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International audience; Neisseria meningitidis serogroup B is the most prevalent cause of invasive meningococcal disease in Europe and members of laboratories working on meningococci are at risk due to frequent handling. Recommendation for anti-meningococcal vaccination among these workers has been recently updated upon the licensure in Europe of Bexsero® vaccine. We tested the immunogenicity and safety of this vaccine among adults laboratory staff using the recommended schedule of 2 doses at 5 weeks interval. The vaccine was well tolerated in spite of frequent local side effects and all participants reported at least one side effect after each dose. Immunogenicity was evaluated 6 weeks and one year after the second dose. All participants showed increase in their bactericidal titers against the components of the vaccine 6 weeks after the second dose, however titers declined significantly one year later.

International audience

International audience; We identified the genes encoding the proteins for the transport of glucose and maltose in Neisseria meningitidis strain 2C4-3. A mutant deleted for NMV_1892(glcP) no longer grew on glucose and deletion of NMV_0424(malY) prevented the utilization of maltose. We also purified and characterized glucokinase and α-phosphoglucomutase, which catalyze early catabolic steps of the two carbohydrates. N. meningitidis catabolizes the two carbohydrates either via the Entner-Doudoroff (ED) pathway or the pentose phosphate pathway, thereby forming glyceraldehyde-3-P and either pyruvate or fructose-6-P, respectively. We purified and characterized several key enzymes of the two pathways. The genes required for the transformation of glucose into gluconate-6-P and its further catabolism via the ED pathway are organized in two adjacent operons. N. meningitidis also contains genes encoding proteins which exhibit similarity to the gluconate transporter (NMV_2230) and gluconate kinase (NMV_2231) of Enterobacteriaceae and Firmicutes. However, gluconate might not be the real substrate of NMV_2230 because N. meningitidis was not able to grow on gluconate as the sole carbon source. Surprisingly, deletion of NMV_2230 stimulated growth in minimal medium in the presence and absence of glucose and drastically slowed the clearance of N. meningitidis cells from transgenic mice after intraperitoneal challenge.

International audience; الخلاصة: تعتبر النيسرية السحائية - أحد الأسباب الرئيسية لالتهاب السحايا الجرثومي وغيره من الأمراض المُعدية الخطيرة - مسؤولة عن حوالي ثلث حالات التهاب السحايا الجرثومي في مستشفى الأطفال بمدينة تونس. وقد حُدِّد توزع المجموعات المصلية، والحساسية للمضادات الحيوية، والمميزات المستضدية والجزيئية، للنيسرية السحائية المعزولة من مرضى تتراوح أعمارهم بين 3 أيام و 13 عاماً في الفترة ما بين فبراير/شباط 1998 ويونيو/حزيران 2013. لقد تم عزل 107 سلالات غازية للنيسيرية السحائية. وشوهد انخفاض في الحساسية للبنسلين G لدى %55.7 من المعزولات، مع تدني مستوى المقاومة في جميع الحالات؛ كما أظهرت %28.4 مستوى متدنياً من المقاومة للأموكسيسيلين. وكانت السلالات المعزولة للمجموعة المصلية B الأكثرَ شيوعاً (%80.4)، تليها المجموعة المصلية C (%12.2) و A (%5.6). وكان لمعزولات المجموعة المصلية A نفس الصيغة المستضدية (A:4:P1.9)، ونفس النواحي المتغيرة VR1 و VR2 و VR3، وتنتمي إلى نفس المجمع النسيلي (CC5). وكانت معزولات المجموعتين المصليتين B و C أكثر تغايراً وذات صيغ مستضدية متعددة. وكان المجمع النسيلي الأكثر شيوعاً في هذه السلالات CC35. وقد استأثرت المجموعة المصلية B بنسبة مئوية كبيرة من معزولاتنا، مع وجود تنوع ملحوظ.; Neisseria meningitidis, a leading cause of bacterial meningitis and other serious infections, is responsible for approximately one-third of cases of bacterial meningitis in the Children's Hospital of Tunis. The serogroup distribution, antibiotic susceptibility and antigenic and molecular characteristics of N. meningitidis isolates were determined in patients aged 3 days-13 years between February 1998 and June 2013. In all 107 invasive strains of N. meningitidis were isolated. Reduced susceptibility to penicillin G was seen in 55.7% of isolates, with a low level of resistance in all cases; 28.4% showed a low level of resistance to amoxicillin. Serogroup B isolates were the most frequent (80.4%), followed by serogroups C (12.2%) and A (5.6%). Isolates of serogroup A had the same antigenic formula (A:4:P1.9), the same variable regions VR1, VR2 and VR3, and belonged to the same clonal complex (CC5). Isolates of serogroups B and C were more heterogeneous with several antigenic formulae. The most frequent clonal complex in these isolates was CC35. Serogroup B accounted for a large percentage of our isolates with marked diversity.; La bactérie Neisseria meningitidis, l'une des causes principales de méningite bactérienne et d'autres infections graves, est responsable d'environ un tiers des cas de méningite bactérienne à l'Hôpital d'enfants de Tunis. La distribution par sérogroupe, la sensibilité aux antibiotiques et les propriétés antigéniques et moléculaires des isolats de N. meningitidis ont été déterminées chez des patients âgés de 3 jours à 13 ans entre février 1998 et juin 2013. En tout, 107 souches invasives de N. meningitidis ont été isolées. Une sensibilité réduite à la pénicilline G a été observée dans 55,7 % des isolats, avec un bas niveau de résistance pour tous les cas ; et 28,4 % ont montré un bas niveau de résistance à l'amoxicilline. Les isolats du sérogroupe B étaient les plus fréquents (80,4 %), suivis par les sérogroupes C (12,2 %) et A (5,6 %). Les isolats du sérogroupe A avaient la même formule antigénique (A:4:P1.9), les mêmes régions variables VR1, VR2 et VR3, et appartenaient au même complexe clonal (CC5). Les isolats des sérogroupes B et C étaient davantage hétérogènes, avec plusieurs formules antigéniques. Le complexe clonal le plus fréquent de ces isolats était CC35. Le sérogroupe B comptait pour un pourcentage élevé des isolats avec une diversité marquée.

Differential modulation of NF-κB during meningococcal infection is critical in innate immune response to meningococcal disease. Non-invasive isolates of Neisseria meningitidis provoke a sustained NF-κB activation in epithelial cells. However, the hyperinvasive isolates of the ST-11 clonal complex (ST-11) only induce an early NF-κB activation followed by a sustained activation of JNK and apoptosis. We show that this temporal activation of NF-κB was caused by specific cleavage at the C-terminal region of NF-κB p65/RelA component within the nucleus of infected cells. This cleavage was mediated by the secreted 150 kDa meningococcal ST-11 IgA protease carrying nuclear localisation signals (NLS) in its α-peptide moiety that allowed efficient intra-nuclear transport. In a collection of non-ST-11 healthy carriage isolates lacking NLS in the α-peptide, secreted IgA protease was devoid of intra-nuclear transport. This part of iga polymorphism allows non-invasive isolates lacking NLS, unlike hyperinvasive ST-11 isolates of N. meningitides habouring NLS in their α-peptide, to be carried asymptomatically in the human nasopharynx through selective eradication of their ability to induce apoptosis in infected epithelial cells., Author Summary Strains of Neisseria meningitidis isolated from patients induce apoptotic cell death, whereas strains isolated from healthy carriage isolates do not. Part of the difference has been shown to arise from differential modulation of NF-κB during meningococcal infection. While non-invasive isolates of Neisseria meningitidis provoke a sustained NF-κB activation in epithelial cells, hyperinvasive isolates only induce an early NF-κB activation followed by a sustained activation of JNK and apoptosis. Here, we elucidate the mechanism conferring this differential modulation, specifically showing that ST-11 hyperinvasive isolates promote specific cleavage of NF-κB p65/RelA component in a manner dependent on the secreted IgA protease. This cleavage occurs within the nuclear compartment. Secreted IgA protease from non-invasive isolates was unable to reach the nuclear compartment of infected cells, resulting in a sustained activation of NF-κB activity and subsequent cytoprotective effect. Modulation of NF-κB-related signaling is likely a double-edged sword to decide the fate of meningococcal infection.

International audience

Neisseria meningitidis or meningococcus is divided into 12 distinct serogroups of which A, B, C, W, X, and Y are medically most important and cause health problems in different parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. Globally, serogoup A has been prevalent in the African meningitis belt whereas serogroup B and C have predominated in Europe. In a paper published earlier in this journal(1), an increase in serogroup Y invasive meningococcal disease (IMD) in some European countries was reported based on the epidemiological data for 2010, 2011 and 2012. Here, we report additional data from 30 European countries indicating that high or increased serogroup Y disease levels have continued in 2013 in certain regions of Europe. In the Western and Central Europe, there were no major changes in the proportion of serogroup Y IMD cases in 2013 compared to 2012. In the Scandinavian countries, proportion of serogroup Y disease remained high, ranging from 26% to 51% in 2013. This was in contrast to Baltic, Eastern and most Southern European countries, where the proportion of serogroup Y IMD was low similarly to previous years. For the last 2 decades, the mean age of patients affected by serogroup Y was 41 y for 7 countries from which data was available and 50% of cases were in patients aged 45 to 88 y. The age distribution of serogroup Y was bimodal and did not change significantly despite the increase of the total number and the proportion of serogroup Y IMD in some European regions.

International audience; BackgroundFor the past 20 years, three vaccines against the three main bacterial species implicated in meningitis in children have been included in the French vaccine calendar: Haemophilus influenzae b in 1993, 7-valent pneumococcal conjugate vaccine (PCV7) in 2003 (replaced by 13-valent in 2010) and Neisseria meningitidis C in 2009. The French active surveillance network from the GPIP/ACTIV monitors the change in the epidemiological, clinical, and biological features of bacterial meningitis due to vaccine use.MethodsOver a 12-year period, 233 pediatric wards working with 168 microbiology departments throughout France were asked to report all cases of bacterial meningitis.ResultsFrom January 2001 to December 2012, 4808 bacterial meningitis cases were reported. Between 2001 and 2012, the number of pneumococcal meningitis (PM) cases decreased by 23.4%, and by 32.2% for children less than 2 years old. During this period, the proportion of cases attributable to PCV7 and six additional PCV13 types decreased from 63.3% to 8.1% and 83.7% to 32.4%, respectively. In 2012, the main vaccine types (accounting for 25.8% of cases) were 7F (12.2%), 19A (6.8%), and 19F (6.8%), and the most frequent non-vaccine types were 12F (14.9%), 24F (14.9%), 15B/C (6.8%), 22F (6.8%), and 10A (5.4%). In 2012, the rate of strains with decreased susceptibility to cefotaxime/ceftriaxone (MIC > 0.5 μg/mL) represented less than 3% of cases, with no identified resistant strain since 2010 (MIC > 2 μg/mL). Between 2001 (n = 67) and 2012 (n = 9), the number of NmC meningitis cases decreased by 87%.ConclusionWith more than 4800 bacterial meningitis cases reported in 12 years, this nationwide survey provides essential information on the microbiological and clinical characteristics of bacterial meningitis (epidemiology or resistance data). These results could lead to changing antibiotic treatment of pneumococcal meningitis before the results of antibiotic susceptibility tests.; ObjectifsDepuis 20 ans, 3 vaccins dirigés contre les 3 principales espèces bactériennes impliquées dans les méningites font parties du calendrier vaccinal recommandé en France : Haemophilus influenzae sérotype b en 1993, pneumocoque conjugué heptavalent (PCV7) en 2003 (remplacé par le PCV13 en 2010) et méningocoque C en 2009. L’observatoire national des méningites bactériennes de l’enfant du Groupe de pathologie infectieuse pédiatrique et de l’Association clinique et thérapeutique infantile du Val-de-Marne (GPIP/ACTIV) a pour objectif de suivre les changements induits par les vaccinations en colligeant l’épidémiologie bactérienne et les données anamnestiques, cliniques, biologiques et évolutives des méningites bactériennes de l’enfant.MéthodesDeux cent trente-trois services de pédiatrie et 168 services de microbiologie ont inclus depuis 12 ans tous les patients de moins de 18 ans ayant eu une méningite bactérienne documentée.RésultatsDe 2001 à 2012, 4808 méningites ont été documentées. Le nombre de méningites à pneumocoque (MP) a diminué de 23,4 % et chez les enfants de moins de 2 ans de 32,2 %. La proportion des sérotypes (ST) du PCV7 a diminué de 63,3 % en 2001 à 8,1 % en 2012 (p < 0,0001) et les ST du PCV13 ont diminué de 83,7 à 32,4 % sur la même période (p < 0,0001). En 2012, les ST vaccinaux les plus fréquents étaient 7F (12,2 %), 19A (6,8 %) et 19F (6,8 %) ; ils représentaient 25,8 % des cas de MP. Les sérotypes non vaccinaux les plus fréquents étaient 12F (14,9 %), 24F (14,9 %), 15B/C (6,8 %), 22F (6,8 %) et 10A (5,4 %). En 2012, les souches intermédiaires aux céphalosporines de 3e génération représentaient moins de 3 % des cas. Aucune souche résistante aux céphalosporines de 3e génération (C3G) n’a été isolée depuis 2010. Entre 2001 (n = 67) et 2012 (n = 9), le nombre de méningite à méningocoque C a diminué de 87 %.ConclusionAvec plus de 4800 méningites bactériennes recueillies en 12 ans, l’observatoire est un outil indispensable de surveillance des modifications épidémiologiques et de la résistance aux antibiotiques des bactéries impliquées dans les méningites de l’enfant. Les données actuelles sont en faveur d’une modification de la stratégie de prise en charge des méningites suspectées à pneumocoque.

New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed, with some being licensed in Europe. Coverage depends on the distribution of disease-associated genotypes, which may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease, and these lineages are associated with particular antigens, including vaccine candidates. A collection of 4,048 representative meningococcal disease isolates from 18 European countries, collected over a 3-year period, were characterized by multilocus sequence typing (MLST). Age data were available for 3,147 isolates. The proportions of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age groups. Subjects

New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed, with some being licensed in Europe. Coverage depends on the distribution of disease-associated genotypes, which may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease, and these lineages are associated with particular antigens, including vaccine candidates. A collection of 4,048 representative meningococcal disease isolates from 18 European countries, collected over a 3-year period, were characterized by multilocus sequence typing (MLST). Age data were available for 3,147 isolates. The proportions of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age groups. Subjects = 25-year-olds were more likely to experience disease due to less common ccs and unassigned STs. Younger and older subjects were vulnerable to a more diverse set of genotypes, indicating the more clonal nature of genotypes affecting adolescents and young adults. Knowledge of temporal and spatial diversity and the dynamics of meningococcal populations is essential for disease control by vaccines, as coverage is lineage specific. The nonrandom 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.