Neisseria Meningitidis Strains Research Articles

Antigenic determinants driving serogroup-specific antibody response to Neisseria meningitidis C, W, and Y capsular polysaccharides: Insights for rational vaccine design

Meningococcal glycoconjugate vaccines sourced from capsular polysaccharides (CPSs) of pathogenic Neisseria meningitidis strains are well-established measures to prevent meningococcal disease. However, the exact structural factors responsible for antibody recognition are not known.CPSs of Neisseria meningitidis serogroups Y and W differ by a single stereochemical center, yet they evoke specific immune responses. Herein, we developed specific monoclonal antibodies (mAbs) targeting serogroups C, Y, and W and evaluated their ability to kill bacteria. We then used these mAbs to dissect structural elements responsible for carbohydrate-protein interactions. First, Men oligosaccharides were screened against the mAbs using ELISA to select putative lengths representing the minimal antigenic determinant. Next, molecular interaction features between the mAbs and serogroup-specific sugar fragments were elucidated using STD-NMR. Moreover, X-ray diffraction data with the anti-MenW CPS mAb enabled the elucidation of the sugar-antibody binding mode.Our findings revealed common traits in the epitopes of all three sialylated serogroups. The minimal binding epitopes typically comprise five to six repeating units. Moreover, the O-acetylation of the neuraminic acid moieties was fundamental for mAb binding.These insights hold promise for the rational design of optimized meningococcal oligosaccharides, opening new avenues for novel production methods, including chemical or enzymatic approaches.

Epidemiology and genetic diversity of invasive Neisseria meningitidis strains circulating in Portugal from 2003 to 2020.

Invasive meningococcal disease (IMD) continues to be a public health problem due to its epidemic potential, affecting mostly children. We aimed to present a detailed description of the epidemiology of IMD in Portugal, including insights into the genetic diversity of Neisseria meningitidis strains. Epidemiological analysis included data from the Portuguese National Reference Laboratory of Neisseria meningitidis during 2003 to 2020. Since 2012, N. meningitidis isolates have also been assessed for their susceptibility to antibiotics and were characterized by whole genome sequencing. During 2003-2020, 1392 confirmed cases of IMD were analyzed. A decrease in the annual incidence rate was observed, ranging from 1.99 (2003) to 0.39 (2020), with an average case fatality rate of 7.1%. Serogroup B was the most frequent (69.7%), followed by serogroups C (9.7%), Y (5.7%), and W (2.6%). Genomic characterization of 329 isolates identified 20 clonal complexes (cc), with the most prevalent belonging to serogroup B cc41/44 (26.3%) and cc213 (16.3%). Isolates belonging to cc11 were predominantly from serogroups W (77.3%) and C (76.5%), whereas cc23 was dominant from serogroup Y (65.7%). Over the past 4years (2017-2020), we observed an increasing trend of cases assigned to cc213, cc32, and cc11. Regarding antimicrobial susceptibility, all isolates were susceptible to ceftriaxone and 61.8% were penicillin-nonsusceptible, whereas 1.4% and 1.0% were resistant to ciprofloxacin and rifampicin. This is the first detailed study on the epidemiology and genomics of invasive N. meningitidis infections in Portugal, providing relevant data to public health policy makers for a more effective control of this disease.

Characterizing Neisseria meningitidis in Southern Vietnam between 2012 and 2021: A predominance of the chloramphenicol-resistant ST-1576 lineage

ObjectivesOur goal was to describe Invasive Meningococcal Disease (IMD) in Southern Vietnam over the last 10 years. We characterized 109 Neisseria meningitidis strains in Southern Vietnam isolated between 1980s to 2021, that were collected from IMD (n = 44), sexually transmitted infections (n = 2), and healthy carriage (n = 63). MethodsIMD were confirmed by bacterial culture and/or real-time polymerase chain reaction at the national reference laboratory in Pasteur Institute of Ho Chi Minh City (PIHCM). Antimicrobial resistance was determined on 31 IMD and two sexually transmitted infection isolates with E-test for chloramphenicol (CHL), penicillin (PEN), ciprofloxacin (CIP), ceftriaxone (CRO), and rifampicin (RIF). Sequencing was performed for analyzing of multilocus-sequence-typing (MLST), porA, fetA, and antibiotic resistance genes, including gyrA, penA, and rpoB. ResultsThe incidence rate during this period was 0.02 per 100,000 persons/year. Serogroup B accounted for over 90% of cases (50/54). ST-1576 were mainly responsible for IMD, 27/42 MLST profiles, and associated with CHL resistance. Resistance was prevalent among IMD isolates. Thirteen were resistant to CHL (minimum inhibitory concentration [MIC] ≥16 mg/l), 12 were intermediate to PEN (MIC between 0.19 and 0.5 mg/l), and five were CIP-resistant (MIC between 0.19 and 0.5 mg/l). Particularly, one was non-susceptible to CRO (MIC at 0.125 mg/l), belonging to ST-5571 lineage. The resistance was due to carrying resistant alleles of penA and gyrA genes, and catP gene. Notably, seven isolates were resistant/non-susceptible to two or more antibiotics. ConclusionOur results suggest the persistence of the circulating ST-1576 in Southern Vietnam, with a spread of antimicrobial resistance across the community.

Characterisation of Neisseria meningitidis cc11/ET-15 variant by whole genome sequencing.

BACKGROUND Neisseria meningitidis strains belonging to clonal complex 11 is the cause of numerous outbreaks and epidemics in the United States, Canada and Europe, accounting for 49.5% of cases of meningococcal disease caused by serogroup C worldwide. In Brazil, it is the second most frequent clonal complex within this serogroup. The genetic characterisation of cc11/ET-15 variants is important for the epidemiological monitoring of meningococcal disease, through the identification of circulating epidemic clones, to support specific actions of Health Surveillance aiming outbreaks control.OBJECTIVES The objective of this study was to identify features in the genome of cc11/ET-15 clones through whole-genome sequencing (WGS), that differ from cc11/non-ET-15 strains that could explain their virulence.METHODS The whole genome of three cc11/ET-15 representative strains were sequenced with a minimum coverage of 100X with the MiSeq System and compared to the genome of cc11/non-ET-15 strains.RESULTS Genome analysis of cc11/ET-15 variants showed the presence of resistance factors, mobile genetic elements and virulence factors not found in cc11/non-ET-15 strains.MAIN CONCLUSIONS Our results show that these strains carry virulence factors not identified in cc11/non-ET-15 strains, which could explain the high lethality rates attributed to this clone worldwide.

Genetic characterization of clonal complex sequence type 2057 (cc2057) serogroup B Neisseria meningitidis strains unique to Japan and identification of a capsular-switched serogroup Y isolate cc2057.

Introduction. Only approximately 40 cases of invasive meningococcal diseases are reported annually in Japan, and the dominant strains are serogroup Y meningococci (MenY) followed by serogroup B meningococci (MenB). Within the last 10 years, Neisseria meningitidis strains belonging to clonal complex (cc)2057 have become dominant among Japanese MenB and have not been identified in countries other than Japan.Hypothesis/Gap Statement. The uniqueness of cc2057 N. meningitidis strains was considered to be epidemiologically of importance, and some genetic features could be hidden in the genome of cc2057 meningococci.Method. We investigated 22 cc2057 MenB and one cc2057 MenY using whole genome sequencing (WGS) and also predicted the potential coverage of 4CMenB and bivalent rLP2086 vaccines in silico.Results. cc2057 N. meningitidis strains were phylogenetically assigned to two clades. Three hypothetical genes homologous to those in Neisseria lactamica and sequences related to a new CRISPR Cas9 system were found only in the genome of cc2057 strains. Moreover, one cc2057 MenY strain was presumed to be capsular-switched at the capsule synthesis (cps) locus. The potential coverage of 4CMenB and rLP2086 for cc2057 MenB strains was estimated to be very low.Conclusion. To the best of our knowledge, this is the first study to provide genetic insights from epidemiologically unique N. meningitidis cc2057 strains isolated only in Japan, an island country.

The Emergence of a Ciprofloxacin-Resistant Non-Groupable Neisseria meningitidis Strain of the Clonal Complex ST-175 in the Russian Federation

Relevance. Unencapsulated strains of meningococcus (NmNG) very rarely cause invasive meningococcal disease. A new ciprofloxacin-resistant strain NmNG ST-175 cc175, which has recently caused several cases of invasive meningococcal infection in Europe, has been discovered in the Russian Federation.Aim. To compare the new Russian strains of NmNG ST-175 with the already characterized NmNG ST-175 and to analyze the genetic markers associated with antibiotic resistance.Materials and methods. The nucleotide sequences of NmNG ST-175 strains of more than 2 million base pairs were exported from the PubMLST database. Comparison was carried out for 1605 core genome loci using the N. meningitidis cgMLST v1.0 ". Genetic relationships of 127 NmNG ST-175 strains, including 8 Russian carrier strains, were visualized using the SplitsTree software (version 4.16.2).Results. Of the eight Russian strains, six found themselves in a cluster with German and Swedish isolates that caused invasive meningococcal infection. Two more Russian strains were closest to the isolates of the cluster, including carrier isolates from England. Seven strains showed resistance to ciprofloxacin and possessed the gyrA-187 and gyrA-152 alleles, which, based on the phylogenetic analysis of the alleles, belonged to the genetic branches of Neisseria cinerea and Nm.Conclusion. Protein vaccines alone could potentially provide protection against ST-175 NmNG. It seems promising to study the antigenic characteristics of Russian Nm strains, including NmNG ST-175, to assess the potential vaccination coverage with existing protein vaccines, the possibility of their registration on the territory of the Russian Federation, as well as the development of domestic vaccines.

Analysis on antimicrobial sensitivity of Neisseria meningitidis in China from 2005 to 2019

Objective: To analyze the antimicrobial resistance characteristics of 538 Neisseria meningitidis isolated from 2005 to 2019 in China. Method: Total of 538 Neisseria meningitidis strains collected from 30 provinces in China from 2005 to 2019. Antimicrobial susceptibility test were performed based on the standards of clinical and laboratory standardization association (CLSI) including 11 recommended antibiotics. Gradient diffusion method was used to detect the antibiotic sensitivity of Neisseria meningitidis. Results: All 538 strains were sensitive to azithromycin, meropenem, chloramphenicol, rifampicin and ceftriaxone. As to other six antibiotics, the antibiotics sensitivity rates were cefotaxime (97.4%, 524 strains), ampicillin (87.7%, 472 strains), penicillin (84.8%, 456 strains), minocycline (95.2%, 512 strains), ciprofloxacin (24.9%, 134 strains) and trimethoprim/sulfamethoxazole (11.2%, 60 strains) respectively. Conclusions: Neisseria meningitidis isolated from 2005-2019 in China were all sensitive to azithromycin, meropenem, chloramphenicol, rifampicin and ceftriaxone. It should highlight Neisseria meningitidis resistant to cefotaxime, ampicillin and penicillin. Ciprofloxacin and sulfamethoxazole are not recommended as the priority choice for clinical treatment and prophylactic medication.

Emergence of Neisseria meningitidis serogroup X in the 2017/2018 Cerebrospinal Meningitis outbreak, Nigeria

Background: Outbreaks of meningitis occur periodically in Nigeria, with the northern parts mostly affected. Neisseria meningitidis is the commonest cause of meningitis outbreaks; Streptococcus pneumoniae and Haemophilus influenzae causes. Following a large outbreak in 2016/2017, another outbreak occurred in 2017/2018, with Neisseria meningitis C being the cause. This study is aimed at characterizing Neisseria meningitidis strains using genotypic technique (PCR) and bringing to limelight the need for continued surveillance, especially with the emergence of Neisseria meningitidis serogroup X, which like serogroup C, is also capable of causing epidemics. Methods and materials: We conducted active surveillance of suspected meningitis cases that met the WHO case definition in states that reported cases of meningitis between November 2017 and June 2018. CSF was collected from suspected meningitis cases and aliquots sent to the National Reference Laboratory, Abuja from States that reported cases and analysed by culture, Rapid Diagnostic Test (Pastorex®) and Polymerase Chain Reaction for detection of N. meningitidis, S. pneumoniae and H. influenzae. Results: 548 samples were analysed by PCR to detect sodC, lytA and hpd genes. Neisseria meningitidis (n = 236, 43.1.0%; NmC = 182, 33.2%, NmX = 43, 8.0%. others = 11, 2.0%) was the predominant cause of meningitis followed by S. pneumoniae (n = 22, 4.0%) and Haemophilus influenzae (n = 26, 4.7%). Conclusion: This study detected an unusual serogroup of Nm, although outbreaks of meningitis in Nigeria have previously been caused by NmA and NmC. Our data underscores the urgent need for ongoing bio surveillance. The increasing incidence of Neisseria meningitidis X is worrisome, because the reactive and preventive vaccination for meningitis does not cover this serogroup, countries in the African meningitis belt must prepare to face this potential new challenge. Information has been shared with the Nigeria Centre for Disease Control and WHO for further action.

Combined therapy with ceftriaxone and doxycycline does not improve the outcome of meningococcal meningitis in mice compared to ceftriaxone monotherapy

BackgroundMeningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10–20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM.MethodsBALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi.ResultsAnalysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX.ConclusionsTreatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.

Polymorphism at variable regions (VRs) of porA gene from Neisseria meningitidis strains isolated in Northern Vietnam

Meningococcal bacterium Neisseria meningitidis is one of the major causes of meningitis worldwide. Currently in Vietnam, N. meningitidis B and C are the most prevalent invasive serogroups. N. meningitidis expresses two major transmembrane proteins, PorA and PorB, of which PorA showed high levels of polymorphism among strains and has been studied as one component of vaccines against N. meningitidis B. Polymorphisms in porA gene clustered into three variable regions VR1, VR2 and VR3. In this study, we sequenced the entired porA gene of 19 N. meningitidis strains isolated from military units in northern Vietnam during the period 2008 – 2017 in order to: (1) evaluate the polymorphism of porA gene at nucleotide level and predict its immuno-reactivity from annotated amino acide sequences; and (2) compare porA variants of Vietnamese strains with known strains worldwide. Our results showed a high level of polymorphisms among Vietnamese strains, with the highest polymorphism found in VR1, followed by VR2 and VR3. Notably, 5/19 strains in this study showed novel variants at VR2 with unknown immunological reactivity. This result suggested potential novel immunological characteristics of meningococcal strains from Vietnam.

Meningococcal W135 Disease Vaccination Intent, the Netherlands, 2018-2019.

To control the rise in Neisseria meningitidis strain W infections, during 2018–2019, the Netherlands launched a catch-up meningococcal conjugate (MenACWY) vaccination campaign for teenagers (13–18 years of age). Applying a mental models approach, we surveyed teenagers and their parents about their knowledge and beliefs about meningococcal disease, the MenACWY vaccination, vaccinations in general, and their MenACWY vaccination intentions. Using random forest analysis, we studied predictions of vaccination intentions by knowledge and beliefs. Survey response rate was 52.8% among teenagers and 59.4% among parents. MenACWY vaccination intentions were best predicted by knowledge and beliefs about vaccinations in general, surpassing knowledge and beliefs about meningococcal disease and the MenACWY vaccination. For teenagers, their parents’ intention that the teenager be vaccinated was a strong predictor of the teenagers’ own vaccination intention. To optimize vaccination uptake during future outbreaks, we recommend that communications emphasize the effectiveness and safety of vaccines and continue to focus on parents.

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.

Estimates of the reproductive numbers and demographic reconstruction of outbreak associated with C:P1.5–1,10–8:F3–6:ST–11(cc11) Neisseria meningitidis strains

BackgroundNeisseria meningitidis can cause sporadic cases and outbreaks of invasive disease, including meningitis and sepsis. The meningococcal serogroup C (MenC) is the second most common serogroup in Italy after MenB. In this study we have estimated the reproductive numbers and the demographic reconstruction on the genomes of invasive N. meningitidis C:P1.5–1,10–8:F3–6:ST–11(cc11) strains isolated in Italy in 2012 – 2017, a period that includes the outbreak in Tuscany. MethodsThe genomes of N. meningitidis were sequenced using the Illumina MiSeq platform, through the whole genome sequencing (WGS) method and were analyzed by the core genome MLST (cgMLST) approach, using the BIGSdb Genome Comparator tool implemented on the PubMLST website. A Bayesian method was applied to study population dynamics across the entire N. meningitidis dataset. The basic reproduction number R0, which indicates the average number of secondary cases generated by a single primary case, was calculated using a Bayesian method, on the dataset and on the two subsets. The effective reproduction number R(t), defined as the average number of secondary cases per infectious case in a population, made up of susceptible and non-susceptible hosts was studied on the Tuscany dataset, with a Bayesian method. ResultsAn increase in the effective number of the N. meningitidis infections was observed between 2013 and 2016. The estimated R0 parameter was 1.31 (95% HPD: 1.03 – 1.64), 1.22 (95% HPD: 0.90 – 1.64) and 1.4 (95% HPD: 0.91 – 1.9) for the entire dataset, first and second subset, respectively. The BDSKY estimated an initial R(t) of about 2.0 (95% HPD: 0.04 – 5.0), which showed a growing trend at the end of 2014, reaching an average value of 3.22 in 2015, and then declining below 1 from the year 2016. ConclusionMonitoring the effective reproduction number can help to inform future vaccination strategies. The increase in the reproductive number for the Tuscany dataset, was consistent with the amplification event that led to the Tuscany outbreak. Subsequently, the intervention that led to the decline of the cases was followed, suggesting a high effectiveness of the vaccination campaign.

Characterization of invasive Neisseria meningitidis isolates recovered from children in Turkey during a period of increased serogroup B disease, 2013–2017

Diverse Neisseria meningitidis strains belonging to various serogroups and clonal complexes cause epidemic and endemic life-threatening disease worldwide. This study aimed to investigate the genetic diversity of recent invasive meningococci in Turkey with respect to multilocus sequence type (MLST) and also meningococcal serogroup B (MenB) vaccine antigens to enable assessment of potential MenB strain coverage using the genetic Meningococcal Antigen Typing System (gMATS). Fifty-four isolates, representing 37.5% of all pediatric (ages 0–18 years) invasive meningococcal disease cases in Turkey from January 2013 to December 2017, underwent genome sequence analysis. Thirty-six (66.7%) isolates were MenB, 10 (18.5%) were serogroup W (MenW), 4 (7.4%) were serogroup A (MenA), 3 (5.6%) were serogroup Y (MenY) and 1 (1.8%) was serogroup X (MenX). The MenB isolates were diverse with cc35 (19.4%), cc41/44 (19.4%) and cc32 (13.8%) as the most prevalent clonal complexes. The MenW isolates (n = 10) comprised cc11 (n = 5), ST-2754 (cc-unassigned; n = 4) and cc22 (n = 1). gMATS was indicative of high 4CMenB coverage (72.2–79.1%) of Turkish invasive MenB strains from pediatric patients. Strain coverage of several clonal complexes differed from that seen elsewhere in Europe highlighting the importance of performing local assessments and also the use of phenotypic methods, i.e. MATS, where possible. All of the isolates possessed in-frame fhbp alleles and so were potentially covered by MenB-fHbp. Continued surveillance is essential to guide recommendations for current and future vaccines as well as understanding changes in epidemiology.

Culture-Confirmed Invasive Meningococcal Disease in Canada, 2010 to 2014: Characterization of Serogroup B Neisseria meningitidis Strains and Their Predicted Coverage by the 4CMenB Vaccine.

The molecular epidemiology of culture-confirmed invasive meningococcal disease (IMD) in Canada from 2010 to 2014 was studied with an emphasis on serogroup B Neisseria meningitidis (MenB) isolates, including their predicted coverage by the 4CMenB vaccine. The mean annual incidence rates of culture confirmed IMD varied from 0.19/100,000 in Ontario to 0.50/100,000 in New Brunswick and 0.59/100,000 in Quebec. In both Quebec and Atlantic region, MenB was significantly more common than other serogroups, while in other provinces, both MenB and serogroup Y (MenY) were almost equally common. The majority of MenB cases (67.0%) were in those aged ≤24 years, while most MenC (75.0%) and MenY (69.6%) cases were in adults more than 24 years old. The 349 MenB isolates were grouped into 103 sequence types (STs), 90 of which belonged to 13 clonal complexes (CCs). A large number of 4CMenB antigen genes were found among the Canadian MenB, which is predicted to encode 50 factor H binding protein (fHbp) types, 40 NHBA types, and 55 PorA genotypes. Provinces and regions were found to have their own unique MenB STs. A meningococcal antigen typing system assay predicted an overall MenB coverage by 4CMenB to be 73.6%, with higher coverage predicted for the two most common STs: 100% for ST154 and 95.9% for ST269, leading to higher coverage in both the Atlantic region and Quebec. Higher coverage (81.4%) was also found for MenB recovered from persons aged 15 to 24 years, followed by strains from infants and children ≤4 years old (75.2%) and those aged 5 to 14 years (75.0%).IMPORTANCE Laboratory surveillance of invasive meningococcal disease (IMD) is important to our understanding of the evolving nature of the Neisseria meningitidis strain types causing the disease and the potential coverage of disease strains by the newly developed vaccines. This study examined the molecular epidemiology of culture-confirmed IMD cases in Canada by examining the strain types and the potential coverage of a newly licensed 4CMenB vaccine on Canadian serogroup B N. meningitidis strains. The strain types identified in different parts of Canada appeared to be unique as well as their predicted coverage by the 4CMenB vaccine. These data were compared to data obtained from previous studies done in Canada and elsewhere globally. For effective control of IMD, laboratory surveillance of this type was found to be essential and useful to understand the dynamic nature of this disease.

Deletion of major porins from meningococcal outer membrane vesicle vaccines enhances reactivity against heterologous serogroup B Neisseria meningitidis strains

Detergent-extracted detoxified outer membrane vesicle (dOMV) vaccines are effective at preventing invasive serogroup B meningococcal (MenB) disease caused by the homologous Neisseria meningitidis strain from which they are produced, but offer limited protection from heterologous strains. Differences in vaccine efficacy are partially due to strain-specific variations in the antigenic sequence types and expression levels of outer membrane proteins (OMPs), including the immunodominant OMP PorA. In this study, dOMV vaccines deficient in major OMPs, including PorA, PorB, and RmpM were isolated and used to immunize rabbits and mice. Serum samples were obtained from each animal and tested for antibody responses against five MenB strains. Immunization with wild type dOMVs elicited antibodies to major antigens including PorA, PorB, RmpM, and lipooligosaccharide (LOS), and demonstrated limited bactericidal activity against heterologous strains. In contrast, OMP-deficient dOMV vaccines elicited broadly cross-reactive bactericidal antibodies, with PorA/PorB-dual deficient dOMVs inducing antibodies exhibiting the greatest cross-reactivity. Enhanced killing of heterologous strains correlated with binding to unique protein bands in immunoblots, suggestive of improved immunogenicity of antigens under-represented in the wild type vaccine.

Susceptibility of invasive Neisseria meningitidis strains isolated in Germany to azithromycin, an alternative agent for post-exposure prophylaxis.

Post-exposure prophylaxis (PEP) for close contacts of invasive meningococcal disease (IMD) cases is recommended in most countries to avoid secondary cases by eradicating supposed meningococcal colonization. Currently, rifampicin, ciprofloxacin and ceftriaxone are recommended in many countries including Germany. Azithromycin has been shown to eradicate meningococcal colonization. To assess the azithromycin susceptibility of invasive Neisseria meningitidis isolates. A subset of German invasive meningococcal isolates from 2006-18 was selected for this study. Azithromycin MIC was determined using broth microdilution and agar gradient diffusion. Azithromycin MICs as determined by broth microdilution ranged from <0.003 to 2 mg/L (median 0.50 mg/L, Q75 1 mg/L). All isolates were susceptible to azithromycin according to the CLSI breakpoint (95% CI 0.0%-1.5%). There was no significant correlation between MICs determined by broth microdilution and agar gradient diffusion. Nevertheless, the two methods were consistent regarding the categorization of all isolates as susceptible. Azithromycin is an eligible antibiotic for PEP of IMD close contacts. It is approved for adults as well as children and may even be used in pregnancy. Because of easier application and lower toxicity, it might be an alternative to rifampicin and ciprofloxacin, as we found no resistant isolates. Since a gonococcal gene associated with elevated azithromycin MICs has been reported in N. meningitidis, careful monitoring of the emergence of resistant strains is nevertheless necessary for meningococci. Lack of concordance of MICs between broth microdilution and agar gradient diffusion needs to be considered.

Estimated susceptibility of Canadian meningococcal B isolates to a meningococcal serogroup B vaccine (MenB-FHbp)

BackgroundInvasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) remains a health risk in Canada and globally. Two MenB vaccines are now approved for use. An understanding of the genotype of Canadian strains and the potential strain coverage conferred by the MenB-FHbp vaccine is needed to inform immunization policies. MethodsSerogroup B Neisseria meningitidis strains responsible for meningococcal disease in Canada from 2006 to 2012 were collected as part of the Canadian Immunization Monitoring Program Active surveillance network. Genotypic analysis was done on MenB isolates from 2006 to 2012 with determination of fHbp surface expression for a subset of isolates: those occurring from 2010 to 2012. ResultsTwo clonal complexes (cc269 and cc41/44) were observed in 68.8% of the 276 isolates. A total of 50 different fHbp peptides were identified among isolates from 2006 to 2012. Surface expression of fHbp was detected on 95% of MenB isolates from 2010 to 2012 and 91% of isolates expressed fHbp at levels that are predicted to be susceptible to the bactericidal immune response elicited by the MenB-FHbp vaccine. Some regional differences were observed, particularly in isolates from British Columbia and Quebec. ConclusionThe majority of MenB isolates responsible for meningococcal disease in Canada expressed fHbp at levels predicted to be sufficient for complement mediated bactericidal activity in the presence of MenB-FHbp induced serum antibodies.

Comparison of Pathogenicity of Invasive and Carried Meningococcal Isolates of ST-4821 Complex in China.

Serotype 4821 (ST-4821) clonal complex (cc4821) Neisseria meningitidis strains are divided into two groups (groups I and II) according to the core genome-based phylogenetic analysis. Group I contains the greater number of invasive disease isolates. However, the differences in pathogenicity between the two groups are unclear. In this study, the pathogenicity of cc4821 isolates (n = 28) belonging to group I and group II (each containing eight invasive isolates and six isolates from healthy carriers) was investigated, including adhesion, invasion, and induction of interleukin-6 (IL-6) and interleukin-8 (IL-8) release from host cells (Hep2 and A549). The invasive isolates had higher adhesion and invasion capabilities than the carried isolates in both groups. The carried cc4821 isolates in group I had stronger invasion capability than those in group II. Invasive isolates induced more IL-6 and IL-8 secretion than carried isolates in both groups. The carried cc4821 isolates stimulated higher levels of IL-8 in group I than in group II. The isolates were defined as hyperadherent and hypoadherent groups according to their adhesion ability and as hyperinvasive and hypoinvasive groups based on their invasion ability. The hyperadherent and hyperinvasive isolates mediated more IL-6 and IL-8 release than the hypoadherent and hypoinvasive isolates. There was no difference in the level of cytokine release when cc4821 isolates lost their adhesion and invasion capability after lysis. The results revealed that differences in pathogenicity existed between the two groups and that the differences were mainly determined by differences in adhesion and invasion capabilities.

Increase in ST-11 serogroup W Neisseria meningitidis invasive meningococcal disease in Canada, 2016-2018.

Many countries have experienced increases in invasive meningococcal disease (IMD) due to a serogroup W Neisseria meningitidis (MenW) strain of the multilocus sequence type (ST)-11 clonal complex (CC). MenW ST-11 was first reported in Ontario, Canada, in 2014. By 2016, this strain caused IMD in five provinces and was responsible for 18.8% of the IMD cases in Canada. To provide an update on invasive MenW disease in Canada including the strain characteristics, specimen source of isolates, age, sex and geographic distribution of cases. N. meningitidis from culture-positive IMD cases are routinely submitted to the National Microbiology Laboratory (NML) for serogroup, serotype, serosubtype and sequence type analysis. The data from January 1, 2016 to December 31, 2018 were analyzed by calculating the proportion of IMD cases caused by MenW compared with other serogroups. In addition, trends based on age, sex and geographic distribution of cases and specimen source of isolates were analyzed based on information on specimen requisition forms. Over the 3-year period, 292 individual IMD case isolates were analyzed. The percentage of IMD case isolates typed as MenW more than doubled from 19% (n=15) to 44% (n=51) in 2018 when MenW became the most common serogroup, exceeded the number of MenB, MenC or MenY. In total, 93 MenW case isolates were identified, 91% (n=85) belonged to the ST-11 CC. The increase in MenW affected all age groups (but was most common in those older than 60) and both sexes, and occurred across the country but most prevalent in western Canada. The most common specimen source was blood. In 2018, MenW was the most common serogroup for isolates received by the NML from culture-positive IMD cases in Canada. Over 90% of the MenW serogroup isolates belonged to the ST-11 CC. The quadrivalent ACWY meningococcal conjugate vaccine protects against IMD caused by strains in the A, C, W or Y serogroups and therefore may protect against IMD caused by the new MenW ST-11 strain; however, more research is needed. The emergence of variant strains highlight the importance of strain characterization in IMD surveillance and research.