report a set of OMPs that may contribute to the previously observed cross-protection and provide potential antigen targets to guide the next steps in gonorrhea vaccine development.IMPORTANCE Gonorrhea, a sexually transmitted disease, causes substantial global morbidity and economic burden. New prevention and control measures for this disease are urgently needed, as strains resistant to almost all classes of antibiotics available for treatment have emerged. Previous reports demonstrate that cross-protection from gonococcal infections may be conferred by meningococcal serogroup B (MenB) outer membrane vesicle (OMV)-based vaccines. Among 1,525 common proteins shared across the genomes of both N. gonorrhoeae and N. meningitidis, 57 proteins were predicted to be surface expressed (outer membrane proteins [OMPs]) and thus preferred targets for vaccine development. The majority of these OMPs showed high sequence identity between the 2 bacterial species. Our results provide valuable insight into the meningococcal antigens present in the current OMV-containing MenB-4C vaccine that may contribute to cross-protection against gonorrhea and may inform next steps in gonorrhea vaccine development.