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1.  Opacity-Associated Adhesin Repertoire in Hyperinvasive Neisseria meningitidis†  
Infection and Immunity  2006;74(9):5085-5094.
The opacity (Opa) proteins mediate a variety of interactions between the bacterium Neisseria meningitidis and its human host. These interactions are thought to be of central importance in both the asymptomatic colonization of the nasopharynx and the sporadic occurrence of meningococcal disease. The receptor specificities of a limited number of Opa protein variants have been explored, but the high level of amino acid sequence diversity among variants has complicated the assignment of specific roles to individual Opa variants or combinations of variants. In addition, the distribution of Opa protein variants among diverse meningococci, information that is potentially informative for studies of Opa function, is poorly understood. A systematic survey of the genetic diversity in the four opa gene loci in each of 77 meningococcal isolates was undertaken. These isolates were representative of the seven hyperinvasive meningococcal clonal complexes that caused the majority of meningococcal disease over the last 50 years. Consistent with previous studies, a high level of sequence diversity was observed among the opa genes and the proteins that they encoded; however, particular sets of Opa protein variants were consistently associated with each of the clonal complexes over time periods often spanning decades and during global spread. These observations were consistent with the postulate that particular combinations of Opa proteins confer fitness advantages to individual clonal complexes and have implications for studies of Opa function and the inclusion of Opa proteins in novel meningococcal vaccines.
PMCID: PMC1594835  PMID: 16926400
2.  Potential of Recombinant Opa Proteins as Vaccine Candidates against Hyperinvasive Meningococci ▿ † 
Infection and Immunity  2011;79(7):2810-2818.
Neisseria meningitidis causes half a million cases of septicemia and meningitis globally each year. The opacity (Opa) integral outer membrane proteins from N. meningitidis are polymorphic and highly immunogenic. Particular combinations of Opa proteins are associated with the hyperinvasive meningococcal lineages that have caused the majority of serogroup B and C meningococcal disease in industrialized countries over the last 60 years. For the first time, this genetic structuring of a diverse outer membrane protein family has been used to select a novel combination of representative antigens for immunogenicity testing. Fourteen recombinant Opa variants were produced and used in murine immunizations inducing an increase in specific antimeningococcal total IgG levels. All 14 Opa proteins elicited bactericidal antibodies against at least one hyperinvasive meningococcal isolate, and most isolates from each hyperinvasive lineage were killed by at least one Opa antiserum at a titer of 1:16 or greater. Cross-reactive bactericidal antibody responses were observed among clonal complexes. A theoretical coverage of 90% can be achieved by using a particular combination of 6 Opa proteins against an isolate collection of 227 recent United Kingdom disease cases. This study indicates the potential of Opa proteins to provide broad coverage against multiple meningococcal hyperinvasive lineages.
PMCID: PMC3191958  PMID: 21464082
3.  Evolutionary and genomic insights into meningococcal biology 
Future microbiology  2012;7(7):873-885.
Epidemic disease caused by Neisseria meningitidis, the meningococcus, has been recognised for two centuries, but remains incompletely controlled and understood. There have been dramatic reductions in serogroup A and C meningococcal disease following the introduction of protein-polysaccharide conjugate vaccines but there is currently no comprehensive vaccine against serogroup B meningococci. Genetic analyses of meningococcal populations have provided many insights into the biology, evolution, and pathogenesis of this important pathogen. The meningococcus, and its close relative the gonococcus, are the only pathogenic members of the genus Neisseria, and the invasive propensity of meningococci varies widely, with around a dozen ‘hyper invasive lineages’ responsible for most disease. Despite this, attempts to identify a ‘pathogenome’, a subset of genes associated with the invasive phenotypes have failed; however, genome-wide studies of representative meningococcal isolates using high throughput sequencing are beginning to provide detail on the relationship of invasive phenotype and genotype in this fascinating organism and how this relationship has evolved.
PMCID: PMC3492750  PMID: 22827308
Neisseria meningitidis; population genomics; pathogenomics; molecular evolution; molecular epidemiology
4.  Distribution of transferrin binding protein B gene (tbpB) variants among Neisseria species 
BMC Microbiology  2008;8:66.
Transferrin binding protein B (tbpB), an outer membrane lipoprotein, is required for the acquisition of iron from human transferrin. Two tbpB families have been documented in Neisseria meningitidis: an isotype I tbpB gene of 1.8 kb and an isotype II tbpB gene of 2.1 kb, the former expressed by meningococci in the disease-associated ST-11 clonal complex and the latter found among meningococci belonging to the hyper-invasive clonal complexes including ST-8, ST-18, ST-32, ST-41/44 as well as N. gonorrhoeae isolates. The origin of the isotype I tbpB gene is unknown, however several features in common with non-pathogenic Neisseria and the ST-11 clonal complex N. meningitidis isolate FAM18 have been documented leading to the hypothesis that the isotype I tbpB gene may also be shared between non-pathogenic Neisseria and ST-11 meningococci. As a result, the diversity of the tbpB gene was investigated in a defined collection of Neisseria species.
Two families of isotype I tbpB were identified: family A containing conserved genes belonging to ST-11 meningococci, N. polysaccharea and N. lactamica isolates and family B including more diverse isotype I tbpB genes from N. sicca, N. mucosa, N. flava, N. subflava as well as N. cinerea, N. flavescens and N. polysaccharea isolates. Three isotype II tbpB families were identified with: family C containing diverse tbpB genes belonging to N. polysaccharea, N. lactamica, N. gonorrhoeae and N. meningitidis isolates, family D including another subset of isotype II tbpB genes from N. lactamica isolates and family E solely composed of N. gonorrhoeae tbpB genes.
This study reveals another instance of similarity between meningococci of the ST-11 clonal complex and non-pathogenic Neisseria with the origin of the isotype I tbpB gene resulting from a horizontal genetic transfer event occurring between these two populations.
PMCID: PMC2386816  PMID: 18430216
5.  Two-Partner Secretion Systems of Neisseria meningitidis Associated with Invasive Clonal Complexes▿ †  
Infection and Immunity  2008;76(10):4649-4658.
The two-partner secretion (TPS) pathway is widespread among gram-negative bacteria and facilitates the secretion of very large and often virulence-related proteins. TPS systems consist of a secreted TpsA protein and a TpsB protein involved in TpsA transport across the outer membrane. Sequenced Neisseria meningitidis genomes contain up to five TpsA- and two TpsB-encoding genes. Here, we investigated the distribution of TPS-related open reading frames in a collection of disease isolates. Three distinct TPS systems were identified among meningococci. System 1 was ubiquitous, while systems 2 and 3 were significantly more prevalent among isolates of hyperinvasive clonal complexes than among isolates of poorly invasive clonal complexes. In laboratory cultures, systems 1 and 2 were expressed. However, several sera from patients recovering from disseminated meningococcal disease recognized the TpsAs of systems 2 and 3, indicating the expression of these systems during infection. Furthermore, we showed that the major secreted TpsAs of systems 1 and 2 depend on their cognate TpsBs for transport across the outer membrane and that the system 1 TpsAs undergo processing. Together, our data indicate that TPS systems may contribute to the virulence of N. meningitidis.
PMCID: PMC2546848  PMID: 18678657
6.  Meningococcal carriage and disease—Population biology and evolution 
Vaccine  2009;27(4):B64-B70.
Meningococcal disease occurs worldwide with incidence rates varying from 1 to 1000 cases per 100,000. The causative organism, Neisseria meningitidis, is an obligate commensal of humans, which normally colonizes the mucosa of the upper respiratory tract without causing invasive disease, a phenomenon known as carriage. Studies using molecular methods have demonstrated the extensive genetic diversity of meningocococci isolated from carriers, in contrast to a limited number of genetic types, known as the hyperinvasive lineages, associated with invasive disease. Population and evolutionary models that invoke positive selection can be used to resolve the apparent paradox of virulent lineages persisting during the global spread of a non-clonal and normally commensal bacterium. The application of insights gained from studies of meningococcal population biology and evolution is important in understanding the spread of disease, as well as in vaccine development and implementation, especially with regard to the challenge of producing comprehensive vaccines based on sub-capsular antigens and measuring their effectiveness.
PMCID: PMC2719693  PMID: 19464092
Meningococcal disease; Carriage; Population structure
7.  Distribution of Surface Protein Variants among Hyperinvasive Meningococci: Implications for Vaccine Design  
Infection and Immunity  2004;72(10):5955-5962.
The bacterium Neisseria meningitidis is a major cause of meningitis and septicemia worldwide. Outer membrane proteins (OMPs) are candidates in the search for comprehensive meningococcal vaccines; however, the formulation of OMP vaccines is complicated by antigenic diversity, which is generated by high levels of genetic reassortment and strong positive selection in the meningococcal antigen genes. The genetic and antigenic diversity of three OMPs (FetA, PorA, and PorB) among a global collection of meningococcal isolates representative of the major hyperinvasive clonal complexes was determined. There was evidence for antigenic structuring among the three OMPs that could not be explained purely by descent. These observations violated the predictions of the clonal and epidemic clonal models of population structure but were in concordance with models of strain structure which propose that host immunity selects for nonoverlapping antigen combinations. The patterns of antigenic variant combinations suggested that an OMP-based vaccine with as few as six PorA and five FetA variant sequences could generate homologous immune responses against all 78 isolates examined.
PMCID: PMC517544  PMID: 15385499
8.  The Distribution and ‘In Vivo’ Phase Variation Status of Haemoglobin Receptors in Invasive Meningococcal Serogroup B Disease: Genotypic and Phenotypic Analysis 
PLoS ONE  2013;8(9):e76932.
Two haemoglobin-binding proteins, HmbR and HpuAB, contribute to iron acquisition by Neisseria meningitidis. These receptors are subject to high frequency, reversible switches in gene expression - phase variation (PV) - due to mutations in homopolymeric (poly-G) repeats present in the open reading frame. The distribution and PV state of these receptors was assessed for a representative collection of isolates from invasive meningococcal disease patients of England, Wales and Northern Ireland. Most of the major clonal complexes had only the HmbR receptor whilst the recently expanding ST-275-centred cluster of the ST-269 clonal complex had both receptors. At least one of the receptors was in an ‘ON’ configuration in 76.3% of the isolates, a finding that was largely consistent with phenotypic analyses. As PV status may change during isolation and culture of meningococci, a PCR-based protocol was utilised to confirm the expression status of the receptors within contemporaneously acquired clinical specimens (blood/cerebrospinal fluid) from the respective patients. The expression state was confirmed for all isolate/specimen pairs with <15 tract repeats indicating that the PV status of these receptors is stable during isolation. This study therefore establishes a protocol for determining in vivo PV status to aid in determining the contributions of phase variable genes to invasive meningococcal disease. Furthermore, the results of the study support a putative but non-essential role of the meningococcal haemoglobin receptors as virulence factors whilst further highlighting their vaccine candidacy.
PMCID: PMC3786947  PMID: 24098814
9.  Variation and molecular evolution of HmbR, the Neisseria meningitidis haemoglobin receptor 
Microbiology  2010;156(Pt 5):1384-1393.
Meningococcal disease caused by serogroup B Neisseria meningitidis remains an important health problem in many parts of the world, and there are currently no comprehensive vaccines. Poor immunogenicity, combined with immunological identity to human sialic acids, have hindered the development of a serogroup B conjugate vaccine, resulting in the development of alternative vaccine candidates, including many outer-membrane protein (OMP)-based formulations. However, the design of protein-based meningococcal vaccines is complicated by the high level of genetic and antigenic diversity of the meningococcus. Knowledge of the extent and structuring of this diversity can have implications for the use of particular proteins as potential vaccine candidates. With this in mind, the diversity of the meningococcal OMP HmbR was investigated among N. meningitidis isolates representative of major hyper-invasive lineages. In common with other meningococcal antigens, the genetic diversity of hmbR resulted from a combination of intraspecies horizontal genetic exchange and de novo mutation. Furthermore, genealogical analysis showed an association of hmbR genes with clonal complexes and the occurrence of two hmbR families, A and B. Three variable regions (VR1–VR3), located in loops 2, 3 and 4, were observed with clonal complex structuring of VR types. A minority of codons (3.9 %), located within putative surface-exposed loop regions of a 2D model, were under diversifying selection, indicating regions of the protein likely to be subject to immune attack.
PMCID: PMC3068627  PMID: 20150237
10.  Differential Modulation of TNF-α–Induced Apoptosis by Neisseria meningitidis 
PLoS Pathogens  2009;5(5):e1000405.
Infections by Neisseria meningitidis show duality between frequent asymptomatic carriage and occasional life-threatening disease. Bacterial and host factors involved in this balance are not fully understood. Cytopathic effects and cell damage may prelude to pathogenesis of isolates belonging to hyper-invasive lineages. We aimed to analyze cell–bacteria interactions using both pathogenic and carriage meningococcal isolates. Several pathogenic isolates of the ST-11 clonal complex and carriage isolates were used to infect human epithelial cells. Cytopathic effect was determined and apoptosis was scored using several methods (FITC-Annexin V staining followed by FACS analysis, caspase assays and DNA fragmentation). Only pathogenic isolates were able to induce apoptosis in human epithelial cells, mainly by lipooligosaccharide (endotoxin). Bioactive TNF-α is only detected when cells were infected by pathogenic isolates. At the opposite, carriage isolates seem to provoke shedding of the TNF-α receptor I (TNF-RI) from the surface that protect cells from apoptosis by chelating TNF-α. Ability to induce apoptosis and inflammation may represent major traits in the pathogenesis of N. meningitidis. However, our data strongly suggest that carriage isolates of meningococci reduce inflammatory response and apoptosis induction, resulting in the protection of their ecological niche at the human nasopharynx.
Author Summary
Acquisition of Neisseria meningitidis often leads to asymptomatic colonization (carriage) and rarely results in invasive disease associated with tissue injury. The reasons that make disease-associated isolates (pathogenic isolates) but not asymptomatic carriage isolates able to invade the host to establish disease are not understood. Isolates belonging to the ST-11 clonal complex are most frequently associated with the disease and rarely found in carriers. These hyper-invasive isolates may be able to induce cytopathic effects in target cells. We aimed to investigate the cytopathic effect of meningococcal isolates on epithelial cells using both ST-11 pathogenic isolates and carriage isolates. We showed that cytopathic effects were strongly associated with pathogenic isolates and infected cells exhibited features of apoptosis. This effect is mainly mediated by bacterial endotoxin (lipooligosaccharide) and involved an autocrine signaling mechanism of secreted TNF-α through its receptor TNF-RI. In contrast, carriage isolates down-regulate TNF-RI on the surface of infected cells by increasing TNF-RI shedding into the medium. We suggest that chelating secreted TNF-α protects cells from apoptosis. Our results unravel a differential modulation of TNF-α signaling by meningococcal isolates leading to cell survival or death and would therefore contribute to better understanding of the duality between carriage and invasiveness.
PMCID: PMC2669886  PMID: 19412525
11.  Disease Susceptibility to ST11 Complex Meningococci Bearing Serogroup C or W135 Polysaccharide Capsules, North America1 
Emerging Infectious Diseases  2004;10(10):1812-1815.
Study population was susceptible to ST11 complex meningococci bearing both C and W135 polysaccharide capsules; vaccine against serogroup C meningococci may not prevent ST11 disease.
Clusters of meningococcal disease caused by a hyperinvasive lineage of Neisseria meningitidis, the ST11 complex, bearing a serogroup C polysaccharide capsule, have been prominent in Europe and North America since the early 1990s. This situation has led to expensive public health measures for outbreak control and, finally, to the introduction of a serogroup C glyconjugate vaccine into the primary immunization schedule in the United Kingdom and elsewhere. ST11 complex meningococci may also express serogroup W135 polysaccharide capsules. We investigated the level of population immunity to this hyperinvasive clone in association with the appearance of outbreaks of meningococcal disease in southern British Columbia. We found that most adults and almost all children were apparently susceptible to infection with ST11 complex meningococci bearing both C and W135 polysaccharide capsules, which suggests that a vaccine program directed against only serogroup C meningococci may be insufficient to prevent hyperinvasive ST11 disease.
PMCID: PMC3323278  PMID: 15504268
Neisseria meningitides; population immunity; meningococcal disease; research
12.  Three Outbreak-causing Neisseria meningitidis Serogroup C Clones, Brazil1 
Emerging Infectious Diseases  2013;19(11):1847-1850.
During 2003–2012, 8 clusters of meningococcal disease were identified in Rio de Janeiro State, Brazil, all caused by serogroup C Neisseria meningitidis. The isolates were assigned to 3 clonal complexes (cc): cc11, cc32, and cc103. These hyperinvasive disease lineages were associated with endemic disease, outbreaks, and high case-fatality rates.
PMCID: PMC3837672  PMID: 24229563
Neisseria meningitidis; serogroup C; bacteria; clones; epidemiology; public health; population surveillance; data collection; Brazil
13.  NmeSI Restriction-Modification System Identified by Representational Difference Analysis of a Hypervirulent Neisseria meningitidis Strain 
Infection and Immunity  2001;69(3):1816-1820.
Neisseria meningitidis is a gram-negative bacterium that may cause meningitis, sepsis, or both. The increase in the incidence of meningococcal disease in various countries in the past 2 decades is mainly due the genotypically related lineage III meningococci. The chromosomal DNA differences between lineage III strains and non-lineage III strains were identified using representational difference analysis. Thus, a 1.8-kb locus that is specific for lineage III meningococci was identified. The locus contains three open reading frames encoding the NmeSI restriction-modification system. The methyltransferase gene was cloned and expressed in Escherichia coli. Site AGTACT was found to be modified by the enzyme. In conclusion, lineage III strains differ from endemic strains by the presence of a specific restriction-modification system. This restriction-modification system may contribute to the clonal and hypervirulent character of lineage III strains by influencing horizontal gene transfer and transcription.
PMCID: PMC98088  PMID: 11179359
14.  Invasive Serogroup B Neisseria meningitidis in Québec, Canada, 2003 to 2010: Persistence of the ST-269 Clone Since It First Emerged in 2003 
Journal of Clinical Microbiology  2012;50(5):1545-1551.
In the era after the introduction of the meningococcal serogroup C conjugate vaccine, from 1 January 2003 to 31 December 2010, serogroup B meningococci were the major cause of invasive meningococcal disease in the province of Québec, Canada, being responsible for 72% of all meningococcal disease cases. Of the 334 invasive serogroup B Neisseria meningitidis strains analyzed, 53.9% belonged to the ST-269 clonal complex (CC). Since it first emerged in 2003, the percentage of invasive serogroup B isolates that belonged to the ST-269 CC had increased from 35% in 2003 to 76% in 2010. Among the 180 meningococci in the ST-269 CC, 91.7% belonged to a single ST (ST-269). The most common PorA genotypes identified in the ST-269 CC were (i) VR1 19-1, VR2 15-11, VR3 36 (84%) and (ii) VR1 18-7, VR2 9, VR3 35-1 (9%). Cases of invasive disease due to the ST-269 CC were commonly found in those aged 11 to 19 years (30.5%) and 20 to 40 years (25.5%). Meningococci of the ST-269 CC were uncommon in other Canadian provinces. In contrast to the ST-269 CC, invasive serogroup B meningococci that belonged to the ST-41/44 CC were much more diverse genetically. However, one ST (ST-571), which is uncommon in the United States, accounted for 35% of all cases due to this CC. The current finding suggests that the ST-269 clone may indeed represent an emerging hypervirulent clone of meningococci.
PMCID: PMC3347115  PMID: 22337990
15.  The Effect of Immune Selection on the Structure of the Meningococcal Opa Protein Repertoire 
PLoS Pathogens  2008;4(3):e1000020.
The opa genes of the Gram negative bacterium Neisseria meningitidis encode Opacity-associated outer membrane proteins whose role is to promote adhesion to the human host tissue during colonisation and invasion. Each meningococcus contains 3–4 opa loci, each of which may be occupied by one of a large number of alleles. We analysed the Opa repertoire structure in a large, well-characterised collection of asymptomatically carried meningococci. Our data show an association between Opa repertoire and meningococcal lineages similar to that observed previously for meningococci isolated from cases of invasive disease. Furthermore, these Opa repertoires exhibit discrete, non-overlapping structure at a population level, and yet low within-repertoire diversity. These data are consistent with the predictions of a mathematical model of strong immune selection upon a system where identical alleles may occupy different loci.
Author Summary
Neisseria meningitidis is a globally important pathogen that causes 2,000–3,000 cases of invasive meningococcal disease annually in the United Kingdom. The meningococcal Opa proteins are important in mediating adhesion to and invasion of human tissues, and are important for evasion of the host immune response. They are encoded by a repertoire of 3–4 genomic loci in each meningococcus and exhibit high levels of sequence diversity. Here we analyzed the Opa repertoires of a large, well-characterised, asymptomatically carried meningococcal isolate collection. We found that the Opa repertoires were specific to individual meningococcal genotypes, similar to that observed in isolates from cases of invasive disease. These repertoires exhibited discrete, non-overlapping structure at a population level, and yet low within-repertoire diversity. These data were consistent with the predictions of a mathematical model of strong immune selection, suggesting that the collective immune response of the host population shapes the antigenic diversity of the meningococcal Opa repertoire. This study provides new insights into Opa-mediated meningococcal pathogenesis and the effect of host population immunity on the biodiversity and population structure of bacterial pathogens. These data may also have implications for the design of new meningococcal vaccines based on surface proteins.
PMCID: PMC2265424  PMID: 18369470
16.  Genetic and antigenic analysis of invasive serogroup C Neisseria meningitidis in Canada: A decrease in the electrophoretic type (ET)-15 clonal type and an increase in the proportion of isolates belonging to the ET-37 (but not ET-15) clonal type during the period from 2002 to 2009 
Serogroup C meningococcal disease has been endemic in Canada since the early 1990s, with periods of hyperendemic disease documented in the past two decades. The present study characterized invasive serogroup C meningococci in Canada during the period from 2002 to 2009.
Serogroup C meningococci were serotyped using monoclonal antibodies. Their clonal types were identified by either multilocus enzyme electrophoresis or multilocus sequence typing.
The number of invasive serogroup C Neisseria meningitidis isolates received at the National Microbiology Laboratory (Winnipeg, Manitoba) for characterization has dropped from a high of 173 isolates in 2001 to just 17 in 2009, possibly related to the introduction of the serogroup C meningococcal conjugate vaccine. Before 2006, 80% to 95% of all invasive serogroup C meningococci belonged to the electrophoreic type (ET)-15 clonal type, and the ET-37 (but not ET-15) type only accounted for up to 5% of all isolates. However, beginning in 2006, the percentage of the ET-15 clonal type decreased while the ET-37 (but not ET-15) type increased from 27% in 2006 to 52% in 2009. The percentage of invasive serogroup C isolates not belonging to either ET-15 or ET-37 also increased. Most ET-15 isolates expressed the antigenic formula of C:2a:P1.7,1 or C:2a:P1.5. In contrast, the ET-37 (but not ET-15) isolates mostly expressed the antigens of C:2a:P1.5,2 or C:2a:P1.2.
A shift in the antigenic and clonal type of invasive serogroup C meningococi was noted. This finding suggests vigilance in the surveillance of meningoccocal disease is warranted.
PMCID: PMC3476562  PMID: 23997785
ET-15; ET-37; Meningococci; Serogroup C
17.  A common gene pool for the Neisseria FetA antigen 
Meningococcal FetA is an iron-regulated, immunogenic outer membrane protein and vaccine component. The most diverse region of this protein is a previously defined variable region (VR) that has been shown to be immunodominant. In this analysis, a total of 275 Neisseria lactamica isolates, collected during studies of nasopharyngeal bacterial carriage in infants were examined for the presence of a fetA gene. The fetA VR nucleotide sequence was determined for 217 of these isolates, with fetA apparently absent from 58 isolates, the majority of which belonged to the ST-624 clonal complex. The VR in N. lactamica was compared to the same region in Neisseria meningitidis, Neisseria gonorrhoeae and a number of other commensal Neisseria. Identical fetA variable region sequences were identified among commensal and pathogenic Neisseria, suggesting a common gene pool, differing from other antigens in this respect. Carriage of commensal Neisseria species, such as N. lactamica, that express FetA may be involved in the development of natural immunity to meningococcal disease.
PMCID: PMC3968273  PMID: 18718812
FetA; Neisseria meningitidis; commensal Neisseria; gene pool
18.  Meningococcal disease: changes in epidemiology and prevention 
Clinical Epidemiology  2012;4:237-245.
The human bacterial pathogen Neisseria meningitidis remains a serious worldwide health threat, but progress is being made toward the control of meningococcal infections. This review summarizes current knowledge of the global epidemiology and the pathophysiology of meningococcal disease, as well as recent advances in prevention by new vaccines. Meningococcal disease patterns and incidence can vary dramatically, both geographically and over time in populations, influenced by differences in invasive meningococcal capsular serogroups and specific genotypes designated as ST clonal complexes. Serogroup A (ST-5, ST-7), B (ST-41/44, ST-32, ST-18, ST-269, ST-8, ST-35), C (ST-11), Y (ST-23, ST-167), W-135 (ST-11) and X (ST-181) meningococci currently cause almost all invasive disease. Serogroups B, C, and Y are responsible for the majority of cases in Europe, the Americas, and Oceania; serogroup A has been associated with the highest incidence (up to 1000 per 100,000 cases) and large outbreaks of meningococcal disease in sub-Saharan Africa and previously Asia; and serogroups W-135 and X have emerged to cause major disease outbreaks in sub-Saharan Africa. Significant declines in meningococcal disease have occurred in the last decade in many developed countries. In part, the decline is related to the introduction of new meningococcal vaccines. Serogroup C polysaccharide-protein conjugate vaccines were introduced over a decade ago, first in the UK in a mass vaccination campaign, and are now widely used; multivalent meningococcal conjugate vaccines containing serogroups A, C, W-135, and/or Y were first used for adolescents in the US in 2005 and have now expanded indications for infants and young children, and a new serogroup A conjugate vaccine has recently been introduced in sub-Saharan Africa. The effectiveness of these conjugate vaccines has been enhanced by the prevention of person-to-person transmission and herd immunity. In addition, progress has been made in serogroup B-specific vaccines based on conserved proteins and outer membrane vesicles. However, continued global surveillance is essential in understanding and predicting the dynamic changes in the epidemiology and biological basis of meningococcal disease and to influence the recommendations for current and future vaccines or other prevention strategies.
PMCID: PMC3470458  PMID: 23071402
Neisseria meningitidis; meningococcal disease; conjugate vaccines; meningococcal vaccines
19.  Clonal Analysis of Neisseria meningitidis Serogroup B Strains in South Africa, 2002 to 2006: Emergence of New Clone ST-4240/6688 
Journal of Clinical Microbiology  2012;50(11):3678-3686.
From August 1999 through July 2002, hyperinvasive Neisseria meningitidis serogroup B (MenB) clonal complexes (CCs), namely, ST-32/ET-5 (CC32) and ST-41/44/lineage 3 (CC41/44), were predominant in the Western Cape Province of South Africa. This study analyzed MenB invasive isolates from a national laboratory-based surveillance system that were collected from January 2002 through December 2006. Isolates were characterized by pulsed-field gel electrophoresis (PFGE) (n = 302), and multilocus sequence typing (MLST) and PorA and FetA typing were performed on randomly selected isolates (34/302, 11%). In total, 2,400 cases were reported, with the highest numbers from Gauteng Province (1,307/2,400, 54%) and Western Cape Province (393/2,400, 16%); 67% (1,617/2,400) had viable isolates and 19% (307/1,617) were identified as serogroup B. MenB incidence remained stable over time (P = 0.77) (average incidence, 0.13/100,000 population [range, 0.10 to 0.16/100,000 population]). PFGE (302/307, 98%) divided isolates (206/302, 68%) into 13 clusters and 96 outliers. The largest cluster, B1, accounted for 25% of isolates (76/302) over the study period; its prevalence decreased from 43% (20/47) in 2002 to 13% (8/62) in 2006 (P < 0.001), and it was common in the Western Cape (58/76, 76%). Clusters B2 and B3 accounted for 10% (31/302) and 6% (19/302), respectively, and showed no significant change over time and were predominant in Gauteng. Randomly selected isolates from clusters B1, B2, and B3 belonged to CC32, CC41/44, and the new CC4240/6688, respectively. Overall, 15 PorA and 12 FetA types were identified. MenB isolates were mostly diverse with no single dominant clone; however, CC32 and CC41/44 accounted for 35% and the new CC4240/6688 was the third most prevalent clone.
PMCID: PMC3486271  PMID: 22972827
20.  Characterization of serogroup A Neisseria meningitidis from invasive meningococcal disease cases in Canada between 1979 and 2006: Epidemiological links to returning travellers 
Serogroup A Neisseria meningitidis has repeatedly caused epidemics of invasive meningococcal disease (IMD) in developing nations since the 1960s. The present study is the first detailed study of serogroup A bacteria isolated in Canada.
Thirty-four serogroup A meningococcal isolates collected from individuals with IMD in Canada between 1979 and 2006 were characterized by serology and multilocus sequence typing of seven housekeeping enzyme genes and genes encoding three outer membrane protein antigens.
Isolates were assigned to either the sequence type (ST)-1 or the ST-5 clonal complex. Clones within the ST-1 complex were recovered between 1979 and 1992, while clones of the ST-5 complex were isolated between 1987 and 2006; respectively, they accounted for 70.6% and 29.4% of all isolates studied. Isolates of the ST-1 complex were characterized by serosubtype antigen P1.3 or P1.3,6 with PorB allele 60 (serotype 4) and FetA sequence F5-1, while isolates of the ST-5 complex were characterized by serosubtype antigen P1.9 with PorB allele 47 (also serotype 4) and FetA sequence F3-1.
The Canadian serogroup A IMD isolates likely originated in travellers returning from hyperendemic or epidemic areas of the globe where serogroup A bacteria circulate. Although the Canadian cases of serogroup A IMD were caused by clones known to have caused epidemics in developing countries, disease incidence remained low in Canada.
PMCID: PMC2605869  PMID: 19412379
Canada; Invasive meningococcal disease; Neisseria meningitides; Serogroup A
21.  Clonal diversity of Neisseria meningitidis from a population of asymptomatic carriers. 
Infection and Immunity  1988;56(8):2060-2068.
Genetic diversity and relationships among 109 isolates of Neisseria meningitidis obtained from throat cultures of healthy individuals in Norway in 1984 were assessed by analyzing electrophoretically demonstrable allelic variation at 15 enzyme-encoding chromosomal genes. Seventy-eight distinctive electrophoretic types (ETs), representing multilocus genotypes, were identified. The mean genetic diversity per locus among the 78 ETs (0.538) was equivalent to that among 19 ETs represented by 66 isolates collected from patients with meningococcal disease in Norway in the first 5 months of 1984. The clonal composition of the collection of carrier strains was, however, quite different from that of strains from patients. The two groups of clones, the ET-5 complex and the ET-37 complex, that were responsible for 91% of the cases of systemic disease in Norway in 1984 were identified in only 7 and 9%, respectively, of the throat cultures from healthy individuals, and their frequencies in the human population sampled were only 0.7% for clones of the ET-5 complex and 0.9% for those of the ET-37 complex. The complex of clones that was most frequently represented by isolates from carriers (19%) has never been recovered from patients with meningococcal disease in Norway or elsewhere, which suggests that these clones have a low virulence potential. Children attending the same day care center or school seldom harbored the same clone in their throats.
PMCID: PMC259523  PMID: 3135270
22.  Persistence of Hyperinvasive Meningococcal Strain Types during Global Spread as Recorded in the PubMLST Database 
PLoS ONE  2012;7(9):e45349.
Neisseria meningitidis is a major cause of septicaemia and meningitis worldwide. Most disease in Europe, the Americas and Australasia is caused by meningococci expressing serogroup B capsules, but no vaccine against this polysaccharide exists. Potential candidates for ‘serogroup B substitute’ vaccines are outer membrane protein antigens including the typing antigens PorA and FetA. The web-accessible PubMLST database ( was used to investigate the temporal and geographical patterns of associations among PorA and FetA protein variants and lineages defined by combinations of housekeeping genes, known as clonal complexes. The sample contained 3460 isolates with genotypic information from 57 countries over a 74 year period. Although shifting associations among antigen variants and clonal complexes were evident, a subset of strain types associated with several serogroups persisted for decades and proliferated globally. Genetic stability among outer membrane proteins of serogroup A meningococci has been described previously, but here long-lived genetic associations were also observed among meningococci belonging to serogroups B and C. The patterns of variation were consistent with behaviour predicted by models that invoke inter-strain competition mediated by immune selection. There was also substantial geographic and temporal heterogeneity in antigenic repertoires, providing both opportunities and challenges for the design of broad coverage protein-based meningococcal vaccines.
PMCID: PMC3460945  PMID: 23028953
23.  Influence of the combination and phase variation status of the haemoglobin receptors HmbR and HpuAB on meningococcal virulence 
Microbiology  2011;157(Pt 5):1446-1456.
Neisseria meningitidis can utilize haem, haemoglobin and haemoglobin–haptoglobin complexes as sources of iron via two TonB-dependent phase variable haemoglobin receptors, HmbR and HpuAB. HmbR is over-represented in disease isolates, suggesting a link between haemoglobin acquisition and meningococcal disease. This study compared the distribution of HpuAB and phase variation (PV) status of both receptors in disease and carriage isolates. Meningococcal disease (n = 214) and carriage (n = 305) isolates representative of multiple clonal complexes (CCs) were investigated for the distribution, polyG tract lengths and ON/OFF status of both haemoglobin receptors, and for the deletion mechanism for HpuAB. Strains with both receptors or only hmbR were present at similar frequencies among meningococcal disease isolates as compared with carriage isolates. However, >90 % of isolates from the three CCs CC5, CC8 and CC11 with the highest disease to carriage ratios contained both receptors. Strains with an hpuAB-only phenotype were under-represented among disease isolates, suggesting selection against this receptor during systemic disease, possibly due to the receptor having a high level of immunogenicity or being inefficient in acquisition of iron during systemic spread. Absence of hpuAB resulted from either complete deletion or replacement by an insertion element. In an examination of PV status, one or both receptors were found in an ON state in 91 % of disease and 71 % of carriage isolates. We suggest that expression of a haemoglobin receptor, either HmbR or HpuAB, is of major importance for systemic spread of meningococci, and that the presence of both receptors contributes to virulence in some strains.
PMCID: PMC3352162  PMID: 21310784
24.  Molecular Epidemiology of Neisseria meningitidis Serogroup B in Brazil 
PLoS ONE  2012;7(3):e33016.
Neisseria meningitidis serogroup B has been predominant in Brazil, but no broadly effective vaccine is available to prevent endemic meningococcal disease. To understand genetic diversity among serogroup B strains in Brazil, we selected a nationally representative sample of clinical disease isolates from 2004, and a temporally representative sample for the state of São Paulo (1988–2006) for study (n = 372).
We performed multi-locus sequence typing (MLST) and sequence analysis of five outer membrane protein (OMP) genes, including novel vaccine targets fHbp and nadA.
In 2004, strain B:4:P1.15,19 clonal complex ST-32/ET-5 (cc32) predominated throughout Brazil; regional variation in MLST sequence type (ST), fetA, and porB was significant but diversity was limited for nadA and fHbp. Between 1988 and 1996, the São Paulo isolates shifted from clonal complex ST-41/44/Lineage 3 (cc41/44) to cc32. OMP variation was associated with but not predicted by cc or ST. Overall, fHbp variant 1/subfamily B was present in 80% of isolates and showed little diversity. The majority of nadA were similar to reference allele 1.
A predominant serogroup B lineage has circulated in Brazil for over a decade with significant regional and temporal diversity in ST, fetA, and porB, but not in nadA and fHbp.
PMCID: PMC3303791  PMID: 22431994
25.  Preclinical evidence for the potential of a bivalent fHBP vaccine to prevent Neisseria meningitidis serogroup C disease 
Human Vaccines  2011;7(Suppl):68-74.
A bivalent factor H binding protein (fHBP) vaccine for the prevention of disease caused by Neisseria meningitidis serogroup B is currently in clinical development. Since fHBP is also expressed by other meningococcal serogroups, antifHBP antibodies may have bactericidal activity against meningococci independent of serogroup. To begin examining the susceptibility of other meningococcal serogroups to anti-fHBP antibodies, meningococcal serogroup C invasive isolates (n = 116) were collected from the Centers for Disease Control and Prevention's Active Bacterial Core surveillance (ABCs) sites during 2000–2001. These isolates were analyzed for the presence of the fhbp gene. All serogroup C isolates contained the gene, and sequence analysis grouped the proteins into two subfamilies, A and B. Flow cytometry analysis demonstrated that fHBP was expressed on the surface of ∼70% of isolates in vitro with varying levels of expression. fHBP was accessible to antibodies on the cell surface even in the presence of the polysaccharide capsule. Nine isolates from different geographic regions were identified which harboured an identical single nucleotide deletion that could result in a truncated subfamily B fHBP. Analysis by flow cytometry using a polyclonal fHBP antibody preparation revealed that a subpopulation of each of these isolates expressed fHBP. rabbit and non-human primate immune sera generated with bivalent fHBP vaccine were tested for bactericidal activity against a panel of diverse serogroup C clinical isolates using human complement. Sera from both species demonstrated serum bactericidal antibody activity against the serogroup C isolates tested. These promising findings suggest that a bivalent fHBP vaccine may be capable of providing protection against meningococcal disease caused by both serogroup C and B.
PMCID: PMC3367671  PMID: 21245657
Neisseria meningitidis serogroup C; vaccine; fHBP

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