Genetic basis for nongroupable Neisseria meningitidis

Nongroupable Neisseria meningitidis may constitute one-third or more of meningococcal isolates recovered from the nasopharynx of human carriers. The genetic basis for nongroupability was determined in isolates obtained from a population-based study in which 60 (30.9%) of 194 meningococcal isolates from asymptomatic carriers were not groupable. Forty-two percent of nongroupable isolates were related to serogroup Y ET-508/ST-23 clonal complex strains, the most common groupable carrier isolate from the study population. Nongroupable isolates were all rapidly killed by 10% normal human serum. The capsule loci of 6 of the ET-508/ST-23 complex strains and of 25 other genetically diverse nongroupable meningococci were studied in detail. Serogroup A or novel capsule biosynthesis genes were not found. Nongroupable isolates were genetically serogroup Y, B, or C isolates that did not express capsule but were related to groupable isolates found in the population (class I); capsule deficient because of insertion element-associated deletions of capsule biosynthesis genes (class II); or isolates that lacked all capsule genes and formed a distinct genetic cluster not associated with meningococcal disease (class III).     

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

BACKGROUND:

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.

METHODS:

Serogroup C meningococci were serotyped using monoclonal antibodies. Their clonal types were identified by either multilocus enzyme electrophoresis or multilocus sequence typing.

RESULTS:

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.

CONCLUSION:

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.     

Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination

The UK was the first place to introduce meningococcal serogroup C conjugate (MCC) vaccines. From November, 1999, all people younger than 18 years, about 14 million individuals, were offered MCC immunisation. The uptake rate was more than 70% by November, 2000. We compared the carriage of meningococci in isolates we obtained from 14,064 students aged 15-17 years during vaccination in 1999, with those from 16,583 students of the same age surveyed 1 year later. Carriage of serogroup C meningococci was reduced by 66% (p=0.004). Our results show that MCC vaccines protect against carriage of meningococci that express serogroup C polysaccharide capsules.     

Neisseria meningitidis serogroup W-135 carriage among US travelers to the 2001 Hajj

In 2000, a large international outbreak of meningococcal disease caused by Neisseria meningitidis serogroup W-135 was identified among pilgrims returning from the Hajj in Saudi Arabia. To assess ongoing risk, we evaluated N. meningitidis carriage among US travelers to the 2001 Hajj. Of 25 N. meningitidis isolates obtained, 15 (60%) were nongroupable and 8 (32%) were serogroup W-135 when tested by standard slide-agglutination techniques. Two additional nongroupable isolates were characterized as serogroup W-135 when tested by polymerase chain reaction. Nine of 10 serogroup W-135 isolates were indistinguishable from the Hajj-2000 clone. None of the departing, but 9 (1.3%) of the returning, pilgrims carried serogroup W-135 (P=.01); all carriers reported previous vaccination. Carriage of N. meningitidis serogroup W-135 increased significantly in pilgrims returning from the Hajj. Although the risk of disease to pilgrims appears to be low, the risk of spread to others of this pathogenic strain remains a concern.     

Carriage of serogroup W-135, ET-37 meningococci in The Gambia: implications for immunisation policy?

We found high levels of symptomless carriage of a hyperinvasive Neisseria meningitidis strain (electrophoretic type 37 [ET-37], serogroup W-135) during a vaccine trial in Gambian children in 1996. Serogroup C, ET-37 complex meningococci cause 30-40% of meningococcal disease in countries such as the UK, and have a point prevalence of 0.5-1.0%. The recent Haj-associated spread of serogroup W-135, ET-37 complex meningococci, which has been accompanied by numerous secondary cases, might be explained by the apparently raised carriage rates reported here.     

Lack of immunity in university students before an outbreak of serogroup C meningococcal infection

Immunity to meningococci was determined in infected and uninfected students before and during an outbreak of serogroup C meningococcal infection at a university in the United Kingdom. No immunity against the outbreak strain was detected in serum taken from infected students prior to the outbreak or at the time of admission; bactericidal activity developed during convalescence. Carriage of all strains of serogroup C meningococci in asymptomatic students was low (0.9%), and no carriage of the outbreak strain could be detected. Immunity in the at-risk student population before the outbreak was low: 90% of students had no significant bactericidal activity against the outbreak strain. A low prevalence of carriage of the outbreak strain, together with a low prevalence of protective immunity within the student population, was associated with a high incidence of invasive disease in those who acquired the outbreak strain.     

Prospective study of a serogroup X Neisseria meningitidis outbreak in northern Ghana

After an epidemic of serogroup A meningococcal meningitis in northern Ghana, a gradual disappearance of the epidemic strain was observed in a series of five 6-month carriage surveys of 37 randomly selected households. As serogroup A Neisseria meningitidis carriage decreased, an epidemic of serogroup X meningococcal carriage occurred, which reached 18% (53/298) of the people sampled during the dry season of 2000, coinciding with an outbreak of serogroup X disease. These carriage patterns were unrelated to that of Neisseria lactamica. Multilocus sequence typing and pulsed-field gel electrophoresis of the serogroup X bacteria revealed strong similarity with other strains isolated in Africa during recent decades. Three closely related clusters with distinct patterns of spread were identified among the Ghanian isolates, and further microevolution occurred after they arrived in the district. The occurrence of serogroup X outbreaks argues for the inclusion of this serogroup into a multivalent conjugate vaccine against N. meningitidis.     

Emergence of W135 meningococcal meningitis in Ghana

Neisseria meningitidis serogroup W135, well known for a long time as a cause of isolated cases of meningococcal meningitis, has recently increasingly been associated with disease outbreaks of considerable magnitude. Burkina Faso was hit by W135 epidemics in the dry seasons of 2002-2004, but only four W135 meningitis cases were recorded between February 2003 and March 2004 in adjoining Ghana. This reconfirms previous findings that bottlenecks exist in the spreading of new epidemic N. meningitidis clones within the meningitis belt of sub-Saharan Africa. Of the four Ghanaian W135 meningitis patients one died and three survived, of whom one had profound neurosensory hearing loss and speech impairment. All four disease isolates were sensitive to penicillin G, chloramphenicol, ciprofloxacin and cefotaxime and had the multi-locus sequence type (ST) 11, which is the major ST of the ET-37 clonal complex. Pulsed-field gel electrophoresis (PFGE) profiles of the Ghanaian disease isolates and recent epidemic isolates from Burkina Faso were largely identical. We conducted meningococcal colonization surveys in the home communities of three of the patients and in the Kassena Nankana District located at the border to Burkina Faso. W135 carriage rates ranged between 0% and 17.5%. When three consecutive surveys were conducted in the patient community with the highest carrier rate, persistence of W135 colonization over a period of 1 year was observed. Differences in PFGE profiles of carrier isolates taken at different times in the same patient community were indicative of rapid microevolution of the W135 bacteria, emphasizing the need for innovative fine typing methods to reveal the relationship between W135 isolates.     

Surveillance of invasive meningococcal disease in the Czech Republic

Routine notification of invasive meningococcal disease has a long tradition in the Czech Republic: mortality data are available from 1921 and morbidity data from 1943. The collection of Neisseria meningitidis strains kept in the NRL for Meningococcal Infections in Prague dates from 1970 onwards, and represents more than 3500 strains isolated from invasive disease and their contacts, from healthy carriers and from respiratory infection. Analysis of these strains showed that the Czech meningococcal population is different from that seen in western Europe. In 1993, the incidence serogroup C meningococcal disease increased and was associated with the emergence of the hypervirulent complex Neisseria meningitidis C, ST-11, ET-15/37, and caused an increase in the incidence of invasive meningococcal disease which peaked in 1995 (2.2/100,000). A vaccination strategy targeting the part of the population at highest risk of invasive meningococcal disease was adopted in the country.     

Genetic analysis of meningococci carried by children and young adults

BACKGROUND: Neisseria meningitidis is a diverse commensal bacterium that occasionally causes severe invasive disease. The relationship between meningococcal genotype and capsular polysaccharide, the principal virulence factor and vaccine component, was investigated in carried meningococci isolated from 8000 children and young adults in Bavaria, Germany. METHODS: Of the 830 meningococci isolated (carriage rate, 10.4%) by microbiological techniques, 822 were characterized by serogrouping, multilocus sequence typing, and genetic analysis of the capsule region. Statistical and population genetic analyses were applied to these data. RESULTS: The rapid increase in carriage rates with age of carrier, the low prevalence of hyperinvasive meningococci, and the relative prevalence of the 4 disease-associated serogroups were consistent with earlier observations. There was no genetic structuring of the meningococcal population by age of carrier or sampling location; however, there was significant geographic structuring of the meningococci isolated in civil, but not military, institutions. The rate of capsule gene expression did not vary with age of carrier or meningococcal genotype, except for serogroup C, for which increased expression was associated with ST-11 (formerly ET-37) complex meningococci. CONCLUSIONS: Serogroup C capsule expression during carriage may contribute to the invasive character of ST-11 complex meningococci and to the high efficacy of meningococcal serogroup C conjugate polysaccharide vaccine.     

Meningococcal disease and control in China: Findings and updates from the Global Meningococcal Initiative (GMI)

The Global Meningococcal Initiative (GMI) is a global expert group, including scientists, clinicians and public health officials from a wide range of specialities. The goal of the GMI is to prevent meningococcal disease worldwide through education, research, and co-operation. The Chinese GMI roundtable meeting was held in June 2017. The GMI met with local experts to gain insight into the meningococcal disease burden in China and current prevention and vaccination strategies in place. China experienced five epidemics of serogroup A meningococcal disease (MenA) between 1938 and 1977, with peak incidence of 403/100,000 recorded in 1967. MenA incidence rates have significantly declined following the universal introduction of the MenA polysaccharide vaccine in China in the 1980s. Further, surveillance data indicates changing meningococcal epidemiology in China with the emergence of new clones of serogroup B from serogroup C clonal complex (cc) 4821 due to capsular switching, and the international spread of serogroup W cc11. The importance of carriage and herd protection for controlling meningococcal disease was highlighted with the view to introduce conjugate vaccines and serogroup B vaccines into the national immunization schedule. Improved disease surveillance and standardized laboratory techniques across and within provinces will ensure optimal epidemiological monitoring.     

Outbreak of W135 meningococcal disease in 2000: not emergence of a new W135 strain but clonal expansion within the electophoretic type-37 complex

In 2000, >400 cases of disease caused by Neisseria meningitidis serogroup W135 (MenW135), the largest MenW135 outbreak reported to date, occurred worldwide among Hajj pilgrims and their contacts. To elucidate the origin of the outbreak strains and to investigate their relatedness to major clonal groups, genotypic and phenotypic subtyping was performed on 26 MenW135 outbreak-associated isolates and 50 MenW135 isolates collected worldwide from 1970 through 2000. All outbreak-associated isolates were members of a single clone of the hypervirulent electrophoretic type (ET)-37 complex, designated the "(W)ET-37 clone"; 19 additional MenW135 strains were also members of this clone, and the remaining 31 MenW135 strains were clearly distinct. The 2000 MenW135 outbreak was not caused by emergence of a new MenW135 strain but rather by expansion of the (W)ET-37 clone that has been in circulation at least since 1970; the strains most closely related to those causing the 2000 outbreak have been isolated in Algeria, Mali, and The Gambia in the 1990s.     

Meningitis caused by a serogroup W135 clone of the ET-37 complex of Neisseria meningitidis in West Africa

Summary Meningococci belonging to serogroup W135 caused several cases of meningococcal meningitis in The Gambia in 1995 and were isolated during a serogroup A epidemic in Mali in 1994. The eight isolates tested belonged to the same clone of the ET-37 complex and differed in several bands from the pulsed-field gel electrophoresis restriction pattern of serogroup C meningococci of the ET-37 complex isolated in Mali. Three of 6 patients infected in The Gambia died, indicating that this W135 clone is virulent. Vaccines that protect only against infections with meningococci belonging to serogroups A and C are usually used to control outbreaks in Africa, although vaccines containing the W135 polysaccharide are available. The findings of this study indicate that outbreaks of meningococcal meningitis in Africa can be associated with serogroup W135 infections and that serogrouping is essential before vaccination campaigns are started.     

Meningococcal carriage in the African meningitis belt

A meningococcal serogroup A polysaccharide/tetanus toxoid conjugate vaccine (PsA‐TT) (MenAfriVac^?) is being deployed in countries of the African meningitis belt. Experience with other polysaccharide/protein conjugate vaccines has shown that an important part of their success has been their ability to prevent the acquisition of pharyngeal carriage and hence to stop transmission and induce herd immunity. If PsA‐TT is to achieve the goal of preventing epidemics, it must be able to prevent the acquisition of pharyngeal carriage as well as invasive meningococcal disease and whether PsA‐TT can prevent pharyngeal carriage needs to be determined. To address this issue, a consortium (the African Meningococcal Carriage (MenAfriCar) consortium) was established in 2009 to investigate the pattern of meningococcal carriage in countries of the African meningitis belt prior to and after the introduction of PsA‐TT. This article describes how the consortium was established, its objectives and the standardised field and laboratory methods that were used to achieve these objectives. The experience of the MenAfriCar consortium will help in planning future studies on the epidemiology of meningococcal carriage in countries of the African meningitis belt and elsewhere.     

Neisseria meningitidis serogroups A and W-135: carriage and immunity in Burkina Faso, 2003

OBJECTIVES: We sought to describe Neisseria meningitidis immunity and its association with pharyngeal carriage in Burkina Faso, where N. meningitidis serogroup W-135 and serogroup A disease are hyperendemic and most of the population received polysaccharide A/C vaccine during 2002. METHODS: We collected oropharyngeal swab samples from healthy residents of Bobo-Dioulasso (4-14 years old, n=238; 15-29 years old, n=250) monthly during February-June 2003; N. meningitidis isolates were analyzed using polymerase chain reaction and serogrouped using immune sera. Serum samples were collected at the first and last clinic visit and analyzed for anti-A, anti-C, anti-W-135, and anti-Y immunoglobulin G (IgG) concentrations and anti-A and anti-W-135 bactericidal titers. RESULTS: N. meningitidis was carried at least once by 18% of participants; this carriage included strains from serogroups W-135 (5%) and Y and X (both <1%) but not from serogroups A, B, or C. At baseline, the prevalence of putatively protective specific IgG concentrations (> or =2 microg/mL) and bactericidal titers (> or =8) was 85% and 54%, respectively, against serogroup A, and 6% and 22%, respectively, against serogroup W-135. Putatively protective anti-W-135 IgG concentrations and bactericidal titers were of short duration and were not associated with carriage. CONCLUSION: N. meningitidis serogroup W-135 strains did not induce immunity, despite their circulation. Carriage of serogroup A strains was rare despite the hyperendemic incidence of serogroup A meningitis during 2003 in Bobo-Dioulasso. A vaccine that includes serogroup W-135 antigen and eliminates serogroup A carriage is needed for sub-Saharan Africa.     

Serogroup W135 meningococcal disease in Hajj pilgrims

An outbreak of W135 meningococcal disease occurred in the spring of 2000 among pilgrims returning from Saudi Arabia and their contacts. Clinical isolates from England and France were examined and compared with reference strains from other countries. Characterisation of isolates by a range of typing methods showed them to be of clonal origin (ET-37) and closely related to other meningococci with an established propensity to cause disease clusters. A reappraisal of vaccination strategies for travellers is required.     

Meningococcal carriage in relation to an outbreak of invasive disease due to Neisseria meningitidis serogroup C in the Netherlands.

BACKGROUND: a cross-sectional study on meningococcal carriage was performed in Putten, a small rural town in the Netherlands where an unusual high incidence of invasive meningococcal disease (IMD) due to Neisseria meningitidis C:2a:P1.5 occurred. The outbreak was controlled by mass vaccination of all inhabitants aged 2 to 20 years. METHODS: meningococcal carriage was studied in three groups: (1) a systematic age-specific sample of 2-20 year olds who visited the immunization clinic in Putten (January 1998: n=411); (2) children and adolescents in the same age range recruited through a kindergarten and schools in Venlo, a town where the causative strain of IMD had not been encountered (February 1998; n=374); (3) all initial carriers in Putten and a sample of non-carriers in that town (March 1998: n=145). Oropharyngeal swabs were taken for the purpose of isolating N. menigitidis. RESULTS: the prevalence of carriage was 12.4% in Putten and 18.2%, in Venlo, but the prevalence of group C meningococci was higher in Putten (1.7%) than Venlo (0.5%). N. meningitidis C:2a:P1.5 was isolated twice in Putten and not at all in Venlo. A second examination in Putten showed that 18 of the 22 repeatedly tested carriers were still carriers, and six new carriers were found among the 55 initial non-carriers. Of the two known carriers of C:2a:P1.5, one was still carrying the same strain, and the other did not participate in the second investigation. Carriage was associated with increasing family size, discotheque visits and visits to youth clubs and sports clubs. In contrast, visits to the swimming pool appeared to be related to a lower risk, as was recent antibiotic use. CONCLUSION: the prevalence of carriage with the invasive strain C:2a:P1.5 was low in the population that experienced a community-wide outbreak recently: the specific strain was not found in the reference population. This indicates a relatively high risk of developing the invasive disease for those who become infected with such strains.     

Systematic review: Impact of meningococcal vaccination on pharyngeal carriage of meningococci

Objective To investigate the effect of meningococcal vaccines on pharyngeal carriage of meningococci. Methods Systematic review. MEDLINE and EMBASE were searched for relevant studies. Controlled trials and observational studies which used comparison groups or compared carriage rates before and after vaccination were included in the review. Results Twenty‐nine studies satisfied the inclusion criteria. Twenty‐five studies reported the effect of a polysaccharide vaccine, one the effect of a serogroup C conjugate vaccine and three the impact of serogroup B outer‐membrane vaccines on overall and/or serogroup‐specific meningococcal carriage rates. Ten studies of meningococcal polysaccharide vaccines found reduced serogroup‐specific carriage; seven of these focussed on high‐risk groups and had a short follow‐up period. Only one of five studies of civilian populations in Africa showed a significantly reduced carriage. Many studies had methodological shortcomings. The one study which assessed the effect of a meningococcal conjugate vaccine on carriage showed a significant impact. Three studies of serogroup B outer‐membrane protein vaccines showed no effect on carriage. Conclusions A few well‐designed trials of the impact of meningococcal vaccines on carriage have been undertaken. Such studies should be an essential component of the evaluation of new meningococcal vaccines, particularly those introduced to control epidemic meningococcal disease in Africa.     

Emergence of endemic serogroup W135 meningococcal disease associated with a high mortality rate in South Africa.

BACKGROUND: In the African meningitis belt, Neisseria meningitidis serogroup W135 has emerged as a cause of epidemic disease. The establishment of W135 as the predominant cause of endemic disease has not been described. METHODS: We conducted national laboratory-based surveillance for invasive meningococcal disease during 2000-2005. The system was enhanced in 2003 to include clinical data collection of cases from sentinel sites. Isolates were characterized by pulsed-field gel electrophoresis and multilocus sequence typing. RESULTS: A total of 2135 cases of invasive meningococcal disease were reported, of which 1113 (52%) occurred in Gauteng Province, South Africa. In this province, rates of disease increased from 0.8 cases per 100,000 persons in 2000 to 4.0 cases per 100,000 persons in 2005; the percentage due to serogroup W135 increased from 7% (4 of 54 cases) to 75% (221 of 295 cases). The median age of patients infected with serogroup W135 was 5 years (interquartile range, 2-23 years), compared with 21 years (range, 8-26 years) for those infected with serogroup A (P<.001). The incidence of W135 disease increased in all age groups. Rates were highest among infants (age, <1 year), increasing from 5.1 cases per 100,000 persons in 2003 to 21.5 cases per 100,000 persons in 2005. Overall case-fatality rates doubled, from 11% in 2003 to 22% in 2005. Serogroup W135 was more likely to cause meningococcemia than was serogroup A (82 [28%] of 297 cases vs. 11 [8%] of 141 cases; odds ratio, 8.9, 95% confidence interval, 2.2-36.3). A total of 285 (95%) of 301 serogroup W135 isolates were identified as 1 clone by pulsed-field gel electrophoresis; 7 representative strains belonged to the ST-11/ET-37 complex. CONCLUSIONS: Serogroup W135 has become endemic in Gauteng, South Africa, causing disease of greater severity than did the previous predominant serogroup A strain.     

Antibodies against IgA1 protease are stimulated both by clinical disease and asymptomatic carriage of serogroup A Neisseria meningitidis.

IgA1 protease was purified from a strain of serogroup A Neisseria meningitidis subgroup IV-1, representative of bacteria that caused an epidemic of meningococcal meningitis in The Gambia in 1982-1983. ELISAs and immunoblot assays were done using this protease as antigen with paired acute- and convalescent-phase sera from patients from that epidemic and from one in Finland caused by other serogroup A meningococci. Paired sera were also tested from healthy Gambians who were persistent nasopharyngeal carriers, persistent noncarriers, or persons who became carriers after the first serum sample was taken. The results correlated well between the two methods: Antibodies were stimulated by disease or acquisition of carriage, and they remained at a constant level upon continued carriage.