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Background. In the absence of an efficacious broadly protective vaccine, serogroup B Neisseria meningitidis (MenB) is the leading cause of bacterial meningitis and septicemia in many industrialized countries. An investigational recombinant vaccine that contains 3 central proteins; Neisserial adhesin A (NadA), factor H binding protein (fHBP) and Neisserial heparin binding antigen (NHBA) has been developed. These antigens have been formulated with and without outer membrane vesicles (rMenB+OMV and rMenB, respectively) from the New Zealand epidemic strain (B:4:P1.7–2,4). In this trial, we assessed the immunogenicity of these formulations in infants, who are at greatest risk of contracting MenB disease. Methods. A total of 147 infants from the United Kingdom were enrolled and randomly assigned to receive rMenB or rMenB+OMV at 2, 4, 6, and 12 months of age or a single dose at 12 months of age. Serum samples taken before and after vaccination were assayed in a standardized serum bactericidal antibody assay against 7 MenB strains. Local and systemic reactogenicity were recorded for 7 days after each vaccination. Analysis was according to protocol. Results. After 3 doses, both vaccines were immunogenic against strains expressing homologous or related NadA and fHBP. rMenB+OMV demonstrated greater immunogenicity than did rMenB and was immunogenic against strains expressing homologous PorA. Both vaccines elicited anamnestic responses after the fourth dose. For both vaccines, responses were lower against strains expressing heterologous fHBP variants and after a single dose at 12 months. Conclusions. The rMenB+OMV vaccine has the potential to protect infants from MenB disease, although the breadth of protection afforded to heterologous antigens requires additional investigation.

Recently, a meningococcal vaccine for group B was approved and deployed into clinical practice. In this trial, the effect of widespread use of this vaccine on the nasopharyngeal carriage of meningococcus group B was assessed in more than 24,000 adolescents in Australia.

A novel multicomponent vaccine against meningococcal capsular group B (MenB) disease contains four major components: factor-H-binding protein, neisserial heparin binding antigen, neisserial adhesin A, and outer-membrane vesicles derived from the strain NZ98/254. Because the public health effect of the vaccine, 4CMenB (Novartis Vaccines and Diagnostics, Siena, Italy), is unclear, we assessed the predicted strain coverage in Europe. We assessed invasive MenB strains isolated mainly in the most recent full epidemiological year in England and Wales, France, Germany, Italy, and Norway. Meningococcal antigen typing system (MATS) results were linked to multilocus sequence typing and antigen sequence data. To investigate whether generalisation of coverage applied to the rest of Europe, we also assessed isolates from the Czech Republic and Spain. 1052 strains collected from July, 2007, to June, 2008, were assessed from England and Wales, France, Germany, Italy, and Norway. All MenB strains contained at least one gene encoding a major antigen in the vaccine. MATS predicted that 78% of all MenB strains would be killed by postvaccination sera (95% CI 63–90, range of point estimates 73–87% in individual country panels). Half of all strains and 64% of covered strains could be targeted by bactericidal antibodies against more than one vaccine antigen. Results for the 108 isolates from the Czech Republic and 300 from Spain were consistent with those for the other countries. MATS analysis showed that a multicomponent vaccine could protect against a substantial proportion of invasive MenB strains isolated in Europe. Monitoring of antigen expression, however, will be needed in the future. Novartis Vaccines and Diagnostics.

In Italy, Invasive Meningococcal Disease (IMD) due to Neisseria meningitidis serogroup B (MenB) showed the highest incidence rates in infants under one year of age. This study describes the main characteristics of MenB responsible for invasive diseases circulating in Italy from 2010 to 2021. Data collected within the framework of National Surveillance System (NSS) for IMD were analysed. Serogroup confirmed IMD cases were included in the study. For unspecified meningococcal serogroup, a multinomial model was used to impute the serogroup. Antimicrobial susceptibility and genotyping by Sanger or whole genome sequencing were performed on viable meningococci. Core genome MLST (cgMLST) was evaluated using a gene-by-gene approach, and MenDeVAR analyses were used to assess potential coverage by MenB vaccines. A total of 1845 IMD cases were reported to the NSS, of which 704 were laboratory confirmed as MenB and another 232 were statistically attributed to this serogroup. The highest incidence rate for IMD due to MenB was observed in infants <1 year, followed by children aged 1-4 years. MenB isolates were susceptible to antimicrobials except for 4 isolates, of which 2 resistant to penicillin G, 1 to rifampicin and 1 to ciprofloxacin. High genetic variability was observed, with clonal complex (cc) cc41/44 being replaced by the cc162 since 2015. MenDeVAR analyses highlighted a high proportion of genomes classified as \"insufficient data,\" especially among recent isolates. Despite the low incidence of IMD in Italy, MenB increased in specific age groups during the study period. Continuous genomic surveillance, including MenDeVAR monitoring, remains essential to detect changes in circulating MenB and predict vaccine coverage.

Since the incorporation of serogroups A and C meningococcal vaccines into China's national immunization program, the epidemiological profile of Neisseria meningitidis (Nm) has shifted toward serogroups not covered in routine vaccination, particularly Y and B. This study assessed the immunogenicity of the quadrivalent meningococcal polysaccharide vaccine (MPSV4) and the quadrivalent meningococcal polysaccharide conjugate vaccine (MCV4) against a newly identified serogroup Y strain in Tianjin, and characterized its clinical presentation, laboratory features, and antimicrobial resistance profile. Epidemiological investigation and laboratory testing were undertaken to document the clinical manifestations, molecular characteristics, and antimicrobial susceptibility of the isolate. Serum bactericidal activity (SBA) was evaluated in a murine model. Fifty mice were randomized into five groups and immunized with MCV4, MPSV4-A, MPSV4-B, MPSV4-C, or normal saline. Vaccinations were administered at 14-day intervals for a total of three doses. Serum samples were collected 14 days after each immunization for SBA analysis. The bacterial isolate, obtained from a case of invasive meningococcal disease, was confirmed as serogroup Y and classified as sequence type ST-18108. Antimicrobial susceptibility testing against 12 agents revealed resistance solely to nalidixic acid, while susceptibility was retained to seven agents. In SBA assay, MCV4 induced the strongest response, with a geometric mean titer of 294 and a 100 % seroconversion rate after the third dose, exceeding responses observed in all MPSV4 groups. Antibody titers in the MCV4 cohort were significantly higher than those in the MPSV4-A, MPSV4-B, and control groups after both the second and third immunizations (P < 0.05). Furthermore, within the MCV4 group, titers rose significantly between the second and third doses (P = 0.004), whereas no significant increase was observed in MPSV4 groups (P > 0.05). Compared with MPSV4, MCV4 generated stronger bactericidal antibody responses and provided superior protective immunity against serogroup Y in a mouse model, which lays the groundwork for further development of meningococcal vaccines. Moving forward, studies should incorporate a broader range of bacterial strains, larger sample sizes, and ultimately human clinical trials to confirm and extend these findings.

Invasive meningococcal disease (IMD) caused by Neisseria meningitidis can result in life-threatening meningitis and septicaemia. There are twelve serogroups of N. meningitidis, but most cases of IMD are caused by serogroups A, B, C, W, X and Y. In Europe, serogroup B (MenB) accounts for 51 % of documented cases as recently reported by the European Centre for Disease Prevention and Control (ECDC). As a major cause of IMD, genomic surveillance of circulating MenB strains and assessment of the potential impact of vaccination programs could help inform public health policy. In this study, a collection of 493 strains was analysed, collected in Belgium by the National Reference Centre between 2016 and 2022. Slide agglutination was used for serogroup determination and whole genome sequencing (WGS) was used to further characterize these strains. The observed serogroups were: MenB (n = 281), MenY (n = 95), MenW (n = 83), MenC (n = 30), non-groupable isolates (n = 2), MenE (n = 1) and MenX (n = 1). A higher prevalence of MenY and MenW was observed in older adults. MenB isolates were grouped into 110 sequence types (STs), 89 of which belonged to 16 clonal complexes (CCs). Coverage of the MenB-FHbp vaccine (Trumenba, bivalent rLP2086; Pfizer Inc., New York, NY, USA ipv Philadelphia) was predicted using the Meningococcal Deduced Vaccine Antigen Reactivity (MenDeVAR) index. Of the 281 MenB strains collected between 2016 and 2022, 89.1 % (lower limit – upper limit: 78.6–100.0 %) were predicted by MenDeVAR to be covered by the vaccine. This study highlights the benefits of a pathogen surveillance program and the need for experimental characterization of continuously evolving antigenic variants. •MenB was the leading cause of IMD in individuals under 65 years of age in Belgium from 2016 to 2022.•Increased prevalence of MenY and MenW observed in older adults.•High diversity of MenB isolates circulating in Belgium, with 110 STs detected, including 32 novel STs.•MenDeVAR predicts a coverage of 89.1 % for the MenB-FHbp vaccine (range: 78.6 % - 100.0 %).

Bivalent rLP2086 (Trumenba), a vaccine for prevention of Neisseria meningitidis serogroup B (NmB) disease, was licensed for use in adolescents and young adults after it was demonstrated that it elicits antibodies that initiate complement-mediated killing of invasive NmB isolates in a serum bactericidal assay with human complement (hSBA). The vaccine consists of two factor H binding proteins (fHBPs) representing divergent subfamilies to ensure broad coverage. Although it is the surrogate of efficacy, an hSBA is not suitable for testing large numbers of strains in local laboratories. Previously, an association between the in vitro fHBP surface expression level and the susceptibility of NmB isolates to killing was observed. Therefore, a flow cytometric meningococcal antigen surface expression (MEASURE) assay was developed and validated by using an antibody that binds to all fHBP variants from both fHBP subfamilies and accurately quantitates the level of fHBP expressed on the cell surface of NmB isolates with mean fluorescence intensity as the readout. Two collections of invasive NmB isolates ( n = 1,814, n = 109) were evaluated in the assay, with the smaller set also tested in hSBAs using individual and pooled human serum samples from young adults vaccinated with bivalent rLP2086. From these data, an analysis based on fHBP variant prevalence in the larger 1,814-isolate set showed that >91% of all meningococcal serogroup B isolates expressed sufficient levels of fHBP to be susceptible to bactericidal killing by vaccine-induced antibodies. IMPORTANCE Bivalent rLP2086 (Trumenba) vaccine, composed of two factor H binding proteins (fHBPs), was recently licensed for the prevention of N. meningitidis serogroup B (NmB) disease in individuals 10 to 25 years old in the United States. This study evaluated a large collection of NmB isolates from the United States and Europe by using a flow cytometric MEASURE assay to quantitate the surface expression of the vaccine antigen fHBP. We find that expression levels and the proportion of strains above the level associated with susceptibility in an hSBA are generally consistent across these geographic regions. Thus, the assay can be used to predict which NmB isolates are susceptible to killing in the hSBA and therefore is able to demonstrate an fHBP vaccine-induced bactericidal response. This work significantly advances our understanding of the potential for bivalent rLP2086 to provide broad coverage against diverse invasive-disease-causing NmB isolates. Bivalent rLP2086 (Trumenba) vaccine, composed of two factor H binding proteins (fHBPs), was recently licensed for the prevention of N. meningitidis serogroup B (NmB) disease in individuals 10 to 25 years old in the United States. This study evaluated a large collection of NmB isolates from the United States and Europe by using a flow cytometric MEASURE assay to quantitate the surface expression of the vaccine antigen fHBP. We find that expression levels and the proportion of strains above the level associated with susceptibility in an hSBA are generally consistent across these geographic regions. Thus, the assay can be used to predict which NmB isolates are susceptible to killing in the hSBA and therefore is able to demonstrate an fHBP vaccine-induced bactericidal response. This work significantly advances our understanding of the potential for bivalent rLP2086 to provide broad coverage against diverse invasive-disease-causing NmB isolates.

BackgroundMeningococcal epidemics in Africa are generally caused by capsular group A strains, but W-135 or X strains also cause epidemics in this region. Factor H–binding protein (fHbp) is a novel antigen being investigated for use in group B vaccines. Little is known about fHbp in strains from other capsular groups MethodsWe investigated fHbp in 35 group A, W-135, and X strains from Africa ResultsThe 22 group A isolates, which included each of the sequence types (STs) responsible for epidemics since 1963, and 4 group X and 3 group W-135 isolates from recent epidemics had genes encoding fHbp in antigenic variant group 1. The remaining 6 W-135 isolates had fHbp variant 2. Within each fHbp variant group, there was 92%–100% amino acid identity, and the proteins expressed conserved epitopes recognized by bactericidal monoclonal antibodies. Serum samples obtained from mice vaccinated with native outer membrane vesicle vaccines from mutants engineered to express fHbp variants had broad bactericidal activity against group A, W-135, or X strains ConclusionsDespite extensive natural exposure of the African population, fHbp is conserved among African strains. A native outer membrane vesicle vaccine that expresses fHbp variants can potentially elicit protective antibodies against strains from all capsular groups that cause epidemics in the region

This study assessed whether systematically using finetype data in national surveillance of invasive meningococcal disease serogroup B (IMD-B) in the Netherlands could improve cluster detection in order to prevent further cases through public health actions. We analysed 2005–2023 data, including 1,642 IMD-B cases with complete finetype and municipality information (95%; N = 1729). Using a generalized linear model, we calculated expected baselines for each finetype, including temporal trends. Using SaTScan™, we applied Poisson scan-statistics with a 365-day window to identify spatiotemporal clusters, comparing results to epidemiological and core-genome multi-locus sequence typing (cgMLST) data. Of 453 finetypes, 308 (68%) occurred once; diversity was high (Gini-Simpson index 0.96). We identified 42 spatiotemporal clusters across 37 finetypes, comprising 132 cases (8%), with a median cluster size of two (range 2–21) and duration of 45 days (range 6–356). Between zero and five clusters were detected yearly. Among 18 cases with known epidemiological links, 14 (78%) were within detected spatiotemporal clusters. CgMLST data from eight clusters supported some clusters but rejected others. Systematic cluster detection using finetype could reveal missed epidemiological links, potentially enabling public health action. However, its impact in preventing additional IMD-B cases is likely limited due to small cluster sizes, though meaningful given the severity of IMD-B. Simple finetype mapping may provide a resource-efficient alternative to SaTScan™.

From May 16, 2011 to March 13, 2013, Bio-Manguinhos/Fiocruz conducted a randomized Phase II/III study of a vaccine against N. menigitidis serogroup B, involving 280 children aged between 4 and 11 years, evaluating immunogenicity and safety. This was a dose-escalation study evaluating vaccine candidates containing 12.5 μg, 25 μg, and 50 μg of OMV protein per dose, with dLOS administered at half the concentration of the total protein. The VAMENGOC-BC® vaccine was used as a reference. The vaccination schedule included three doses administered two months apart, followed by a booster dose 6–12 months after the third injection. Bactericidal antibody responses were evaluated using the vaccine strains as primary targets and heterologous strains as secondary targets. All vaccines were well tolerated, and only for fever after the first dose there was a statistically significant difference across comparison groups (p = 0,007). Additionally, unsolicited adverse events and serious adverse events were determined not to be causally related to the vaccines. The candidate vaccines elicited a significant increase in total IgG antibodies against the OMV components of the first prevalent strain and achieved high bactericidal titers against both vaccine strains following the immunization schedule. After the booster dose, all children receiving either the experimental or the reference vaccine were protected against the vaccine strains. For heterologous strains, a protective response was observed based on the similarity of PorA, although the antibody levels remained low. Moreover, the inclusion of detoxified LOS in the experimental formulations underscores the need for further investigation into this molecule as a vaccine component, given that the observed response appears to be concentration dependent. The experimental vaccines showed immunogenicity equivalent to VA-MENGOC-BC® with formulations containing two to four times fewer protein components than the reference vaccine.