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.

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.

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.

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.

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.

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.

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.

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.

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.

[Characteristics of meningococcal meningitis in children in France]. / Caractéristiques des méningites à méningocoque de l'enfant en France.

BACKGROUND: In France, meningococcal meningitis account for 50% of bacterial meningitis in children. 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: From 2001 to 2007, 252 French paediatric 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: During the period of the study, 1344 meningococcal meningitis were reported among 2951 (45.5%) bacterial meningitis. Mean age was 4.4 years (+/-4.7, median 2.5) and 2/3 cases occurred in children under 5 years (68.5%). Serogroup B (59.1%) was preponderant following by serogroup C (28.9%). 25% of children had received an antibiotic treatment 24hours before lumbar puncture. A shock was reported in 31.3% of cases. Cerebrospinal fluid culture was positive in 73% of cases. All N. meningitidis isolates were susceptible to cefotaxime and ceftriaxone while 41.6% and 25.7% showed reduced susceptibility to penicillin and amoxicillin respectively. Two cases of meningitis due to isolates of serogroups C and B were reported in two children that were respectively vaccinated using A+C plain saccharide vaccine or two doses of MenBvac vaccine. All patients had received beta-lactamin. Global case fatality rate was 6.6% but was higher (9.9%) for serogroup C than for serogroup B (5.5%) (p=0,007). CONCLUSION: This study is among the largest series of microbiologically documented meningococcal meningitis to date (more than 1300 cases). In France, meningococal is responsible for 50 % of meningitis. Effective meningococcal serogroup B vaccine and serogroup C vaccination recommendation could lessen considerably the burden of meningococal meningitis.

[3rd Workshop on Epidemiology, Prevention and Treatment of Invasive Meningococcal Disease in Würzburg 2006]. / 3. Würzburger Workshop zur Epidemiologie, Prävention und Therapie der invasiven Meningokokkenerkrankung 2006.

On October 5th, 2006, the German Reference Centre for Meningococci (NRZM) held the 3rd Workshop on Epidemiology, Prevention and Treatment of Invasive Meningococcal Disease, in collaboration with the German Society for Hygiene and Microbiology (DGHM). Given the recent recommendation of the German Standing Committee on Vaccination (STIKO) for conjugate meningococcal C vaccination of all children in the second year of life, observations from meningococcal C conjugate vaccination campaigns in other European countries were presented and compared to the German situation. Moreover, the newly implemented cluster detection routines employed at the NRZM and their integration into the interactive geographical information system EpiScanGIS were shown. Based on recent experiences from regional outbreaks in Oberallgäu, Sangerhausen, and Greater Aachen, examples for public health intervention were given at the conference. In addition, current developments in the area of meningococcal research, as well as trends in antimicrobial susceptibility were covered. Finally, the latest evidence concerning the clinical management and chemoprophylaxis of this invasive bacterial disease was discussed.

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.

Prolonged outbreak of B meningococcal disease in the Seine-Maritime department, France, January 2003 to June 2005.

Between January 2003 and June 2005, an outbreak of meningococcal disease occurred in the department of Seine-Maritime in northern France. Eighty six cases were notified, giving an average annual incidence of 2.7 cases per 100,000 inhabitants, compared with 1.6 in France. An especially affected area was defined as the city of Dieppe and its surrounding area (26 cases, giving an annual incidence of 12 cases per 100,000). This outbreak was due to N. meningitidis phenotype B:14:P1.7,16 belonging to the clonal complex ST-32/ET-5. Over the 31 B14:P1.7,16 cases confirmed by phenotyping methods at the national reference centre for meningococci (CNR, Centre National de Reference des meningocoques) the case-fatality rate (19%) and the proportion of purpura fulminans (42%) were especially high. Teenagers aged between 15 and 19 years and children aged 1 to 9 years were the most affected. In 2003, health authorities put in place enhanced epidemiological surveillance and informed practitioners and population about the disease. In 2004, the national vaccination advisory board studied the opportunity of using a non licensed outer membrane vesicle vaccine developed in Norway which may be effective against the B14:P1.7,16 strain. The Ministry of health decided in 2006 to offer vaccination with this vaccine to people aged 1 to 19 years in Seine-Maritime.

Prolonged outbreak of B meningococcal disease in the Seine-Maritime department, France, January 2003 to June 2005.

Between January 2003 and June 2005, an outbreak of meningococcal disease occured in the department of Seine-Maritime in northern France. Eighty six cases were notified, giving an average annual incidence of 2.7 cases per 100 000 inhabitants, compared with 1.6 in France. An especially affected area was defined as the city of Dieppe and its surrounding area (26 cases, giving an annual incidence of 12 cases per 100 000). This outbreak was due to N. meningitidis phenotype B:14:P1.7,16 belonging to the clonal complex ST-32/ET-5. Over the 31 B14:P1.7,16 cases confirmed by phenotyping methods at the national reference centre for meningococci (CNR, Centre National de Référence des méningocoques) the case-fatality rate (19%) and the proportion of purpura fulminans (42%) were especially high. Teenagers aged between 15 and 19 years and children aged 1 to 9 years were the most affected. In 2003, health authorities put in place enhanced epidemiological surveillance and informed practitioners and population about the disease. In 2004, the national vaccination advisory board studied the opportunity of using a non licensed outer membrane vesicle vaccine developed in Norway which may be effective against the B14:P1.7,16 strain. The Ministry of health decided in 2006 to offer vaccination with this vaccine to people aged 1 to 19 years in Seine- Maritime.

Epidemiology of invasive meningococcal disease in France in 2003.

National surveillance of invasive meningococcal disease (IMD) is based on mandatory reporting. The case definition for surveillance notification was changed in mid-2002 to include cases without microbiological confirmation. The IMD alert detection system was enhanced in 2003 with daily reporting and weekly analysis by district, serogroup, and age. Evaluation of the exhaustivity of the surveillance with capture-recapture analysis allowed correcting for underreporting. In 2003, 803 cases were reported. After correction for under-reporting, the estimated incidence was 1.78 / 100 000. After excluding 'new' cases reported with new definition criteria, the 2002-2003 increase was 4%. Incidence decreased with age, with the highest values in infants less than 1 year (20/100 000), children aged between 1 and 2 years (11/100 000) and in teenagers of 17 years old(7/100 000). The overall case fatality rate was 12%. Fifty nine per cent of cases were due to serogroup B, 32% to C, 5% to W135, and 4% to Y and non-groupable meningococci. Patients with purpura fulminans treated with intravenous antibiotics before admission to hospital were shown to have lower fatality rates than those not treated. In 2001-2003, 5 situations required particular attention: two clusters of serogroup B IMD had set off mass prophylaxis, one outbreak due to a specific B IMD clonal complex with high case fatality rate, and two districts crossed the alert threshold for serogroup C IMD, 2/100 000, and mass vaccination was recommended.

Epidemiology of invasive meningococcal disease in France in 2003.

National surveillance of invasive meningococcal disease (IMD) is based on mandatory reporting. The case definition for surveillance notification was changed in mid-2002 to include cases without microbiological confirmation. The IMD alert detection system was enhanced in 2003 with daily reporting and weekly analysis by district, serogroup, and age. Evaluation of the exhaustivity of the surveillance with capture-recapture analysis allowed correcting for underreporting. In 2003, 803 cases were reported. After correction for under-reporting, the estimated incidence was 1.78 / 100,000. After excluding 'new' cases reported with new definition criteria, the 2002-2003 increase was 4%. Incidence decreased with age, with the highest values in infants less than 1 year (20/100,000), children aged between 1 and 2 years (11/100,000) and in teenagers of 17 years old(7/100,000). The overall case fatality rate was 12%. Fifty nine per cent of cases were due to serogroup B, 32% to C, 5% to W135, and 4% to Y and non-groupable meningococci. Patients with purpura fulminans treated with intravenous antibiotics before admission to hospital were shown to have lower fatality rates than those not treated. In 2001-2003, 5 situations required particular attention: two clusters of serogroup B IMD had set off mass prophylaxis, one outbreak due to a specific B IMD clonal complex with high case fatality rate, and two districts crossed the alert threshold for serogroup C IMD, 2/100,000, and mass vaccination was recommended.

[Clinical aspects and outcome of meningococcal disease due to Neisseria meningitidis of serogroup W135 in 5 children]. / Aspects cliniques et évolutifs des infections à méningocoque W135 chez l'enfant: à propos de cinq observations.

Meningococcal disease due to Neisseria meningitidis of serogroup W135 (N. meningitidis W135) is increasing in France. Clinical and outcome data concerning these infections in children are scarce. We report five cases of children hospitalized between June 2000 and December 2002 for N. meningitidis W135 infection. Extra-meningeal septic and/or non-septic complications were frequent and a prolonged post meningococcal inflammatory syndrome was reported. In N. meningitidis W135 infections a careful clinical evaluation of potential extra-meningeal complications and a long term follow up of children are needed.