Community-acquired bacterial meningitis in adults: in-hospital prognosis, long-term disability and determinants of outcome in a multicentre prospective cohort.

OBJECTIVES: To identify factors associated with unfavourable in-hospital outcome (death or disability) in adults with community-acquired bacterial meningitis (CABM). METHODS: In a prospective multicentre cohort study (COMBAT; February 2013 to July 2015), all consecutive cases of CABM in the 69 participating centres in France were enrolled and followed up for 12 months. Factors associated with unfavourable outcome were identified by logistic regression and long-term disability was analysed. RESULTS: Among the 533 individuals enrolled, (Streptococcus pneumoniae 53.8% (280/520 isolates identified), Neisseria meningitidis 21.3% (111/520), others 24.9% (129/520)), case fatality rate was 16.9% (90/533) and unfavourable outcome occurred in 45.0% (225/500). Factors independently associated with unfavourable outcome were: age >70 years (adjusted odds ratio (aOR) 4.64; 95% CI 1.93-11.15), male gender (aOR 2.11; 95% CI 1.25-3.57), chronic renal failure (aOR 6.65; 95% CI 1.57-28.12), purpura fulminans (aOR 4.37; 95% CI 1.38-13.81), localized neurological signs (aOR 3.72; 95% CI 2.29-6.05), disseminated intravascular coagulation (aOR 3.19; 95% CI 1.16-8.79), cerebrospinal fluid (CSF) white-cell count <1500 cells/µL (aOR 2.40; 95% CI 1.42-4.03), CSF glucose concentration (0.1-2.5 g/L: aOR 1.92; 95% CI 1.01-3.67; <0.1 g/L: aOR 2.24; 95% CI 1.01-4.97), elevated CSF protein concentration (aOR 1.09; 95% CI 1.03-1.17), time interval between hospitalization and lumbar puncture >1 day (aOR 2.94; 95% CI 1.32-6.54), and S. pneumoniae meningitis (aOR 4.99; 95% CI 1.98-12.56), or meningitis other than N. meningitidis (aOR 4.54; 95% CI 1.68-12.27). At 12 months, 26.7% (74/277) had hearing loss, 32.8% (87/265) depressive symptoms, 31.0% (86/277) persistent headache, and 53.4% had a physical health-related quality of life (142/266) <25th centile of the distribution of the score in the general French population (p < 0.0001). CONCLUSIONS: The burden of CABM (death, disability, depression, impaired quality of life and hearing loss) is high. Identification of cases from the first symptoms may improve prognosis. CLINICALTRIAL: Gov identification number: NCT01730690.

Cluster of serogroup W invasive meningococcal disease in a university campus.

INTRODUCTION: In France, the expansion of an hypervirulent strain causing serogroup W invasive meningococcal disease (MenW) has been observed since 2015/16. We describe a cluster of three MenW cases, causing two deaths, at the end of 2016 in a university campus, and the vaccination campaign which was consequently organized. METHODS: Epidemiological and microbiological analyses led a multidisciplinary expertise group to recommend the organization of a mass vaccination campaign using ACWY vaccine targeting more than 30,000 students and staff in the university campus. Individual data on vaccination was collected using the lists of students and staff registered at the university to estimate vaccine coverage. RESULTS: Three MenW cases occurred within a 2-month period among students in different academic courses. All three isolates were identical and belonged to the "UK-2013 strain" phylogenetic branch. The attack rate was 10.8/100,000 students. The vaccination campaign was organized only 15 days after the third case occurred. In total, 13,198 persons were vaccinated. Vaccine coverage was estimated at 41% for students of the university and 35% for university staff. CONCLUSION: Timely notification of cases to health authorities was essential for the detection of the cluster and the rapid implementation of the vaccination campaign. No further cases occurred in the campus in the year following the vaccination campaign. This episode is the second cluster of MenW caused by the "UK-2013 strain" in a university since 2016.

Phenotypic and genotypic characterization of meningococcal isolates in Tunis, Tunisia: High diversity and impact on vaccination strategies.

OBJECTIVES: The aim of this study was to characterize Neisseria meningitidis (Men) isolates in Tunisian paediatric patients with invasive meningococcal disease (IMD) in order to target therapeutic and preventive strategies. METHODS: Fifty-nine isolates of Men and four cerebrospinal fluid samples that were culture-negative but Men-positive by PCR (NC-MenPPCR) (2009-2016) were collected from IMD patients. Isolates were analysed for their antimicrobial susceptibility. Whole-genome sequencing (WGS) was used to characterize isolates and multilocus sequence typing for NC-MenPPCR. Coverage of Men serogroup B (MenB) was determined by Genetic Meningococcal Antigen Typing System (gMATS) and fHbp expression by ELISA. RESULTS: MenB was the predominant type (88.9%). The majority of isolates (81%) had reduced susceptibility to penicillin G with altered penA alleles. The clonal complex CC461 (27.1%) was the most frequent. Among the MenB vaccine targets neisserial heparin binding antigen (NHBA) and fHbp, the predominant variants were NHBA118 (30.8%) and fHbp peptide 47 (25%), respectively. The nadA gene was present in 17.3% of isolates. Using gMATS, 36.5% of MenB were predicted to be covered by the 4CMenB vaccine. ELISA showed that 92.4% of the MenB were expected to be killed by anti-fHbp antibodies. CONCLUSIONS: MenB was the leading serogroup in IMD, and more than 90% had a sufficient level of fHbp expression for vaccine coverage. The study results will be useful for the Tunisian vaccination programme.

Identification of Neisseria meningitidis by MALDI-TOF MS may not be reliable.

OBJECTIVES: The matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) technique is increasingly used in hospital laboratories for routine identification of microorganisms. However, its performance is variable, particularly for highly variable species such as Neisseria meningitidis. Reliable identification of N. meningitidis is crucial for the management of invasive meningococcal disease by rapid implementation of treatment and preventive measures among close contacts. We assessed and improved N. meningitidis identification by MALDI-TOF MS by enriching the databases with reference strains identified using whole genome sequencing (WGS) as a reference standard. METHODS: We first built a collection of 24 strains from several species of the Neisseria genus that we characterized by WGS. This collection was added to the available database to test by MALDI-TOF MS another collection of 32 clinical isolates received between 2015 and 2017 at the French National Reference Laboratory for Meningococci. RESULTS: Using the commercially available library of mass spectrometry profiles, only 67% (95% confidence interval (CI), 47-82) concordance was observed at the species level between MALDI-TOF MS and WGS characterization. However, when the new enriched reference collection was used on the second subset of isolates, the identification of N. meningitidis was significantly improved (p 0.0016), showing 92% (95% CI, 75-98) specificity while that of the manufacturer's database alone was 52% (95% CI, 34-70). CONCLUSIONS: Our data highlight the need to update the available MALDI-TOF MS database with high-quality references to enhance the identification of N. meningitidis and avoid unwarranted preventive measures or missing identification.

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.

Characterization of invasive Neisseria meningitidis strains isolated at the Children's Hospital of Tunis, Tunisia.

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.

Global Meningococcal Initiative: guidelines for diagnosis and confirmation of invasive meningococcal disease.

The Global Meningococcal Initiative (GMI) is an international group of scientists and clinicians with recognized expertise in meningococcal disease including microbiology, immunology, epidemiology, public health and vaccinology. The GMI was established to promote the global prevention of meningococcal disease through education, research and international cooperation. The GMI held its second summit meeting in 2013 to discuss the different aspects of existing meningococcal immunization programmes and surveillance systems. Laboratory confirmation and characterization were identified as essential for informing evidence-based vaccine implementation decisions. The relative merits of different confirmatory methodologies and their applications in different resource settings were a key component of the discussions. This paper summarizes the salient issues discussed, with special emphasis on the recommendations made and any deficiencies that were identified.

Characterization of invasive Neisseria meningitidis strains isolated at the Children's Hospital of Tunis, Tunisia

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 marquee

Low immunogenicity of quadrivalent meningococcal vaccines in solid organ transplant recipients.

Immunization against meningococcal disease is recommended for solid organ transplant (SOT) recipients at high risk for meningococcal disease or travelling to an endemic country. However, the immunogenicity of meningococcal vaccines has not been studied in this population. We analyzed the immune response of quadrivalent (against Neisseria meningitidis serogroups A, C, Y, and W) polysaccharidic non-conjugate and conjugate meningococcal vaccines in kidney- and liver-transplant patients using bactericidal assays against the targeted serogroups. Upon vaccination with a non-conjugate (n = 5) or a conjugate vaccine (n = 10), respectively, 40% and 50% of patients were able to mount an immune response, achieving at least the threshold correlated with protection defined as human serum bactericidal antibody titers of ≥4. Responders showed only partial and low responses (titers ≤64), thus predicting a rapid decline in bactericidal response. Only 1 patient developed a booster response to preexisting immunity. Our data argue for the need of additional measures for SOT recipients, when they are at risk of meningococcal disease.

[Complement terminal fraction deficiency revealed at first invasive meningococcal infection]. / Déficit en fraction terminale du complément révélé dès le premier épisode d'infection invasive à méningocoque.

Prevalence of complement protein deficiency in the general population is rare and its association with an increased risk of meningococcal infection is well established. However, management of these patients with potentially serious infections and indications warranting a search for such a deficiency have not met with consensus. We report the case of a 3-year-old child with no significant medical history who consulted in an emergency department for a fever after a stay in Senegal. Medical explorations concluded in septicemia and meningococcal W meningitis with a favorable outcome. Secondarily, we highlighted a complete deficiency of complement component C6. We diagnosed the same deficit in his twin sister who presented no infection. A long-term prophylactic antibiotic therapy and a meningococcal conjugate vaccine A,C,Y,W were set up for the twins. Recurrent invasive meningococcal infections and highlighting certain meningococcal serogroups are currently indications for complement protein exploration. We suggest expanding the search criteria for a complement protein deficiency after a single event of invasive meningococcal infection. This is an easy, rapid, and cost-effective screening system by dosage of CH50, C3, C4, and AP50. The arrival of the new meningococcal B vaccine will contribute to improving these patients' care. Family screening is necessary for prophylactic therapy.

[Changes in bacterial meningitis in French children resulting from vaccination]. / Évolution des méningites bactériennes de l'enfant en France sous l'effet des vaccinations.

BACKGROUND: For 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. METHODS: Over a 12-year period, 233 pediatric wards working with 168 microbiology departments throughout France were asked to report all cases of bacterial meningitis. RESULTS: From 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%. CONCLUSION: With 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.

[Impact of corticosteroids in the immediate management of invasive meningococcal disease associated with hyperinvasive strains of the ST-11 clonal complex in children]. / Impact des corticoïdes dans la prise en charge immédiate des infections invasives à méningocoque liées aux souches hyper-invasives du complexe clonal ST-11 chez l'enfant.

OBJECTIVES: We used data from the Groupe de pathologie infectieuse pédiatrique and Association clinique et thérapeutique infantile du Val-de-Marne (GPIP/ACTIV) National Survey of Bacterial Meningitis in children and the National Reference Center for Meningococci (CNRM) microbiological data to assess the potential impact of corticosteroids on the immediate management of invasive meningococcal disease (IMD) associated with different genotypes, including highly pro-inflammatory strains of the ST-11 clonal complex (genotype ST-11). METHODS: From 2001 to 2009, 259 pediatric wards and 168 microbiology laboratories distributed throughout France prospectively included all under-18-year-old patients with IMD (meningitis or purpura fulminans). The strains were sent to the CNRM for genotyping. We linked the ACTIV clinical data of IMD cases, where information on corticosteroid therapy was available, to strains isolated by the CRNM. RESULTS: A total of 1981 IMD cases were identified during the 8-year study, 805 cases (712 [88.5%] bacterial meningitis and 93 [11.5%] purpura fulminans) had steroid treatment data (33.8% received corticosteroids). The genotype of the strains was available for 410 patients (24.4% related to genotype ST-11; 100 patients). For all cases and regardless of the corticosteroids, mortality was significantly associated with the genotype ST-11 (OR=2.39, 95% CI [1.29; 4.42], P=0.004). For all cases and regardless of the genotypes of the isolates, mortality was also significantly higher for children with than without corticosteroid therapy (12.7% versus 4.5%, P<0.001). However, this treatment had been prescribed more frequently in severe cases, including shock, PF, coma and/or mechanical ventilation. For children who did not receive corticosteroids, the mortality rate was significantly higher with genotype ST-11 compared to other genotypes (OR=4.68 [1.91, 11.46], P=0.001). This difference disappeared in children who received corticosteroids. CONCLUSION: This study indicates that in the absence of corticosteroids, higher mortality in invasive meningococcal disease is associated with the ST-11 clonal complex strains. This suggests a possible positive effect of corticosteroid therapy depending on the genotype of the strain involved.

Meningococcal carriage during a clonal meningococcal B outbreak in France.

The aim of this study performed in Normandy, France, was to analyze the pharyngeal meningococcal carriage at the peak of a clonal meningococcal B outbreak, which was subsequently controlled using an outer membrane vesicle vaccination. This cross-sectional study included randomly selected subjects aged 1-25 years. Carriers and non carriers were compared using unconditional logistic regression. Among the 3,522 volunteers, there were 196 (standardized rate: 6.46 %) Neisseria meningitidis carriers, of which there were only five with the outbreak strain (B:14:P1.7,16/ST-32; standardized rate: 0.18 %). From the multivariate analysis, older age, smoking, higher degree of socialization, and social deprivation appear to favor the carriage of all the strains included. Prior antibiotic treatment up to 12 months before swabbing, even with ß-lactam, was protective against carriage. Our data indicate a low overall meningococcal carriage rate with a surprising protective effect of prior antibiotic exposure. The observed low carriage rate of the epidemic strain (B:14:P1.7,16/ST-32) contrasts with the high incidence of invasive meningococcal diseases (IMD) due to this strain. Hence, our data underline the high virulence of the strain and suggest a low level of natural immunity of the population against this strain. Although highly resource-consuming, carriage studies are helpful in guiding the implementation of control measures of IMD, such as mass vaccination or chemoprophylaxis.

Management of a rifampicin-resistant meningococcal infection in a teenager.

We report a secondary case of rifampicin-resistant meningococcal disease and our experience in managing contact cases. Rifampicin resistance resulting from rpoB gene mutations is still uncommon enough that changing the current recommendations for chemoprophylaxis is unwarranted. However, ensuring limited but appropriate chemoprophylaxis may prevent the development of antimicrobial resistance. Thus, the definition of contact cases should be strictly respected. In the case of culture-positive Neisseria meningitidis, in vitro susceptibility testing to rifampicin must be systematically performed in order to detect rifampicin-resistant strains and, thus, institute appropriate prophylaxis in order to prevent secondary transmission.

[Paediatric meningococcal meningitis in France: ACTIV/GPIP network results]. / Méningites à méningocoques de l'enfant en France: résultats de l'observatoire ACTIV/GPIP.

BACKGROUND: The GPIP/ACTIV (Groupe de Pathologie Infectieuse Pédiatrique and Association Clinique et Thérapeutique Infantile du Val de Marne) set up an active surveillance network to analyze the epidemiological, clinical and biological features of meningococcal meningitis. METHODS: French pediatric wards working with 166 microbiology laboratories enrolled all children (0-18 years old) with bacterial meningitis. Risk factors, signs and symptoms, vaccination status, cerebrospinal fluid analysis, treatments and case fatality rate were recorded. RESULTS: Since 2001, 1661 meningococcal meningitis were reported among 3769 (44.1%) bacterial meningitis. Mean age was 4.4- year- old (± 4.8, median 2.5) and 2/3 cases occurred in children under 5- year- old (68.8%). Serogroup B (61.3%) is preponderant following by serogroup C (27.0%). 27.5% of children had received an antibiotic treatment 24 hours before lumbar puncture. A shock is reported in 31.0% of cases. No cases of meningococcal meningitis C has been reported in children vaccinated with a conjugate vaccine. Two children vaccinated with MenBvac(®) vaccine had a meningitis B14:P1.7,16. Global case fatality rate was 6.5% but was higher (9.2%) for serogroup C than for serogroup B (5.9%) (p=0.02). CONCLUSION: This is among the largest series of microbiologically documented meningococcal meningitis to date (1661 cases). In France, meningococcal is responsible for approximately 50 % of meningitis. Effective meningococcal serogroup B vaccine and serogroup C vaccination recommendation could control the burden of meningococcal meningitis.

W135 invasive meningococcal infections imported from Sub-Saharan Africa to France, January to April 2012.

From January to April 2012, 16 cases of W135 invasive meningococcal infection were reported in France. Of these, eight were linked to a recent travel history to Sub-Saharan Africa. These cases were reported in France concomitantly with the meningitis epidemic season in Sub-Saharan Africa. Considering the high number of travellers between France and West-African countries belonging to the so-called meningitis belt, the French recommendations for travellers stress the importance of vaccination before travelling to these countries.

Community outbreak of group B meningococcal disease in southwest France--December 2008 to September 2009.

Between December 2008 and September 2009, 11 cases of invasive meningococcal disease (IMD) group B were reported in a 20 km diameter area in the Département Landes, France. Two of them presented with purpura fulminans and one of them died. The strain responsible for this community outbreak was of the clonal complex ST-269.The incidence rate for IMD group B was 3 per 100,000 inhabitants in Landes from week 40 in 2008 to week 40 in 2009; it was the highest in France during that period. The number of cases observed was significantly higher than expected, especially in young adults (standardised incidence ratio: 23.5, p<0.001). A nightclub located in the 20 km diameter area was a possible place of transmission and a prophylaxis recommended for the staff members helped in decreasing the transmission. However, several cases notified later suggested that the bacteria circulated during several months through healthy carriers in the community. This situation prompted increased surveillance of IMD in Landes and medical practitioners were asked to remain vigilant because of the possible emergence of new cases within the following months.

Molecular characterization of resistance to rifampicin in clinical isolates of Neisseria meningitidis.

Among 3904 meningococcal isolates collected between October 2002 and June 2007 by the French Meningococcal Reference Centre, eight (0.20%) were resistant to rifampicin (Rif-R; MIC >1 mg/L) and 27 (0.69%) were intermediate-resistant to rifampicin (Rif-I; MICs between 0.38 mg/L and 1 mg/L) according to the E-test method. The MICs determined by agar dilution were lower, eliminating the E-test intermediate category. All Rif-R isolates had mutations in the rpoB gene, resulting in substitutions at or near amino acid position 552, which were absent in non-resistant isolates. These data suggest that a rifampicin clinical breakpoint of 1.0 mg/L should be adopted for Neisseria meningitidis.

Hyperinvasive genotypes of Neisseria meningitidis in France.

Clinical isolates of Neisseria meningitidis from cases of meningococcal disease, collected between January 2000 and December 2004, were identified and typed at the French National Reference Centre. A representative subset of 546 isolates from among 2882 isolates was further genotyped by multilocus sequence typing to determine their genetic lineages (clonal complexes) and the degree of diversification among different clonal complexes. Representative isolates of the main clonal complexes were tested for their virulence in mice and for proapoptotic effects on human epithelial cells. High genetic diversity in some genetic lineages (ST-32 and ST-41/44) was correlated with heterogeneity in virulence in mice and proapoptotic effects on human epithelial cells. In contrast, the homogeneous genetic structure of isolates of the ST-11 clonal complex, regardless of their serogroup, correlated positively with a fatal outcome of the infection, increased virulence in mice and increased proapoptotic effects on human epithelial cells.