4CMenB Immunization Induces Serum Bactericidal Antibodies Against Non-Serogroup B Meningococcal Strains in Adolescents.

INTRODUCTION: Invasive meningococcal disease (IMD) is an important public health concern. In developed countries, most IMD is caused by meningococcal serogroup B (MenB) and two protein-based MenB vaccines are currently available: the four-component vaccine 4CMenB (Bexsero, GSK) and the bivalent vaccine MenB-FHbp (Trumenba, Pfizer). Genes encoding the 4CMenB vaccine antigens are also present in strains belonging to other meningococcal serogroups. METHODS: To evaluate the potential of 4CMenB vaccination to protect adolescents against non-MenB IMD, we tested the bactericidal activity of sera from immunized adolescents on 147 (127 European and 20 Brazilian) non-MenB IMD isolates, with a serum bactericidal antibody assay using human complement (hSBA). Serum pools were prepared using samples from randomly selected participants in various clinical trials, pre- and post-vaccination: 12 adolescents who received two doses of 4CMenB 2 months apart, and 10 adolescents who received a single dose of a MenACWY conjugate vaccine (as positive control). RESULTS: 4CMenB pre-immune sera killed 7.5% of the 147 non-MenB isolates at hSBA titers ≥ 1:4. In total, 91 (61.9%) tested isolates were killed by post-dose 2 pooled sera at hSBA titers ≥ 1:4, corresponding to 44/80 (55.0%) MenC, 26/35 (74.3%) MenW, and 21/32 (65.6%) MenY isolates killed. CONCLUSION: 4CMenB vaccination in adolescents induces bactericidal killing of non-MenB isolates, suggesting that mass vaccination could impact IMD due to serogroups other than MenB.

Multicomponent meningococcal serogroup B vaccination elicits cross-reactive immunity in infants against genetically diverse serogroup C, W and Y invasive disease isolates.

BACKGROUND: The multicomponent meningococcal serogroup B vaccine (4CMenB) is currently indicated for active immunization against invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB). However, genes encoding the 4CMenB antigens are also variably present and expressed in strains belonging to other meningococcal serogroups. In this study, we evaluated the ability of antibodies raised by 4CMenB immunisation to induce complement-mediated bactericidal killing of non-MenB strains. METHODS: A total of 227 invasive non-MenB disease isolates were collected between 1 July 2007 and 30 June 2008 from England and Wales, France, and Germany; 41 isolates were collected during 2012 from Brazil. The isolates were subjected to genotypic analyses. A subset of 147 isolates (MenC, MenW and MenY) representative of the meningococcal genetic diversity of the total sample were tested in the human complement serum bactericidal antibody assay (hSBA) using sera from infants immunised with 4CMenB. RESULTS: Serogroup and clonal complex repertoires of non-MenB isolates were different for each country. For the European panel, MenC, MenW and MenY isolates belonged mainly to ST-11, ST-22 and ST-23 complexes, respectively. For the Brazilian panel, most MenC and MenW isolates belonged to the ST-103 and ST-11 complexes, respectively, and most MenY isolates were not assigned to clonal complexes. Of the 147 non-MenB isolates, 109 were killed in hSBA, resulting in an overall coverage of 74%. CONCLUSION: This is the first study in which 147 non-MenB serogroup isolates have been analysed in hSBA to evaluate the potential of a MenB vaccine to cover strains belonging to other serogroups. These data demonstrate that antibodies raised by 4CMenB are able to induce bactericidal killing of 109 non-MenB isolates, representative of non-MenB genetic and geographic diversity. These findings support previous evidence that 4CMenB immunisation can provide cross-protection against non-MenB strains in infants, which represents an added benefit of 4CMenB vaccination.

The current situation of meningococcal disease in Latin America and updated Global Meningococcal Initiative (GMI) recommendations.

The Global Meningococcal Initiative (GMI) was established in 2009 and comprises an international team of scientists, clinicians, and public health officials with expertise in meningococcal disease (MD). Its primary goal is to promote global prevention of MD through education, research, international cooperation, and developing recommendations that include decreasing the burden of severe disease. The group held its first roundtable meeting with experts from Latin American countries in 2011, and subsequently proposed several recommendations to reduce the regional burden of MD. A second roundtable meeting was convened with Latin American representatives in June 2013 to reassess MD epidemiology, vaccination strategies, and unmet needs in the region, as well as to update the earlier recommendations. Special emphasis was placed on the emergence and spread of serogroup W disease in Argentina and Chile, and the control measures put in place in Chile were a particular focus of discussions. The impact of routine meningococcal vaccination programs, notably in Brazil, was also evaluated. There have been considerable improvements in MD surveillance systems and diagnostic techniques in some countries (e.g., Brazil and Chile), but the lack of adequate infrastructure, trained personnel, and equipment/reagents remains a major barrier to progress in resource-poor countries. The Pan American Health Organization's Revolving Fund is likely to play an important role in improving access to meningococcal vaccines in Latin America. Additional innovative approaches are needed to redress the imbalance in expertise and resources between countries, and thereby improve the control of MD. In Latin America, the GMI recommends establishment of a detailed and comprehensive national/regional surveillance system, standardization of laboratory procedures, adoption of a uniform MD case definition, maintaining laboratory-based surveillance, replacement of polysaccharide vaccines with conjugate formulations (wherever possible), monitoring and evaluating implemented vaccination strategies, conducting cost-effectiveness studies, and developing specific recommendations for vaccination of high-risk groups.

Caracterización fenotípica y molecular de neisseria meningitidis del serogrupo C asociada con un brote en Bahia, Brasil / Phenotypic and molecular characterization of serogroup C Neisseria meningitidis associated with an outbreak in Bahia, Brazil

Objetivo Caracterizar las cepas de Neisseria meningitidis (Nm) aisladas de cinco pacientes con Enfermedad Meningocócica (EM) asociada a un brote epidémico en Trancoso - BA, que ocurrió en octubre del 2009, luego de una fiesta en zona rural y en la que participaron 1000 jóvenes .Todos los casos fueron secundarios al caso primario a excepción de un paciente varón de 39 años. Materiales y métodos El Servicio de Vigilancia Epidemiológica del Estado de Bahia realizó la investigación epidemiológica y las cepas de Nm se caracterizaron en el Laboratorio Nacional de Referencia para Meningitis, Instituto Adolfo Lutz - São Paulo mediante métodos convencionales (sero - subtipificación y prueba de sensibilidad a los antimicrobianos) y métodos moleculares (electroforesis en gel de campo pulsado- PFGE y Multilocus Sequence Typing - MLST).Resultados La PFGE mostró dos perfiles de restricción estrechamente relacionados designados como PFGE tipos A y A1 con 92% de relación entre sí. Ambos tipos fueron clasificados como ST-3780 mediante MLST, y pertenecientes al complejo clonal ST-103. Todos los aislados mostraron el fenotipo C: 23: P1.5 y eran susceptibles a todos los antibióticos testados. Conclusiones Este es el primer brote de EM reportado asociado a cepas de Nm serogrupo C del complejo clonal ST-103 y relacionado con el consumo de drogas en Brasil (AU)

Objective To characterize meningococcal strains isolated from five cases of meningococcal disease (MD) associated with an outbreak in Trancoso - BA, occurred in October 2009. All cases, with the exception of a 39-year-old male, attended a dance party with approximately 1000 youngsters in a rural site. Materials and methods The epidemiological investigation was conducted by the Epidemiological Surveillance Service of Bahia State. Meningococcal strains were characterized at Adolfo Lutz Institute, the Brazilian National Reference Laboratory for Bacterial Meningitis by conventional techniques (serotype, serosubtype and antimicrobial susceptibility test) and by molecular methods (Pulsed-field gel electrophoresis - PFGE and Multilocus Sequence Typing - MLST).Results The PFGE showed 2 closely related restriction profiles, designated as PFGE types A and A1, having 92% relatedness to each other. MLST characterization showed both A and A1 clones were ST-3780, which belongs to the ST-103 complex. All isolates displayed the phenotype C:23:P1.5 and were susceptible to all antibiotics tested. Conclusions This is the first reported MD outbreak associated with serogroup C ST-103 complex in Brazil, as well as the party and illicit drug-use associated outbreak (AU)

Phenotypic and molecular characterization of serogroup C Neisseria meningitidis associated with an outbreak in Bahia, Brazil.

OBJECTIVE: To characterize meningococcal strains isolated from five cases of meningococcal disease (MD) associated with an outbreak in Trancoso - BA, occurred in October 2009. All cases, with the exception of a 39-year-old male, attended a dance party with approximately 1000 youngsters in a rural site. MATERIALS AND METHODS: The epidemiological investigation was conducted by the Epidemiological Surveillance Service of Bahia State. Meningococcal strains were characterized at Adolfo Lutz Institute, the Brazilian National Reference Laboratory for Bacterial Meningitis by conventional techniques (serotype, serosubtype and antimicrobial susceptibility test) and by molecular methods (Pulsed-field gel electrophoresis - PFGE and Multilocus Sequence Typing - MLST). RESULTS: The PFGE showed 2 closely related restriction profiles, designated as PFGE types A and A1, having 92% relatedness to each other. MLST characterization showed both A and A1 clones were ST-3780, which belongs to the ST-103 complex. All isolates displayed the phenotype C:23:P1.5 and were susceptible to all antibiotics tested. CONCLUSIONS: This is the first reported MD outbreak associated with serogroup C ST-103 complex in Brazil, as well as the party and illicit drug-use associated outbreak.

Antimicrobial susceptibility of Neisseria meningitidis strains isolated from meningitis cases in Brazil from 2006 to 2008.

OBJECTIVE: 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. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Antimicrobial susceptibility of Neisseria meningitidis strains isolated from meningitis cases in Brazil from 2006 to 2008

Objective 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. Materials and methods 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).Results 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. Conclusions 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 (AU)

Objetivo Analizar el perfil de susceptibilidad a los antimicrobianos de las cepas de meningococos aisladas de casos de enfermedad meningocócica en Brasil entre 2006 y 2008 y enviadas al Laboratorio Nacional de Referencia para Meningitis, Instituto Adolfo Lutz, São Paulo. Material y métodos Se determinó la CIM a penicilina, ampicilina, cloranfenicol, ceftriaxona, ciprofloxacino y rifampicina, mediante el procedimiento de microdilución seriada en caldo en una muestra de 1.096 aislados (55% de los aislados recibidos) escogida al azar. Los puntos de corte utilizados fueron los recomendados por el European Monitoring Group on Meningococci (EMGM).Resultados Se detectó disminución de la susceptibilidad a la penicilina y la ampicilina en el 13 y el 12,9% respectivamente. Todos los aislados fueron susceptibles a cloranfenicol, ceftriaxona y ciprofloxacino. Dos cepas (0,2%) mostraron alta resistencia a la rifampicina y el 0,5% de los aislados presentaron resistencia intermedia a la rifampicina. Conclusiones Las cepas de meningococos aisladas en Brasil en el periodo 2006-2008 fueron globalmente susceptibles a los antibióticos actualmente utilizados en el tratamiento o quimioprofilaxis de enfermedad meningocócica en Brasil (AU)

Phenotypic characterization of Neisseria meningitidis strains isolated from invasive disease in Brazil from 1990 to 2001.

Phenotype characterization of 11 181 invasive Neisseria meningitidis isolates collected in Brazil from 1990 to 2001 was performed. Based on laboratory data, there were 7436 (67 %) serogroup B isolates, 3391 (30 %) C, 236 W135, 51 Y, four 29E, three X, one Z, and 59 of unknown serogroup. Phenotype B : 4,7 : P1.19,15 (54 %) remained the most common during the whole of the 12-year period. Two waves were observed within the serogroup C population: the most frequent phenotype C : 2b : P1.3 (47 %) was replaced after 1998 by non-typable isolates (C : NT : NST) (16 %).

Comparison of PorA VR types and porA promoter sequence from Neisseria meningitidis B isolated from non-immunised children and vaccine failures immunised with a serogroup B outer membrane protein vaccine.

PorA protein is an important component of group B meningococcal protein-based vaccines. The goals of this study were: (i) to classify the non-serosubtypable strains recovered from vaccine failures and controls by porA variable region (VR) type; (ii) to investigate if point mutations of VRs of the porA gene are present in P1.19,15 strains recovered from vaccine failures and controls; (iii) to investigate if nucleotide sequence variation in the promoter region of porA gene is related to low expression of PorA protein. VR type P1.19,15 predominated in younger vaccine failures (3-47 months) compared to older failures (48-83 months). No changes in VRs of porA were observed in 46 P1.19,15 strains studied. A promoter spacer of 16bp and 10 guanidine residues in the polymeric G tract was detected in five of six strains with weak PorA expression. Overall, this study indicated that lack of antibody response was probably the major cause of low vaccine efficacy in young children.

Immune response to native NadA from Neisseria meningitidis and its expression in clinical isolates in Brazil.

A mAb against the NadA protein from Neisseria meningitidis strain 3006 (serosubtype B : 2b : P1.2 : P5.2,8) demonstrated strong bactericidal activity against Brazilian epidemic serogroup B strain N44/89 (B : 4,7 : P1.19,15 : P5.5,7) and a serogroup C strain, IMC 2135 (C : 2a : P1.5,2), but not against another serogroup C strain, N1002/90 (C : 2b : P1.3 : P5.8). The immunogenicity of native NadA in an outer-membrane vesicle (OMV) preparation was also tested. Serum from mice immunized with OMV from serogroup B strain N44/89, which contains the NadA protein, showed bactericidal activity against serogroup B and C strains possessing NadA. In dot-blot analysis of 100 serogroup B and 100 serogroup C isolates from Brazilian patients, the mAb to NadA recognized about 60 % of the samples from both serogroups. The molecular mass of the NadA protein from strain N44/89 determined by mass spectrometry was 37 971 Da and the peptide sequences were identical to those of NadA from N. meningitidis strain MC58.