Genomic surveillance of Neisseria meningitidis serogroup B invasive strains: Diversity of vaccine antigen types, Brazil, 2016-2018.

BACKGROUND: Neisseria meningitidis serogroup B remains a prominent cause of invasive meningococcal disease (IMD) in Brazil. Because two novel protein-based vaccines against serogroup B are available, the main purpose of this study was to provide data on the diversity and distribution of meningococcal vaccine antigen types circulating in Brazil. METHODOLOGY: Genetic lineages, vaccine antigen types, and allele types of antimicrobial-associated resistance genes based on whole-genome sequencing of a collection of 145 Neisseria meningitidis serogroup B invasive strains recovered in Brazil from 2016 to 2018 were collected. RESULTS: A total of 11 clonal complexes (ccs) were identified among the 145 isolates, four of which were predominant, namely, cc461, cc35, cc32, and cc213, accounting for 72.0% of isolates. The most prevalent fHbp peptides were 24 (subfamily A/variant 2), 47 (subfamily A/variant 3), 1 (subfamily B/variant 1) and 45 (subfamily A/variant 3), which were predominantly associated with cc35, cc461, cc32, and cc213, respectively. The NadA peptide was detected in only 26.2% of the isolates. The most frequent NadA peptide 1 was found almost exclusively in cc32. We found seven NHBA peptides that accounted for 74.5% of isolates, and the newly described peptide 1390 was the most prevalent peptide exclusively associated with cc461. Mutated penA alleles were detected in 56.5% of the isolates, whereas no rpoB and gyrA mutant alleles were found. CONCLUSION: During the study period, changes in the clonal structure of circulating strains were observed, without a predominance of a single hyperinvasive lineage, indicating that an epidemiologic shift has occurred that led to a diversity of vaccine antigen types in recent years in Brazil.

Genomic analysis of the meningococcal ST-4821 complex-Western clade, potential sexual transmission and predicted antibiotic susceptibility and vaccine coverage.

INTRODUCTION: The ST-4821 complex (cc4821) is a leading cause of serogroup C and serogroup B invasive meningococcal disease in China where diverse strains in two phylogenetic groups (groups 1 and 2) have acquired fluoroquinolone resistance. cc4821 was recently prevalent among carriage isolates in men who have sex with men in New York City (USA). Genome-level population studies have thus far been limited to Chinese isolates. The aim of the present study was to build upon these with an extended panel of international cc4821 isolates. METHODS: Genomes of isolates from Asia (1972 to 2017), Europe (2011 to 2018), North America (2007), and South America (2014) were sequenced or obtained from the PubMLST Neisseria database. Core genome comparisons were performed in PubMLST. RESULTS: Four lineages were identified. Western isolates formed a distinct, mainly serogroup B sublineage with alleles associated with fluoroquinolone susceptibility (MIC <0.03 mg/L) and reduced penicillin susceptibility (MIC 0.094 to 1 mg/L). A third of these were from anogenital sites in men who have sex with men and had unique denitrification gene alleles. Generally 4CMenB vaccine strain coverage was reliant on strain-specific NHBA peptides. DISCUSSION: The previously identified cc4821 group 2 was resolved into three separate lineages. Clustering of western isolates was surprising given the overall diversity of cc4821. Possible association of this cluster with the anogenital niche is worthy of monitoring given concerns surrounding antibiotic resistance and potential subcapsular vaccine escape.

Genomic Characterization of Invasive Meningococcal Serogroup B Isolates and Estimation of 4CMenB Vaccine Coverage in Finland.

Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is a significant cause of morbidity and mortality worldwide. In Finland, the incidence rate of IMD is low, with meningococcal serogroup B (MenB) accounting for around one-third of IMD cases annually. The aim of this study was to investigate the genetic variability of invasive MenB isolates collected in Finland between 2010 and 2017 (n = 81), including the genes encoding the 4-component MenB vaccine (4CMenB; Bexsero; GSK) antigens and their promoters, and to evaluate the 4CMenB potential coverage. Whole-genome sequencing was performed. The meningococcal antigen typing system (MATS) was used to characterize MenB isolates and predict the potential coverage of 4CMenB. MATS was complemented by genetic MATS (gMATS) through association of antigen genotyping and phenotypic MATS results. Multilocus sequence typing revealed predominance of the ST-41/44 clonal complex among which sequence type (ST)-303 was the most common and was predicted to be covered by 4CMenB. Of the 4 major vaccine antigens, the factor H-binding protein variant 1, neisserial heparin binding antigen peptide 2, and the PorA P1.4 antigen were predominant, whereas Neisseria adhesin A was present in only 4% of the 81 isolates. MATS and gMATS 4CMenB strain coverage predictions were 78% and 86%, respectively, in a subpanel of 60 isolates collected during 2010 to 2014, with a gMATS prediction of 84% for all 81 isolates. The results suggest that 4CMenB could reduce the burden of IMD in Finland and that gMATS could be applied to monitor vaccine strain coverage and predict vaccine effectiveness.IMPORTANCE 4CMenB is a 4-component vaccine used against invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B (MenB). We investigated the genetic variability of MenB in Finland and evaluated 4CMenB strain coverage by 2 different methods: MATS (meningococcal antigen typing system) and gMATS (genetic MATS). In a set of MenB isolates, 78% (MATS) and 86% (gMATS) were predicted as covered by 4CMenB, suggesting that use of 4CMenB would help reduce IMD incidence in Finland. MATS has been used in 13 countries worldwide, generating information on phenotypic characteristics that could infer protection by 4CMenB. Based on these data and genetic information, gMATS coverage predictions can be made. gMATS predicts coverage consistent with MATS for about 94% of tested strains. Unlike MATS, gMATS does not require live isolates, thus allowing the analysis also of noncultivable strains, making the coverage predictions more accurate. Therefore, gMATS can replace MATS to assess 4CMenB coverage, including in regions with no prior MATS data.

The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence.

GNA2091 is one of the components of the 4-component meningococcal serogroup B vaccine (4CMenB) vaccine and is highly conserved in all meningococcal strains. However, its functional role has not been fully characterized. Here we show that nmb2091 is part of an operon and is cotranscribed with the nmb2089, nmb2090, and nmb2092 adjacent genes, and a similar but reduced operon arrangement is conserved in many other gram-negative bacteria. Deletion of the nmb2091 gene causes an aggregative phenotype with a mild defect in cell separation; differences in the outer membrane composition and phospholipid profile, in particular in the phosphoethanolamine levels; an increased level of outer membrane vesicles; and deregulation of the zinc-responsive genes such as znuD. Finally, the ∆2091 strain is attenuated with respect to the wild-type strain in competitive index experiments in the infant rat model of meningococcal infection. Altogether these data suggest that GNA2091 plays important roles in outer membrane architecture, biogenesis, homeostasis, and in meningococcal survival in vivo, and a model for its role is discussed. These findings highlight the importance of GNA2091 as a vaccine component.-Seib, K. L., Haag, A. F., Oriente, F., Fantappiè, L., Borghi, S., Semchenko, E. A., Schulz, B. L., Ferlicca, F., Taddei, A. R., Giuliani, M. M., Pizza, M., Delany, I. The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence.

Genomic surveillance of invasive meningococcal disease in the Czech Republic, 2015-2017.

INTRODUCTION: The study presents the results of the genomic surveillance of invasive meningococcal disease (IMD) in the Czech Republic for the period of 2015-2017. MATERIAL AND METHODS: The study set includes all available IMD isolates recovered in the Czech Republic and referred to the National Reference Laboratory for Meningococcal Infections in 2015-2017, a total of 89 Neissseria meningitidis isolates-from 2015 (n = 20), 2016 (n = 27), and from 2017 (n = 42). All isolates were studied by whole genome sequencing (WGS). RESULTS: Serogroup B (MenB) was the most common, followed by serogroups C, W, and Y. Altogether 17 clonal complexes were identified, the most common of which was hypervirulent complex cc11, followed by complexes cc32, cc41/44, cc269, and cc865. Over the three study years, hypervirulent cc11 (MenC) showed an upward trend. The WGS method showed two clearly differentiated clusters of N. meningitidis C: P1.5,2:F3-3:ST-11 (cc11). The first cluster is represented by nine isolates, all of which are from 2017. The second cluster consisted of five isolates from 2016 and eight isolates from 2017. Their genetic discordance is illustrated by the changing nadA allele and subsequently by the variance in BAST type. Clonal complex cc269 (MenB) also increased over the time frame. WGS identified the presence of MenB vaccine antigen genes in all B and non-B isolates of N. meningitidis. Altogether 49 different Bexsero antigen sequence types (BAST) were identified and 10 combinations of these have not been previously described in the PubMLST database. CONCLUSIONS: The genomic surveillance of IMD in the Czech Republic provides data needed to update immunisation guidelines for this disease. WGS showed a higher discrimination power and provided more accurate data on molecular characteristics and genetic relationships among invasive N. meningitidis isolates.

Vaccines and global health: In search of a sustainable model for vaccine development and delivery.

Most vaccines for diseases in low- and middle-income countries fail to be developed because of weak or absent market incentives. Conquering diseases such as tuberculosis, HIV, malaria, and Ebola, as well as illnesses caused by multidrug-resistant pathogens, requires considerable investment and a new sustainable model of vaccine development involving close collaborations between public and private sectors.

Cost Effectiveness of Meningococcal Serogroup B Vaccination in College-Aged Young Adults.

INTRODUCTION: Neisseria meningitidis serogroup B is the most common form of meningococcal infection in young adults in the U.S. Vaccines have recently become available, but it is not clear that the benefits outweigh the costs. The purpose of this study was to assess cost effectiveness and determine potentially favorable conditions for universal vaccination. METHODS: Costs and benefits of universal vaccination at college entry versus no universal vaccination with an outbreak response were estimated in 2018 in the context of a mid-sized U.S.-based 4-year college from both a health sector and a societal perspective. Probability, cost, and utility data were obtained from the published literature. Costs (2015 U.S.$) and benefits were discounted at 3%. One-way and multivariable probabilistic sensitivity analyses were performed including variations in the specific vaccine used. Further testing of the model's parameters at extremes was used to identify favorable conditions for universal vaccination. RESULTS: The incremental cost per quality-adjusted life year gained with universal vaccination was $13.9 million under the health sector perspective and $13.8 million under the societal perspective, each perspective was compared with a willingness-to-pay threshold of $150,000 per quality-adjusted life year. Multivariable probabilistic sensitivity analysis showed that universal vaccination was not the preferred strategy for <$15 million per quality-adjusted life year. Under an extremely favorable model, a universal vaccination strategy became cost effective for vaccine series costing <$65. CONCLUSIONS: This study demonstrates that universal vaccination at college entry is not cost effective. The rarity of N. meningitidis serogroup B contributes to the lack of cost effectiveness for universal vaccination.

A rare case of septic shock due to Neisseria meningitidis serogroup B infection despite prior vaccination in a young adult with paroxysmal nocturnal haemoglobinuria receiving eculizumab.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematopoietic stem cell disease which causes defects in complement inhibiting proteins. The disease presents classically with the triad of haemolytic anaemia, pancytopenia and thrombosis. Eculizumab, a humanized antibody that blocks the cleavage of complement factor 5, was approved for PNH treatment in 2007 and has improved patients' survival since then. However, several cases of invasive meningococcal disease (IMD) have been reported in eculizumab-treated patients, mostly caused by serogroup B infection which was not covered by the previously administered vaccine (MenACWY). We report a rare case of septic shock due to infection with Neisseria meningitis serogroup B despite prior vaccination with 4CMenB in a young PNH patient treated with eculizumab. There are increasing doubts over whether vaccination ensures sufficient immunoprotection against IMD in patients receiving eculizumab. Therefore, besides monitoring the immune response, lifelong chemoprophylaxis should be considered.

Prevalence and serogroup changes of Neisseria meningitidis in South Korea, 2010-2016.

Determination of the major serogroups is an important step for establishing a vaccine programme and management strategy targeting Neisseria meningitidis. From April 2010 to November 2016, a total of 25 N. meningitidis isolates were collected in South Korea, in collaboration with the Korean Society of Clinical Microbiology. Among isolates, 19 isolates were recovered from blood and/or cerebrospinal fluid (CSF) in 46 patients who suffered from invasive meningococcal disease (IMD), and six isolates were found in sputum or the throat. The most common serogroup was serogroup B (overall, 36%, n = 9/25; IMD, 37%, n = 7/19), which was isolated in every year of the research period except for 2011. There were five serogroup W isolates recovered from patients in military service. W was no longer isolated after initiation of a vaccine programme for military trainees, but serogroup B caused meningitis in an army recruit training centre in 2015. In MLST analysis, 14 sequence types were found, and all isolates belonging to W showed the same molecular epidemiologic characteristics (W:P1.5-1, 2-2:F3-9:ST-8912). All isolates showed susceptibility to ceftriaxone, meropenem, ciprofloxacin, minocycline, and rifampin; however, the susceptibility rates to penicillin and ampicillin for isolates with W and C capsules were 22% and 30%, respectively.

An epidemic of meningococcal disease in children in North Norway in the 1970s and 1980s was dominated by a hypervirulent group B strain.

AIM: We examined children hospitalised for invasive meningococcal disease, a leading cause of paediatric sepsis, in Troms County, North Norway, from 1973 to 2016, including the epidemic in the 1970s and 1980s. METHODS: This study was a retrospective review of children under the age of 15 years who were hospitalised for meningococcal disease at the University Hospital of North Norway and Harstad Hospital. We studied hospital and bacteriological records to determine the incidence rates and phenotypes involved. RESULTS: There were 300 cases under 15 years and an incidence rate of 17 per 100,000 cases for 1973-2016. This was broken down into the following: 1973-1980 (n = 130, 49), 1981-1990 (n = 129, 39), and 1991-2016 (n = 41, 4.7), respectively. There were 21 (7%) deaths. Phenotype B:15:P1.7,16 was more common than the other phenotypes in the epidemic period before 1990 than after 1990 (p = 0.02) and had a significantly lower mortality rate than the other phenotypes (p = 0.04). Later years showed a more heterogenous phenotype distribution. Serogroup B was the dominant serogroup. CONCLUSION: The B:15:P1.7,6 strain was more prevalent during the Norwegian epidemic of invasive meningococcal disease, but had a significantly lower mortality rate. The phenotype distribution was more heterogeneous after 1990. The dominant serogroup was B.

Emerging clinical experience with vaccines against group B meningococcal disease.

The prevention of paediatric bacterial meningitis and septicaemia has recently entered a new era with the availability of two vaccines against capsular group B meningococcus (MenB). Both of these vaccines are based on sub-capsular proteins of the meningococcus, an approach that overcomes the challenges set by the poorly immunogenic MenB polysaccharide capsule but adds complexity to predicting and measuring the impact of their use. This review describes the development and use of MenB vaccines to date, from the use of outer membrane vesicle (OMV) vaccines in MenB outbreaks around the world, to emerging evidence on the effectiveness of the newly available vaccines. While recent data from the United Kingdom supports the potential for protein-based vaccines to provide direct protection against MenB disease in immunised children, further research is required to understand the breadth and duration of this protection. A more detailed understanding of the impact of immunisation with these vaccines on nasopharyngeal carriage of the meningococcus is also required, to inform both their potential to induce herd immunity and to preferentially select for carriage of strains not susceptible to vaccine-induced antibodies. Although a full understanding of the potential impact of these vaccines will only be possible with this additional information, the availability of new tools to prevent the devastating effect of invasive MenB disease is a significant breakthrough in the fight against childhood sepsis and meningitis.

The glycointeractome of serogroup B Neisseria meningitidis strain MC58.

Neisseria meningitidis express numerous virulence factors that enable it to interact with diverse microenvironments within the host, during both asymptomatic nasopharyngeal colonization and invasive disease. Many of these interactions involve bacterial or host glycans. In order to characterise the meningococcal glycointeractome, glycan arrays representative of structures found on human cells, were used as a screening tool to investigate host glycans bound by N. meningitidis. Arrays probed with fluorescently labelled wild-type MC58 revealed binding to 223 glycans, including blood group antigens, mucins, gangliosides and glycosaminoglycans. Mutant strains lacking surface components, including capsule, lipooligosaccharide (LOS), Opc and pili, were investigated to identify the factors responsible for glycan binding. Surface plasmon resonance and isothermal calorimetry were used to confirm binding and determine affinities between surface components and host glycans. We observed that the L3 LOS immunotype (whole cells and purified LOS) bound 26 structures, while L8 only bound 5 structures. We further demonstrated a direct glycan-glycan interaction between purified L3 LOS and Thomsen-Friedenreich (TF) antigen, with a KD of 13 nM. This is the highest affinity glycan-glycan interaction reported to date. These findings highlight the diverse glycointeractions that may occur during different stages of meningococcal disease, which could be exploited for development of novel preventative and therapeutic strategies.

Frequent capsule switching in 'ultra-virulent' meningococci - Are we ready for a serogroup B ST-11 complex outbreak?

The meningococcal ST-11 complex (cc11) causes large invasive disease outbreaks with high case fatality rates, such as serogroup C (MenC) epidemics in industrialised nations in the 1990s and the serogroup W epidemic currently expanding globally. Glycoconjugate vaccines are available for serogroups A, C, W and Y. Broad coverage protein-based vaccines have recently been licensed against serogroup B meningococci (MenB), however, these do not afford universal MenB protection. Capsular switching from MenC to MenB among cc11 organisms is concerning because a large MenB cc11 (B:cc11) outbreak has the potential to cause significant morbidity and mortality. This study aimed to assess the potential for licensed and developmental non-capsular meningococcal vaccines to protect against B:cc11. The population structure and vaccine antigen distribution was determined for a panel of >800 geo-temporally diverse, predominantly MenC cc11 and B:cc11 genomes. The two licensed vaccines potentially protect against many but not all B:cc11 meningococci. Furthermore, strain coverage by these vaccines is often due to a single vaccine antigen and both vaccines are highly susceptible to vaccine escape owing to the apparent dispensability of key proteins used as vaccine antigens. cc11 strains with MenB and MenC capsules warrant special consideration when formulating future non-capsular meningococcal vaccines.

Short-term changes in the health state of children with group B meningococcal disease: A prospective, national cohort study.

OBJECTIVES: The short-term impact of childhood invasive meningococcal disease (IMD) on quality-of-life (QoL) remains largely unquantified. This study aimed to quantify QoL loss at the point when illness was at its worst, and assess health state recovery in the months following illness. METHODS: Parents of children aged <16 years with laboratory-confirmed meningococcal group B (MenB) disease in England, with onset dates from November 2012 to May 2013 were asked to complete a short questionnaire, which included EQ-5DY, a version of EQ-5D for 8-15 year-olds. The parents, or child if able, were asked to complete the questionnaires while considering the child's health on the worst day of illness and on the date the questionnaires were completed. RESULTS: The overall response rate was 43% (109/254 children), with no significant differences between respondents and non-respondents. The median time from disease onset to questionnaire completion was 134 days (interquartile range (IQR), 92 to 156 days). After imputation, the median health index was -0.056 (IQR, -0.073 to 0.102) on the worst day of illness, and 1 (IQR 0.866 to 1.000) on the date of questionnaire completion. The respective Visual Analogue Scores (VAS) were 6.5/100.0 (IQR, 0.0 to 20.0) and 95.0/100.0 (IQR, 90.0 to 100.0). The health state of cases with long-term sequelae (n = 41) was significantly worse at follow-up than those who recovered uneventfully (n = 64; 90.0 vs. 98.0; p<0.001), although there was no significant difference on the worst day of illness (5.0 vs. 10.0; p = 0.671). CONCLUSIONS: This work has provided, for the first time, a quantitative estimate of QoL loss at the peak of illness and in the months after MenB disease in children. The magnitude of QoL loss is staggering, with the reported health state being at, or close to, the worst possible outcome imaginable. This study highlights the difficulties in measuring the impact of illness in young children, who often have the highest burden of potentially preventable infectious diseases.

Characteristics and changes in invasive meningococcal disease epidemiology in France, 2006-2015.

OBJECTIVES: This work aimed to describe the epidemiology of invasive meningococcal disease (IMD) in France, 2006-2015, including group- and genotype-specific disease burden, incidence trends before and after introduction of meningococcal C conjugate vaccines (MCCV) in 2010, and factors influencing the case fatality rate. METHODS: Mandatory notification data on incidence and IMD case characteristics were used. Genotyping of invasive strains and whole genome sequencing were performed by the French National Reference Center. Vaccination coverage was estimated from the National Health Insurance Information System's reimbursement data. RESULTS: The decrease in annual IMD incidence rates (per 100,000 inhabitants) from 1.23 in 2006 to 0.78 in 2016 was mainly related to the decrease in group B IMD. Group C incidence decreased from 0.29 in 2006 to 0.13 in 2010 but increased thereafter in age groups not targeted by MCCV. From 2010 onwards, MCCV coverage gradually increased but remained below 25% in 15-19 year-olds in 2015. Age, clinical presentation and, to a lesser extent, clonal complex 11 were the most significant factors determining mortality. CONCLUSIONS: The limited impact of vaccination on group C IMD incidence may be explained by the emergence of a new epidemic cycle in 2011 and the low vaccination coverage rates among adolescents and young adults.

Rapid response to a college outbreak of meningococcal serogroup B disease: Nation's first widespread use of bivalent rLP2086 vaccine.

OBJECTIVE: To outline the reasoning behind use of bivalent rLP2086 in a Rhode Island college meningococcal B disease outbreak, highlighting the timeline from outbreak declaration to vaccination clinic, emphasizing that these two time points are <3 days apart. PARTICIPANTS: Staff, faculty, and students at College X eligible for vaccination. METHODS: An outbreak response was initiated, advantages/disadvantages of available MenB vaccines were discussed, and a vaccination clinic was coordinated. RESULTS: Bivalent rLP2086 was chosen as the vaccination intervention. We achieved a 94% coverage rate for the first dose. To date, this intervention has prevented further cases of Neisseria meningitidis serogroup B disease at College X. CONCLUSIONS: The close, efficient collaboration of public health stakeholders and College X led 94% of the eligible population to be safely vaccinated with at least one dose of bivalent rLP2086. This outbreak marked the first time bivalent rLP2086 was effectively used as an intervention response.

Meningitis neonatal por Neisseria meningitidis serogrupo B / Neonatal meningitis caused by serogroup B Neisseria meningitides

La meningitis meningocóccica es una infección poco frecuente en el período neonatal internacionalmente, y solo hay una publicación previa en la literatura médica cubana hace 25 años atrás, de recién nacidos con meningitis bacteriana causada por Neisseria meningitidis. Se presenta el caso de un recién nacido febril, con manifestaciones de toxicidad, fontanela abombada, y cuando se realizó punción lumbar, se encontró pleocitosis del líquido cefalorraquídeo y se aisló N. meningitidis serogrupo B, por lo que se diagnostica meningitis meningocóccica neonatal. Tuvo evolución favorable. Se describen algunas características de la infección meningocócica, y se destaca el diagnóstico y tratamiento recomendado para este tipo de infección, así como se hace referencia a reportes de casos publicados en la literatura internacional.

Meningoccocal meningitis is a rare infection in the neonatal period worldwide and there is just one publication in the Cuban medical literature dated 25 years ago, which presented some neonates with bacterial meningitis caused by Neisseria meningitides. This is a febrile neonate with toxicity manifestations and bulging fontanelle; he was performed a lumbar puncture to find spinal fluid pleocytosis and the serogroup B N. meningitides was then isolated, so he was diagnosed with neonatal meningococcal meningitis with favorable progression. Some characteristics of the meningococcal infection, the diagnosis and recommended treatment were described in addition to making reference to case reports published in the international literature.

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage.

The degree of phosphorylation and phosphoethanolaminylation of lipid A on neisserial lipooligosaccharide (LOS), a major cell-surface antigen, can be correlated with inflammatory potential and the ability to induce immune tolerance in vitro. On the oligosaccharide of the LOS, the presence of phosphoethanolamine and sialic acid substituents can be correlated with in vitro serum resistance. In this study, we analyzed the structure of the LOS from 40 invasive isolates and 25 isolates from carriers of Neisseria meningitidis without disease. Invasive strains were classified as groups 1-3 that caused meningitis, septicemia without meningitis, and septicemia with meningitis, respectively. Intact LOS was analyzed by high resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Prominent peaks for lipid A fragment ions with three phosphates and one phosphoethanolamine were detected in all LOS analyzed. LOS from groups 2 and 3 had less abundant ions for highly phosphorylated lipid A forms and induced less TNF-α in THP-1 monocytic cells compared with LOS from group 1. Lipid A from all invasive strains was hexaacylated, whereas lipid A of 6/25 carrier strains was pentaacylated. There were fewer O-acetyl groups and more phosphoethanolamine and sialic acid substitutions on the oligosaccharide from invasive compared with carrier isolates. Bioinformatic and genomic analysis of LOS biosynthetic genes indicated significant skewing to specific alleles, dependent on the disease outcome. Our results suggest that variable LOS structures have multifaceted effects on homeostatic innate immune responses that have critical impact on the pathophysiology of meningococcal infections.

Bivalent rLP2086 Vaccine (Trumenba(®)): A Review in Active Immunization Against Invasive Meningococcal Group B Disease in Individuals Aged 10-25 Years.

Bivalent rLP2086 vaccine (Trumenba(®)) [hereafter referred to as rLP2086] is a Neisseria meningitidis serogroup B (MenB) vaccine recently licensed in the USA for active immunization to prevent invasive disease caused by MenB in individuals 10-25 years of age. rLP2086, which contains two variants of the meningococcal surface protein factor H-binding protein (fHBP), was approved by the FDA under the accelerated approval pathway after the immunogenicity of the vaccine was demonstrated in several phase II trials. This article reviews the immunogenicity and reactogenicity of rLP2086 as demonstrated in the trials with a focus on the US setting and on use of the vaccine as per FDA-approved labeling. rLP2086 is approved in the USA as a three-dose series administered in a 0-, 2-, and 6-month schedule. In the phase II trials, rLP2086 elicited a robust immune response against a panel of MenB test strains. A strong immune response was evident in a marked proportion of subjects after two vaccine doses, with a further increase after a third dose. The four primary test strains used were selected to be representative of MenB strains prevalent in the USA, with each expressing an fHBP variant heterologous to the vaccine antigens. rLP2086 was generally well tolerated in the trials, with most adverse reactions being mild to moderate in severity. Although some questions remain, including the duration of the protective response, rLP2086 vaccine has the potential to be a valuable tool for the prevention of invasive MenB disease.

Meningococcal vaccines: Current state and future outlook.

Neisseria meningitidis infections are a major public health problem worldwide. Although conventional approaches have not led to development of a serogroup B meningococcal vaccine, a new technique based on genome sequencing has created new perspectives. Recently, a universal serogroup B meningococcal vaccine, Bexsero(®), was licensed in Europe, Australia and United States, following several clinical studies demonstrating its immunogenicity and safety. Availability of this vaccine could contribute positively to human health, by significantly reducing the incidence of meningococcal infections. However, unfavorable cost-effectiveness analysis means that routine vaccination is not currently recommended. Another serogroup meningococcal vaccine, Trumemba(®), was also recently licensed in United States. Like any drug, Bexsero(®) and Trumemba(®) will require close observation to assess their impact on meningococcal epidemiology.