[show abstract][hide abstract] ABSTRACT: New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed with some being licenced in Europe. Coverage will depend on the distribution of disease-associated genotypes and this may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease and they are associated with particular antigens including vaccine candidates. A collection of 4048 representative meningococcal disease isolates from 18 European countries collected over a three year period were characterised by multilocus sequence typing (MLST). Age data was available for 3147 isolates. The proportion of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age-groups. Those aged under one experienced lower risk of ST-11cc, ST-32cc and ST-269cc disease and higher risk of disease due to unassigned sequence types (STs); 1-4 year olds experienced lower risk of ST-11cc and ST-32cc disease; 5-14 year olds were less likely to experience ST-11cc and ST-269cc disease; those aged 25 years or above were more likely to experience disease due to less common ccs and unassigned STs. The younger and older ends of the spectrum were vulnerable to a more diverse set of genotypes indicating the more clonal nature of genotypes affecting adolescents/young adults. Knowledge of temporal and spatial diversity and dynamics of meningococcal populations is essential for disease control by vaccines as coverage is lineage-specific. The non-random age distribution of hyperinvasive lineages has consequences for the design and implementation of vaccines as different variants or perhaps targets may be required for different age groups.
Clinical and vaccine Immunology: CVI 04/2014; · 2.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Since the introduction of monovalent meningococcal serogroup C (MenC) glycoconjugate (MCC) vaccines and the implementation of national vaccination programmes, the incidence of MenC disease has declined markedly as a result of effective short-term vaccination and reduction in acquisition of MenC carriage leading to herd protection. Monovalent and quadrivalent conjugate vaccines are commonly used vaccines to provide protection against MenC disease worldwide. Studies have demonstrated that MCC vaccination confers protection in infancy (0-12 months) from the first dose but this is only short-term. NeisVac-C(®) has the greatest longevity of the currently licensed MCC vaccines in terms of antibody persistence, however antibody levels have been found to fall rapidly after early infant vaccination with two doses of all MCC vaccines - necessitating a booster at ∼12 months. In toddlers, only one dose of the MCC vaccine is required for routine immunization. If herd protection wanes following catch-up campaigns, many children may become vulnerable to infection. This has led many to question whether an adolescent booster is also required.
[show abstract][hide abstract] ABSTRACT: The Global Meningococcal Initiative (GMI) is an international group of scientists and clinicians with expertise in meningococcal disease (MD). It promotes MD prevention through education and research. Given geographic differences in disease epidemiology, prevention strategies (e.g., vaccination) should be country-specific to ensure local needs are met. However, regional policies/recommendations and standardized disease diagnostic criteria should be implemented to improve surveillance and control strategies, and allow for more robust data comparisons. Consequently, the GMI convened a meeting with Latin American representatives to discuss the burden of MD and vaccination practices/policies, and consider if the global GMI recommendations could be tailored. The group determined that as robust, uniform epidemiologic data are required to make informed health-policy decisions, it would be useful to first summarize the regional situation herein (including disease surveillance, case definitions, epidemiology, vaccination and outbreak control strategies) and then determine a consensus-based meningococcal case definition for use throughout the region.
Expert Review of Vaccines 08/2013; · 4.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND:: Recombinant vaccines containing factor H binding protein (fHBP) have been developed for the purpose of protection from invasive meningococcal serogroup B (MnB) disease. Neisseria meningitidis fHBP sequences can be divided into two genetically and immunologically distinct subfamilies (A and B); thus, cross protection is conferred within but not between subfamilies. A comprehensive understanding of fHBP epidemiology is required to accurately assess the potential vaccine impact when considering different vaccination implementation strategies. METHODS:: Systematically collected invasive MnB isolates from England, Wales, Northern Ireland, the United States, Norway, France, and the Czech Republic were previously characterized for fHBP sequence. The current study expanded this evaluation with additional MnB disease isolates from Spain (n=346) and Germany (n=205). This expanded set (n=1841), collected over a six-year period (2001-2006), was evaluated for fHBP sequence and fHBP subfamily relative to patient age. RESULTS:: All 1841 isolates contained fhbp. fHBP sequences from Spain and Germany fell within the previously described subfamilies, with 69% of isolates belonging to subfamily B and 31% to subfamily A; prevalent sequence variants were also similar. Stratification of data by age indicated that disease in infants < 1 year of age was caused by a significantly higher proportion of isolates with fHBP subfamily A variants than that seen in adolescents and young adults 11-25 years (47.7% vs. 19.5%, p<0.0001), respectively. CONCLUSIONS:: These observations highlight a difference in epidemiology of fHBP subfamilies in different age groups, with fHBP subfamily A strains causing more disease in vulnerable populations, such as infants, than in adolescents.
The Pediatric Infectious Disease Journal 05/2013; · 3.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Novartis Vaccines and Diagnostics.
The Lancet Infectious Diseases 02/2013; · 19.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sequence data of meningococcal gyrA gene, MIC values and mice infection were used to define the breakpoint for ciprofloxacinin Neisseria meningitidis. Residue T91 or D95 of GyrA was altered in all meningococcal isolates with MIC≥0.064 μg/ml but not among isolates displaying MIC≤0.032 μg/ml. Experimental infection in ciprofloxacin-treated mice showed slower bacterial clearance when GyrA was altered. These data suggest MIC≥0.064 μg/ml as the ciprofloxacin breakpoint for meningococci and argue for molecular detection of ciprofloxacin resistance.
Antimicrobial Agents and Chemotherapy 01/2013; · 4.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: The meningococcal antigen typing system (MATS) sandwich enzyme-linked immunosorbent assay (ELISA) was designed to measure the immunologic cross-reactivity and quantity of antigens in target strains of a pathogen. It was first used to measure the factor H-binding protein (fHbp), neisserial adhesin A (NadA), and neisserial heparin-binding antigen (NHBA) content of serogroup B meningococcal (MenB) isolates relative to a reference strain, or "relative potency" (RP). With the PorA genotype, the RPs were then used to assess strain coverage by 4CMenB, a multicomponent MenB vaccine. In preliminary studies, MATS accurately predicted killing in the serum bactericidal assay using human complement, an accepted correlate of protection for meningococcal vaccines. A study across seven laboratories assessed the reproducibility of RPs for fHbp, NadA, and NHBA and established qualification parameters for new laboratories. RPs were determined in replicate for 17 MenB reference strains at laboratories A to G. The reproducibility of RPs among laboratories and against consensus values across laboratories was evaluated using a mixed-model analysis of variance. Interlaboratory agreement was very good; the Pearson correlation coefficients, coefficients of accuracy, and concordance correlation coefficients exceeded 99%. The summary measures of reproducibility, expressed as between-laboratory coefficients of variation, were 7.85% (fHbp), 16.51% (NadA), and 12.60% (NHBA). The overall within-laboratory measures of variation adjusted for strain and laboratory were 19.8% (fHbp), 28.8% (NHBA), and 38.3% (NadA). The MATS ELISA was successfully transferred to six laboratories, and a further laboratory was successfully qualified.
[show abstract][hide abstract] ABSTRACT: Current concepts of vaccines against serogroup B meningococci (MenB) are mainly based on genetically variable protein antigens. Vaccine efficacy studies for meningococcal disease in developed countries are hampered by the low incidence. Licensure must therefore exclusively rely on clinical trials and laboratory investigation of meningococcal strains. In contrast to capsule polysaccharide vaccines, serum bactericidal assays for technical reasons are limited in their practicability as the surrogate of protection provided by MenB vaccines. Therefore, assays are required for reliable laboratory based assessment of expression of those specific antigen variants that are predicted to be targeted by bactericidal antibodies elicited by the vaccine. The MATS ELISA (MATS, meningococcal antigen typing system) reported recently is an example for such an assay. The paper discusses the pre- and post-licensure application of MATS, the role of reference laboratories, concepts of sustained provision of the assay, external quality assessment, and laboratory twinning.
[show abstract][hide abstract] ABSTRACT: The Global Meningococcal Initiative (GMI) is composed of an international group of scientists, clinicians and public health officials with expertise in meningococcal immunology, epidemiology and prevention. The primary goal of the GMI is the promotion of the global prevention of invasive meningococcal disease through education and research. The GMI members reviewed global meningococcal disease epidemiology, immunization strategies, and research needs. Over the past decade, substantial advances in meningococcal vaccine development have occurred and much has been learned about prevention from countries that have incorporated meningococcal vaccines into their immunization programs. The burden of meningococcal disease is unknown for many parts of the world because of inadequate surveillance, which severely hampers evidence-based immunization policy. As the field of meningococcal vaccine development advances, global surveillance for meningococcal disease needs to be strengthened in many regions of the world. For countries with meningococcal vaccination policies, research on vaccine effectiveness and impact, including indirect effects, is crucial for informing policy decisions. Each country needs to tailor meningococcal vaccination policy according to individual country needs and knowledge of disease burden. Innovative approaches are needed to introduce and sustain meningococcal vaccination programs in resource-poor settings with a high incidence of meningococcal disease.
[show abstract][hide abstract] ABSTRACT: To analyze the profile of antimicrobial susceptibility of meningococcal disease isolates collected throughout Brazil from 2006 to 2008 and forwarded to the National Reference Laboratory for Meningitis, Institute Adolfo Lutz - São Paulo.
The MIC to penicillin, ampicillin, chloramphenicol, ceftriaxone, ciprofloxacin and rifampicin was determined in a sample of 1096 (55% of the total isolates received) randomly chosen using the broth microdilution procedure. The breakpoints used were those recommended by the European Monitoring Group on Meningococci (EMGM).
Decreased susceptibility to penicillin and ampicillin was detected in 13% and 12.9% respectively. All isolates were susceptible to chloramphenicol, ceftriaxone, and ciprofloxacin. Two strains (0.2%) showed high resistance to rifampicin and 0.5% of the isolates displayed intermediate resistance to rifampicin.
The meningococcal strains isolated in Brazil during 2006-2008 were globally susceptible to all antibiotics currently used in treatment or chemoprophylaxis of meningococcal disease in Brazil.
[show abstract][hide abstract] ABSTRACT: The mtr gene complex in Neisseria meningitidis encodes an efflux pump that is responsible for export of antibacterial hydrophobic agents. The promoter region of the mtrCDE operon harbours an insertion sequence known as a Correia element, and a binding site for the integration host factor (IHF) is present at the centre of the Correia element. It has been suggested that the expression of the mtrCDE operon in meningococci is subject to transcriptional regulation by the IHF and post-transcriptional regulation by cleavage in the inverted repeat of the Correia element. The promoter region of the mtrCDE operon as well as the association of changes at that point with decreased susceptibility to antimicrobial drugs in 606 Neisseria meningitidis strains were analysed in this study. Two different deletions were present in the analysed region. The first one, found in seven strains, corresponded to absence of the Correia element. The second one, affecting the -10 region and first 100 bp of the mtrR gene and present in 57 isolates, was only found in ST-1624 isolates. None of the deletions were associated with decreased susceptibility to antimicrobial drugs. Although most of the meningococcal strains carry the Correia element at that position, its deletion is not an exception.
Journal of Medical Microbiology 09/2010; 59(Pt 9):1055-60. · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Identification of clinical isolates of Neisseria meningitidis that are resistant to rifampin is important to avoid prophylaxis failure in contacts of patients, but it is hindered by the absence of a breakpoint for resistance, despite many efforts toward standardization. We examined a large number (n = 392) of clinical meningococcal isolates, spanning 25 years (1984 to 2009), that were collected in 11 European countries, Argentina, and the Central African Republic. The collection comprises all clinical isolates with MICs of > or = 0.25 mg/liter (n = 161) received by the national reference laboratories for meningococci in the participating countries. Representative isolates displaying rifampin MICs of < 0.25 mg/liter were also examined (n = 231). Typing of isolates was performed, and a 660-bp DNA fragment of the rpoB gene was sequenced. Sequences differing by at least one nucleotide were defined as unique rpoB alleles. The geometric mean of the MICs was calculated for isolates displaying the same allele. The clinical isolates displaying rifampin MICs of > 1 mg/liter possessed rpoB alleles with nonsynonymous mutations at four critical amino acid residues, D542, H552, S548, and S557, that were absent in the alleles found in all isolates with MICs of < or = 1 mg/liter. Rifampin-susceptible isolates could be defined as those with MICs of < or = 1 mg/liter. The rpoB allele sequence and isolate data have been incorporated into the PubMLST Neisseria database (http://pubmlst.org/neisseria/). The rifampin-resistant isolates belonged to diverse genetic lineages and were associated with lower levels of bacteremia and inflammatory cytokines in mice. This biological cost may explain the lack of clonal expansion of these isolates.
Antimicrobial Agents and Chemotherapy 09/2010; 54(9):3651-8. · 4.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: One Neisseria gonorrhoeae strains highly resistant to azithromycin AzHLR (MIC >2048 mg/L) was isolated in Argentina in 2001 and it has been characterized by N. gonorrhoeae multiantigen sequence typing (NG-MAST) as ST696, suggesting a different event to other isolates in Europe. Neither, mtrR mutations or presence of mef gene were detected.
[show abstract][hide abstract] ABSTRACT: To improve the understanding of serogroup Y invasive meningococcal disease (IMD) in Latin America, particularly IMD molecular epidemiology; 166 Y serogroup isolates received at the National Reference Laboratories of Argentina, Brazil, Chile, Colombia, and Costa Rica during 2000-2006 were characterized by their molecular markers.
This analysis included serological assays to determine serogroup/serotype/serosubtype, DNA sequencing and genotyping of the porB and/or porA genes, multilocus sequence typing (MLST) and fetA allele determination.
Sixteen different antigenic combinations were observed. Sixty-two (37.3%) isolates were NT:P1.5 and 36 (21.7%) isolates were 14:NST. Thirty-two different STs appeared, but 3 STs (ST-1624, ST-23, and ST-5770) accounted for 69.9% (116) of the strains. Most of the IMD isolates belonged to the ST-23, ST-167 clonal complexes or the group composed by ST-5770 and related STs.
Isolates obtained in Colombia and Costa Rica were similar to that of the United States, in that most sequence types belonged to the ST-23 clonal complex. IMD isolates found in Argentina appear to be the result of an independent event and did not spread from nearby countries, being the sequence type ST-1624 (ST-167 clonal complex) the most frequently found. We were unable to correlate an antigenic shift of outer membrane proteins with an increase of serogroup Y meningococcal cases in our collection of isolates.
The Journal of infection 07/2009; 59(2):104-14. · 4.13 Impact Factor