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1.  Shifts in the Antibiotic Susceptibility, Serogroups, and Clonal Complexes of Neisseria meningitidis in Shanghai, China: A Time Trend Analysis of the Pre-Quinolone and Quinolone Eras 
PLoS Medicine  2015;12(6):e1001838.
Background
Fluoroquinolones have been used broadly since the end of the 1980s and have been recommended for Neisseria meningitidis prophylaxis since 2005 in China. The aim of this study was to determine whether and how N. meningitidis antimicrobial susceptibility, serogroup prevalence, and clonal complex (CC) prevalence shifted in association with the introduction and expanding use of quinolones in Shanghai, a region with a traditionally high incidence of invasive disease due to N. meningitidis.
Methods and Findings
A total of 374 N. meningitidis isolates collected by the Shanghai Municipal Center for Disease Control and Prevention between 1965 and 2013 were studied. Shifts in the serogroups and CCs were observed, from predominantly serogroup A CC5 (84%) in 1965–1973 to serogroup A CC1 (58%) in 1974–1985, then to serogroup C or B CC4821 (62%) in 2005–2013. The rates of ciprofloxacin nonsusceptibility in N. meningitidis disease isolates increased from 0% in 1965–1985 to 84% (31/37) in 2005–2013 (p < 0.001). Among the ciprofloxacin-nonsusceptible isolates, 87% (27/31) were assigned to either CC4821 (n = 20) or CC5 (n = 7). The two predominant ciprofloxacin-resistant clones were designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A. The ChinaCC4821-R1-C/B clone acquired ciprofloxacin resistance by a point mutation, and was present in 52% (16/31) of the ciprofloxacin-nonsusceptible disease isolates. The ChinaCC5-R14-A clone acquired ciprofloxacin resistance by horizontal gene transfer, and was found in 23% (7/31) of the ciprofloxacin-nonsusceptible disease isolates. The ciprofloxacin nonsusceptibility rate was 47% (7/15) among isolates from asymptomatic carriers, and nonsusceptibility was associated with diverse multi-locus sequence typing profiles and pulsed-field gel electrophoresis patterns. As detected after 2005, ciprofloxacin-nonsusceptible strains were shared between some of the patients and their close contacts. A limitation of this study is that isolates from 1986–2004 were not available and that only a small sample of convenience isolates from 1965–1985 were available.
Conclusions
The increasing prevalence of ciprofloxacin resistance since 2005 in Shanghai was associated with the spread of hypervirulent lineages CC4821 and CC5. Two resistant meningococcal clones ChinaCC4821-R1-C/B and ChinaCC5-R14-A have emerged in Shanghai during the quinolone era. Ciprofloxacin should be utilized with caution for the chemoprophylaxis of N. meningitidis in China.
Minggui Wang and colleagues assess the genetic origin and changing prevalence of N. meningitidis resistance to ciprofloxacin.
Editors' Summary
Background
Meningitis is a viral, bacterial, or fungal infection of the meninges, the thin membrane that covers the brain and the spinal cord. Neisseria meningitidis is the most common cause of bacterial meningitis in children and is a leading cause of meningitis in adults. N. meningitidis lives harmlessly in the mucous membranes of the nose and throat of 10%–20% of human beings. These symptom-free (asymptomatic) carriers are crucial to the transmission of N. meningitidis, which spreads from person to person through droplets of respiratory or throat secretions produced by infected individuals. Although N. meningitidis usually causes no harm, it occasionally overwhelms its host’s immune system and spreads through the bloodstream and into the brain. The characteristic symptoms of meningococcal meningitis—a rash, fever, stiff neck, sensitivity to light, confusion, headaches, and vomiting—then develop rapidly. Even with early treatment with intravenous antibiotics, about 10% of the 1.2 million people affected by meningococcal meningitis every year die, usually within 24–48 hours of symptom development.
Why Was This Study Done?
Meningococcal meningitis can be prevented by vaccination against N. meningitidis. In addition, experts recommend that the family and close contacts of anyone with meningococcal meningitis be treated immediately with antibiotics to stop the disease spreading (N. meningitidis prophylaxis). The quinolone antibiotic ciprofloxacin is sometimes recommended for N. meningitidis prophylaxis, but quinolones have been used to treat many bacterial infections since the late 1980s and ciprofloxacin-resistant strains of N. meningitidis have recently emerged in some countries. Thus, policymakers in countries where ciprofloxacin may be used for meningococcal prophylaxis (for example, China, which has recommended several antibiotics, including ciprofloxacin, for meningococcal prophylaxis since 2005) need to know whether and how the susceptibility of N. meningitidis to ciprofloxacin is changing in their country. In this time trend analysis, the researchers investigate how the ciprofloxacin susceptibility, serogroup prevalence, and clonal complex prevalence of N. meningitidis have shifted in association with increasing use of quinolones in Shanghai (China), a region where many cases of meningococcal disease occur. A serogroup is a group of bacteria that carries a common antigen (a molecule recognized by the immune system); the prevalence of a serogroup is the proportion of the infected population that carries that serogroup. Only some N. meningitidis serogroups cause meningococcal disease. A clonal complex is a group of genetically related bacteria that may share genes that confer resistance to antibiotics. A strain of N. meningitidis is classified by both its serogoup and its clonal complex; the changing composition of prevalent strains can inform projections for disease spread and plans for disease management, including recommendations for prophylaxis.
What Did the Researchers Do and Find?
The researchers analyzed the characteristics of 374 N. meningitidis isolates collected in Shanghai between 1965 and 2013 from patients with meningococcal disease, their close contacts, and asymptomatic N. meningitidis carriers identified in throat swab surveys. N. meningitidis serogroups and clonal complexes (CCs) shifted from predominantly serogroup A CC5 among isolates collected in 1965–1973, to serogroup A CC1 in 1974–1985, and to serogroup C or B CC4821 in 2005–2013. Notably, the rate of nonsusceptibility to ciprofloxacin in isolates from people with meningococcal meningitis increased from 0% in 1965–1985 to 84% in 2005–2013, and 87% (27/31) of the ciprofloxacin-nonsusceptible disease isolates belonged to either CC4821 or CC5. The researchers identified the two predominant ciprofloxacin-resistant strains (designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A) and showed that a different genetic alteration was responsible for the acquisition of antibiotic resistance in the two strains. Finally, the researchers report that, after 2005, the rate of ciprofloxacin nonsusceptibility among N. meningitidis isolates from asymptomatic carriers was 47%, and that some of the individuals with meningococcal meningitis shared nonsusceptible strains with their close contacts.
What Do These Findings Mean?
These findings suggest that the increased prevalence of ciprofloxacin resistance seen in Shanghai since 2005 is associated with the spread of two hypervirulent clonal complexes of N. meningitidis (CC4821 and CC5) among individuals with meningococcal disease and within the healthy population. The findings also identify two resistant meningococcal strains (ChinaCC4821-R1-C/B and ChinaCC5-R14-A) that have emerged in Shanghai since the use of quinolones to treat bacterial infections became widespread. Because this time trend analysis is based on a limited number of meningococcal isolates and because the researchers analyzed very few isolates collected between 1965 and 1985 and none collected between 1986 and 2004, this study cannot pinpoint exactly when, where, or how ciprofloxacin-resistant N. meningitidis emerged in Shanghai. Nevertheless, these findings suggest that the use of fluoroquinolones for N. meningitidis prophylaxis should be discouraged in China. Instead, the researchers suggest, physicians should turn to one of the other antibiotics recommended in China’s 2005 national scheme (for example, rifampicin) for the prevention and control of meningococcal meningitis.
Additional Information
These websites can be accessed when viewing the PDF on a device, or via the online version of this article at http://dx.doi.org/10.1371/journal.pmed.1001838. The US Centers for Disease Control and Prevention provide information about meningococcal diseaseThe World Health Organization has a fact sheet about meningococcal meningitisThe UK National Health Service Choices website provides information about meningitis, including some personal storiesThe non-profit Meningitis Foundation of America also provides information about meningitis and stories from survivors of meningitisMedlinePlus has links to further resources about meningitis and about meningococcal infections; the MedlinePlus Encyclopedia also provides information about meningococcal meningitis (in English and Spanish)
doi:10.1371/journal.pmed.1001838
PMCID: PMC4461234  PMID: 26057853
2.  Epidemiology, Molecular Characterization and Antibiotic Resistance of Neisseria meningitidis from Patients ≤15 Years in Manhiça, Rural Mozambique 
PLoS ONE  2011;6(6):e19717.
Background
The epidemiology of meningococcal disease in Mozambique and other African countries located outside the “meningitis belt” remains widely unknown. With the event of upcoming vaccines microbiological and epidemiological information is urgently needed.
Methods
Prospective surveillance for invasive bacterial infections was conducted at the Manhiça District hospital (rural Mozambique) among hospitalized children below 15 years of age. Available Neisseria meningitidis isolates were serogrouped and characterized by Multilocus Sequence Typing (MLST). Antibiotic resistance was also determined.
Results
Between 1998 and 2008, sixty-three cases of confirmed meningococcal disease (36 meningitis, 26 sepsis and 1 conjunctivitis) were identified among hospitalized children. The average incidence rate of meningococcal disease was 11.6/100,000 (8/100,000 for meningitis and 3.7/100,000 for meningococcemia, respectively). There was a significant rise on the number of meningococcal disease cases in 2005–2006 that was sustained till the end of the surveillance period. Serogroup was determined for 43 of the 63 meningococcal disease cases: 38 serogroup W-135, 3 serogroup A and 2 serogroup Y. ST-11 was the most predominant sequence type and strongly associated with serogroup W-135. Two of the three serogroup A isolates were ST-1, and both serogroup Y isolates were ST-175. N. meningitidis remained highly susceptible to all antibiotics used for treatment in the country, although the presence of isolates presenting intermediate resistance to penicillin advocates for continued surveillance.
Conclusions
Our data show a high rate of meningococcal disease in Manhiça, Mozambique, mainly caused by serogroup W-135 ST-11 strains, and advocates for the implementation of a vaccination strategy covering serogroup W-135 meningococci in the country.
doi:10.1371/journal.pone.0019717
PMCID: PMC3112148  PMID: 21695194
3.  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.
doi:10.2147/CLEP.S28410
PMCID: PMC3470458  PMID: 23071402
Neisseria meningitidis; meningococcal disease; conjugate vaccines; meningococcal vaccines
4.  New Rapid Diagnostic Tests for Neisseria meningitidis Serogroups A, W135, C, and Y 
PLoS Medicine  2006;3(9):e337.
Background
Outbreaks of meningococcal meningitis (meningitis caused by Neisseria meningitidis) are a major public health concern in the African “meningitis belt,” which includes 21 countries from Senegal to Ethiopia. Of the several species that can cause meningitis, N. meningitidis is the most important cause of epidemics in this region. In choosing the appropriate vaccine, accurate N. meningitidis serogroup determination is key. To this end, we developed and evaluated two duplex rapid diagnostic tests (RDTs) for detecting N. meningitidis polysaccharide (PS) antigens of several important serogroups.
Methods and Findings
Mouse monoclonal IgG antibodies against N. meningitidis PS A, W135/Y, Y, and C were used to develop two immunochromatography duplex RDTs, RDT1 (to detect serogroups A and W135/Y) and RDT2 (to detect serogroups C and Y). Standards for Reporting of Diagnostic Accuracy criteria were used to determine diagnostic accuracy of RDTs on reference strains and cerebrospinal fluid (CSF) samples using culture and PCR, respectively, as reference tests. The cutoffs were 105 cfu/ml for reference strains and 1 ng/ml for PS. Sensitivities and specificities were 100% for reference strains, and 93.8%–100% for CSF serogroups A, W135, and Y in CSF. For CSF serogroup A, the positive and negative likelihood ratios (± 95% confidence intervals [CIs]) were 31.867 (16.1–63.1) and 0.065 (0.04–0.104), respectively, and the diagnostic odds ratio (± 95% CI) was 492.9 (207.2–1,172.5). For CSF serogroups W135 and Y, the positive likelihood ratio was 159.6 (51.7–493.3) Both RDTs were equally reliable at 25 °C and 45 °C.
Conclusions
These RDTs are important new bedside diagnostic tools for surveillance of meningococcus serogroups A and W135, the two serogroups that are responsible for major epidemics in Africa.
There are several strains ofNeisseria meningitidis that can cause seasonal outbreaks of meningitis in Africa. Treatment of patients and containment of the epidemic through vaccination depends on which strain is responsible. The new dipstick tests described here are accurate and suitable for storage and use in resource-poor settings.
Editors' Summary
Background
Bacterial meningitis, a potentially deadly infection of tissues that line the brain and spinal cord, affects over 1 million people each year. Patients with bacterial meningitis usually have fever, headache, and stiff neck, and may become unconscious and die if the disease is not treated within hours. Most cases of bacterial meningitis occur in Africa, particularly in the arid savannah region south of the Sahara known as the Sahel, where epidemic outbreaks of meningitis occur periodically. This region, also called the “meningitis belt,” extends from Senegal and adjacent coastal countries in West Africa across the continent to Ethiopia. Although most outbreaks tend to occur in the dry season, they differ in frequency in different areas of the meningitis belt, and may involve any of several kinds of bacteria. One of the major causes of epidemic meningitis is Neisseria meningitidis, a meningococcus bacterium that exists in several different groups. Group A has been a common cause of epidemic meningitis in Africa, and some outbreaks were due to group C. More recently, group W135 has emerged as an epidemic strain. In addition to prompt diagnosis and treatment of individual cases, effective public health strategies for controlling meningococcal meningitis include rapid identification of outbreaks and determination of the type of bacteria involved, followed by mass vaccination of people in the surrounding area without delay. Vaccines are chosen on the basis of the responsible meningococcal serogroup: either the inexpensive bivalent vaccine A/C or the expensive, less readily available trivalent vaccine A/C/W135. Before the advent of W135 as an epidemic clone, bivalent vaccine was applied in the meningitis belt without identification of the serogroup. With the appearance of the W135 strain in 2003, however, the determination of serogroup before vaccination is important to select an effective vaccine and avoid misspending of limited funds.
Why Was This Study Done?
Because there are few laboratories in the affected countries and epidemiological surveillance systems are inadequate, it is difficult for health authorities to mount a rapid and effective vaccination campaign in response to an outbreak. In addition, because the two main bacteria (meningococcus and pneumococcus) that cause meningitis require different antibiotic treatments, it is important for doctors to find out quickly which bacteria is causing an individual case. The authors of this study wanted to develop a rapid and easy test that can tell whether meningococcus is the cause of a particular case of meningitis, and if so, which group of meningococcus is involved. As most outbreaks in the meningitis belt occur in rural areas that are distant from well-equipped medical laboratories, it was necessary to develop a test that can be carried out at the patient's bedside by nurses, does not require refrigeration or laboratory equipment, and is highly accurate in distinguishing among the different groups of meningococcus.
What Did the Researchers Do and Find?
The researchers have developed a rapid test to determine whether a patient's meningitis is caused by one of the four most common groups of meningococcus circulating in Africa. The test is done on the patient's spinal fluid, which is obtained by a lumbar puncture (spinal tap) as part of the usual evaluation of a patient thought to have meningitis. The test uses two paper strips, also called dipsticks (one for groups A and W135/Y, and the other for groups C and Y), that can be placed in two separate tubes of the patient's spinal fluid. After several minutes, the appearance of red lines on the dipsticks shows whether one of the four groups of meningococcus is present. The dipsticks can be produced in large quantities and relatively cheaply. The researchers showed that the test dipsticks are stable for weeks in hot weather, and are therefore practical for bedside use in resource-poor settings. They examined the test on stored spinal fluid from patients in Niger and found that the dipstick test was able to identify the correct group of meningococcus more than 95% of the time for the three groups represented in these specimens (the results were compared to a standard DNA test or culture that are highly accurate for identifying the type of bacteria present but much more complicated and expensive).
What Do These Findings Mean?
The new dipstick test for meningococcal meningitis represents a major advance for health-care workers in remote locations affected by meningitis epidemics. This test can be stored without refrigeration and used at bedside in the hot temperatures typical of the African savannah during the meningitis season. The dipsticks are easier to use than currently available test kits, give more rapid results, and are more accurate in telling the difference between group Y and the increasingly important group W135. Further research is needed to determine whether the test can be used with other clinical specimens (such as blood or urine), and whether the test is dependable for detecting group C meningococcus, which is common in Europe but rare in Africa. Nonetheless, the dipstick test promises to be an important tool for guiding individual treatment decisions as well as public health actions, including vaccine selection, against the perennial threat of epidemic meningitis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030337.
World Health Organization fact sheet on meningococcal meningitis
PATH Meningitis Vaccine Project
US Centers for Disease Control and Prevention page on meningococcal disease
doi:10.1371/journal.pmed.0030337
PMCID: PMC1563501  PMID: 16953658
5.  The Changing Epidemiology of Meningococcal Disease in Quebec, Canada, 1991–2011: Potential Implications of Emergence of New Strains 
PLoS ONE  2012;7(11):e50659.
Background
In order to inform meningococcal disease prevention strategies, we analysed the epidemiology of invasive meningococcal disease (IMD) in the province of Quebec, Canada, 10 years before and 10 years after the introduction of serogroup C conjugate vaccination.
Methodology
IMD cases reported to the provincial notifiable disease registry in 1991–2011 and isolates submitted for laboratory surveillance in 1997–2011 were analysed. Serogrouping, PCR testing and assignment of isolates to sequence types (ST) by using multilocus sequence typing (MLST) were performed.
Results
Yearly overall IMD incidence rates ranged from 2.2–2.3/100,000 in 1991–1992 to 0.49/100,000 in 1999–2000, increasing to 1.04/100,000 in 2011. Among the 945 IMD cases identified by laboratory surveillance in 1997–2011, 68%, 20%, 8%, and 3% were due to serogroups B, C, Y, and W135, respectively. Serogroup C IMD almost disappeared following the implementation of universal childhood immunization with monovalent C conjugate vaccines in 2002. Serogroup B has been responsible for 88% of all IMD cases and 61% of all IMD deaths over the last 3 years. The number and proportion of ST-269 clonal complex has been steadily increasing among the identified clonal complexes of serogroup B IMD since its first identification in 2003, representing 65% of serogroup B IMD in 2011. This clonal complex was first introduced in adolescent and young adults, then spread to other age groups.
Conclusion
Important changes in the epidemiology of IMD have been observed in Quebec during the last two decades. Serogroup C has been virtually eliminated. In recent years, most cases have been caused by the serogroup B ST-269 clonal complex. Although overall burden of IMD is low, the use of a vaccine with potential broad-spectrum coverage could further reduce the burden of disease. Acceptability, feasibility and cost-effectiveness studies coupled with ongoing clinical and molecular surveillance are necessary in guiding public policy decisions.
doi:10.1371/journal.pone.0050659
PMCID: PMC3510192  PMID: 23209803
6.  Genome-Based Characterization of Emergent Invasive Neisseria meningitidis Serogroup Y Isolates in Sweden from 1995 to 2012 
Journal of Clinical Microbiology  2015;53(7):2154-2162.
Invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup Y has increased in Europe, especially in Scandinavia. In Sweden, serogroup Y is now the dominating serogroup, and in 2012, the serogroup Y disease incidence was 0.46/100,000 population. We previously showed that a strain type belonging to sequence type 23 was responsible for the increased prevalence of this serogroup in Sweden. The objective of this study was to investigate the serogroup Y emergence by whole-genome sequencing and compare the meningococcal population structure of Swedish invasive serogroup Y strains to those of other countries with different IMD incidence. Whole-genome sequencing was performed on invasive serogroup Y isolates from 1995 to 2012 in Sweden (n = 186). These isolates were compared to a collection of serogroup Y isolates from England, Wales, and Northern Ireland from 2010 to 2012 (n = 143), which had relatively low serogroup Y incidence, and two isolates obtained in 1999 in the United States, where serogroup Y remains one of the major causes of IMD. The meningococcal population structures were similar in the investigated regions; however, different strain types were prevalent in each geographic region. A number of genes known or hypothesized to have an impact on meningococcal virulence were shown to be associated with different strain types and subtypes. The reasons for the IMD increase are multifactorial and are influenced by increased virulence, host adaptive immunity, and transmission. Future genome-wide association studies are needed to reveal additional genes associated with serogroup Y meningococcal disease, and this work would benefit from a complete serogroup Y meningococcal reference genome.
doi:10.1128/JCM.03524-14
PMCID: PMC4473204  PMID: 25926489
7.  Molecular epidemiology and emergence of worldwide epidemic clones of Neisseria meningitidis in Taiwan 
Background
Meningococcal disease is infrequently found in Taiwan, a country with 23 million people. Between 1996 and 2002, 17 to 81 clinical cases of the disease were reported annually. Reported cases dramatically increased in 2001–2002. Our record shows that only serogroup B and W135 meningococci have been isolated from patients with meningococcal disease until 2000. However, serogroup A, C and Y meningococci were detected for the first time in 2001 and continued to cause disease through 2002. Most of serogroup Y meningococcus infections localized in Central Taiwan in 2001, indicating that a small-scale outbreak of meningococcal disease had occurred. The occurrence of a meningococcal disease outbreak and the emergence of new meningococcal strains are of public health concern.
Methods
Neisseria meningitidis isolates from patients with meningococcal disease from 1996 to 2002 were collected and characterized by serogrouping, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The genetic relatedness and clonal relationship between the isolates were analyzed by using the PFGE patterns and the allelic profiles of the sequence types (STs).
Results
Serogroups A, B, C, W135, Y, and non-serogroupable Neisseria meningitidis were, respectively, responsible for 2%, 50%, 2%, 35%, 9%, and 2% of 158 culture-confirmed cases of meningococcal disease in 1996–2002. Among 100 N. meningitidis isolates available for PFGE and MLST analyses, 51 different PFGE patterns and 30 STs were identified with discriminatory indices of 0.95 and 0.87, respectively. Of the 30 STs, 21 were newly identified and of which 19 were found in serogroup B isolates. A total of 40 PFGE patterns were identified in 52 serogroup B isolates with the patterns distributed over several distinct clusters. In contrast, the isolates within each of the serogroups A, C, W135, and Y shared high levels of PFGE pattern similarity. Analysis of the allelic profile of the 30 STs suggested the serogroup B isolates be assigned into 5 clonally related groups/ clonal complexes and 7 unique clones. The ST-41/44 complex/Lineage 3, and the ST-3439 and ST-3200 groups represented 79% of the serogroup B meningococci. In contrast, isolates within serogroups A, serogroup W135 (and C), and serogroup Y, respectively, simply belonged to ST-7, ST-11, and ST-23 clones.
Conclusion
Our data suggested that serogroup B isolates were derived from several distinct lineages, most of which could either be indigenous or were introduced into Taiwan a long time ago. The serogroup A, W135 (and C), and Y isolates, respectively, belonged to the ST-7, ST-11, and ST-23, and the represented clones that are currently the major circulating clones in the world and are introduced into Taiwan more recently. The emergence of serogroup A, C and Y strains contributed partly to the increase in cases of meningococcal disease in 2001–2002.
doi:10.1186/1471-2334-6-25
PMCID: PMC1431541  PMID: 16478548
8.  Meningococcal Disease in South Africa, 1999–2002 
Emerging Infectious Diseases  2007;13(2):273-281.
Serogroups and strains differ by location, although hypervirulent strains were identified throughout the country.
We describe the epidemiology of invasive meningococcal disease in South Africa from August 1999 through July 2002, as reported to a laboratory-based surveillance system. Neisseria meningitidis isolates were further characterized. In total, 854 cases of laboratory-confirmed disease were reported, with an annual incidence rate of 0.64/100,000 population. Incidence was highest in infants <1 year of age. Serogroup B caused 41% of cases; serogroup A, 23%; serogroup Y, 21%; serogroup C, 8%; and serogroup W135, 5%. Serogroup B was the predominant serogroup in Western Cape Province, and disease rates remained stable. Serogroup A was most prevalent in Gauteng Province and increased over the 3 years. On pulsed-field gel electrophoresis analysis, serogroup A strains showed clonality, and serogroup B demonstrated considerable diversity. Selected isolates of serogroup A belonged to sequence type (ST)-1 (subgroup I/II) complex, serogroup B to ST-32/electrophoretic type (ET)-5 complex, and serogroup W135 to ST-11/ET-37 complex.
doi:10.3201/eid1302.051553
PMCID: PMC2725855  PMID: 17479891
Neisseria meningitidis; serogroup; meningococcal disease; ST-complex; hypervirulent strains; MLST; PFGE; research
9.  Epidemiology of serogroup B invasive meningococcal disease in Ontario, Canada, 2000 to 2010 
BMC Infectious Diseases  2012;12:202.
Background
Invasive meningococcal disease (IMD) caused by serogroup B is the last major serogroup in Canada to become vaccine-preventable. The anticipated availability of vaccines targeting this serogroup prompted an assessment of the epidemiology of serogroup B disease in Ontario, Canada.
Methods
We retrieved information on confirmed IMD cases reported to Ontario’s reportable disease database between January 1, 2000 and December 31, 2010 and probabilistically-linked these cases to Public Health Ontario Laboratory records. Rates were calculated with denominator data obtained from Statistics Canada. We calculated a crude number needed to vaccinate using the inverse of the infant (<1 year) age-specific incidence multiplied by expected vaccine efficacies between 70% and 80%, and assuming only direct protection (no herd effects).
Results
A total of 259 serogroup B IMD cases were identified in Ontario over the 11-year period. Serogroup B was the most common cause of IMD. Incidence ranged from 0.11 to 0.27/100,000/year, and fluctuated over time. Cases ranged in age from 13 days to 101 years; 21.4% occurred in infants, of which 72.7% were <6 months. Infants had the highest incidence (3.70/100,000). Case-fatality ratio was 10.7% overall. If we assume that all infant cases would be preventable by vaccination, we would need to vaccinate between 33,784 and 38,610 infants to prevent one case of disease.
Conclusions
Although rare, the proportion of IMD caused by serogroup B has increased and currently causes most IMD in Ontario, with infants having the highest risk of disease. Although serogroup B meningococcal vaccines are highly anticipated, our findings suggest that decisions regarding publicly funding serogroup B meningococcal vaccines will be difficult and may not be based on disease burden alone.
doi:10.1186/1471-2334-12-202
PMCID: PMC3472197  PMID: 22928839
Invasive meningococcal disease; Neisseria meningitidis; Serogroup B; Epidemiology; Surveillance; Ontario; Canada
10.  Serogroup W-135 Meningococcal Disease during the Hajj, 2000 
Emerging Infectious Diseases  2003;9(6):665-671.
An outbreak of serogroup W-135 meningococcal disease occurred during the 2000 Hajj in Saudi Arabia. Disease was reported worldwide in Hajj pilgrims and their close contacts; however, most cases were identified in Saudi Arabia. Trends in Saudi meningococcal disease were evaluated and the epidemiology of Saudi cases from this outbreak described. Saudi national meningococcal disease incidence data for 1990 to 2000 were reviewed; cases from January 24 to June 5, 2000 were retrospectively reviewed. The 2000 Hajj outbreak consisted of distinct serogroup A and serogroup W-135 outbreaks. Of 253 identified cases in Saudi Arabia, 161 (64%) had serogroup identification; serogroups W-135 and A caused 93 (37%) and 60 (24%) cases with attack rates of 9 and 6 cases per 100,000 population, respectively. The 2000 Hajj outbreak was the first large serogroup W-135 meningococcal disease outbreak identified worldwide. Enhanced surveillance for serogroup W-135, especially in Africa, is essential to control this emerging epidemic disease.
doi:10.3201/eid0906.020565
PMCID: PMC3000138  PMID: 12781005
Meningococcal infections; meningitis; meningococcal; Neisseria meningitides; epidemiology; disease outbreaks; Saudi Arabia; Africa; research
11.  Clonal Waves of Neisseria Colonisation and Disease in the African Meningitis Belt: Eight- Year Longitudinal Study in Northern Ghana 
PLoS Medicine  2007;4(3):e101.
Background
The Kassena-Nankana District of northern Ghana lies in the African “meningitis belt” where epidemics of meningococcal meningitis have been reoccurring every eight to 12 years for the last 100 years. The dynamics of meningococcal colonisation and disease are incompletely understood, and hence we embarked on a long-term study to determine how levels of colonisation with different bacterial serogroups change over time, and how the patterns of disease relate to such changes.
Methods and Findings
Between February 1998 and November 2005, pharyngeal carriage of Neisseria meningitidis in the Kassena-Nankana District was studied by twice-yearly colonisation surveys. Meningococcal disease was monitored throughout the eight-year study period, and patient isolates were compared to the colonisation isolates. The overall meningococcal colonisation rate of the study population was 6.0%. All culture-confirmed patient isolates and the majority of carriage isolates were associated with three sequential waves of colonisation with encapsulated (A ST5, X ST751, and A ST7) meningococci. Compared to industrialised countries, the colonising meningococcal population was less constant in genotype composition over time and was genetically less diverse during the peaks of the colonisation waves, and a smaller proportion of the isolates was nonserogroupable. We observed a broad age range in the healthy carriers, resembling that of meningitis patients during large disease epidemics.
Conclusions
The observed lack of a temporally stable and genetically diverse resident pharyngeal flora of meningococci might contribute to the susceptibility to meningococcal disease epidemics of residents in the African meningitis belt. Because capsular conjugate vaccines are known to impact meningococcal carriage, effects on herd immunity and potential serogroup replacement should be monitored following the introduction of such vaccines.
An analysis of pharyngeal carriage of meningococci in one district of Ghana examined the features of the isolates that might contribute to the susceptibility to meningococcal epidemics in the African meningitis belt.
Editors' Summary
Background.
Bacterial meningitis is a rare but often fatal infection of the meninges—the thin membrane around the brain and the spinal cord. It can be caused by several types of bacteria, but meningococcal meningitis, which is caused by Neisseria meningitidis, is the most common form of bacterial meningitis in children and the second most common form in adults. About 10% of healthy people have N. meningitidis growing in their nose and throat; the bacteria are spread by exposure to infected respiratory secretions. In these “carriers,” the immune system keeps the bug in check but sometimes this surveillance fails, N. meningitidis enters the bloodstream and travels to the brain, where it infects the meninges and causes inflammation. The symptoms of meningococcal meningitis are sudden fever, headache, and a stiff neck and, even if strong antibiotics are given quickly, 10%–15% of patients die.
Why Was This Study Done?
Outbreaks of meningococcal meningitis occur all over the world, but the highest burden of disease is in the African meningitis belt, which stretches across sub-Saharan Africa from Senegal to Ethiopia. Here, localized epidemics of meningococcal meningitis occur every eight to 12 years during the dry season. Control of these epidemics relies on their early detection followed by mass immunization. This approach can be hard to implement in countries with limited resources, but the introduction of other control measures (for example, routine childhood immunization) requires an understanding of how the spread of different strains of N. meningitides through the community causes periodic epidemics. In this study, the researchers have studied the long-term dynamics of colonization by N. meningitidis and the occurrence of meningococcal meningitis in one region of the African meningitis belt.
What Did the Researchers Do and Find?
The researchers took throat swabs twice a year from people living in rural northern Ghana for eight years. They tested each swab for N. meningitidis and determined the serogroup of the bacteria they found. Bacterial serogroups differ only in terms of the antigens (molecules recognized by the immune system) that they express; N. meningitidis is classified into 13 serogroups based on the sugars that coat its surface. The researchers also used DNA sequencing to group the bacterial isolates into genoclouds—genetically closely related groups of meningococci represented by a sequence type (ST) number. Finally, they monitored meningococcal disease throughout the study and determined the serogroup and genocloud of patient isolates. Their results show colonization of 6% of the study population by N. meningitidis and reveal three consecutive waves of colonization and disease characterized by the presence of a serogroup A ST5 genocloud, a serogroup X ST751 genocloud, and finally a serogroup A ST7 genocloud. Colonizing bacteria isolated in this study in Ghana, the researchers report, changed their genotype more frequently but were less genetically diverse than those isolated in industrialized countries. In addition, the commonest serogroups of N. meningitidis in carriers in Ghana were disease-causing serogroups, whereas in industrialized countries these serogroups are rarely seen in carriers. However, non-groupable bacteria (bacteria that lack surface sugars), although common in industrialized countries, were rare in Ghana.
What Do These Findings Mean?
These findings begin to explain why epidemics of meningococcal meningitis are common in the African meningitis belt. Because there isn't a stable, genetically diverse population of N. meningitidis in carriers, the immune systems of people living here may not be optimally prepared to deal with new bacterial clones that arrive in the region, and this lack of immunity could result in frequent epidemics. However, because the researchers took relatively few samples every six months from one small area of the meningitis belt, the genetic diversity of N. meningitidis over the whole region might be considerably greater than that colonizing the study population. Nevertheless, the description of successive waves of meningococci colonization in Ghana has important implications for the proposed introduction of childhood vaccination against meninogococcal disease in the African meningitis belt. If this vaccination program goes ahead, warn the researchers, it will be essential to monitor which strains of N. meningitidis are colonizing the population and to have emergency plans ready to deal with any emerging disease-causing serogroups that are not covered by the vaccine.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040101.
The Web sites of the institutions at which this research was performed, the Swiss Tropical Institute and the Navrongo Health Research Centre, provide more information about the programs
The World Health Organization provides information on meningococcal disease, including the African meningitis belt (in English, Spanish, Chinese, Russian, and Arabic)
Information on meningitis and vaccines and their potential use in Africa is available from the Meningitis Vaccine Project (in English and French)
Medline Plus has encyclopedia pages on meningococcal meningitis
The US Centers for Disease Control and Prevention provides information on meningococcal disease (in English and Spanish)
doi:10.1371/journal.pmed.0040101
PMCID: PMC1831736  PMID: 17388665
12.  Impact of meningococcal C conjugate vaccination campaign in Emilia-Romagna, Italy 
The incidence of reported meningococcal disease in Italy is among the lowest in Europe. The trend of the disease was increasing up to 2005 and then declined after the gradual introduction of a universal Men C vaccination program in 17/21 Italian regions. Since 2006, in Emilia-Romagna region vaccination against Neisseria meningitidis serogroup C was actively offered free of charge in a single dose to the age groups 12–15 months and 14–15 years, in addition to people with defined epidemiological risk. Our aim was to measure the impact of vaccination on the incidence of meningococcal disease caused by different serogroups among the population of Emilia Romagna Region, Northern Italy (approximately 4.5 million inhabitants) subdivided by age. Using surveillance data, we computed the incidence rates of Neisseria meninigitidis related invasive disease per 100.000 inhabitants for the years 2000 to 2012. In addition, the percentage change in incidence and the mortality rates were calculated. Results indicate a 70.1% decrease in the incidence of meningococcus C-related invasive disease after the introduction of MenC universal vaccination. No case of serogroup C related infection was observed since 2006 in children aged 1–4 years. These findings suggest that the single-dose vaccination strategy against serogroup C N.meningitidis targeted to the age groups 12–15 months and 14–15 years was effective in the Emilia-Romagna population. However, the occurrence of two cases of meningiditis in a 5-month child and in a 9-years child suggests caution and careful consideration in surveillance for the next years.
doi:10.4161/hv.27597
PMCID: PMC4130270  PMID: 24384537
vaccination campaign; meningococcal disease; serogroups; vaccination strategies; surveillance; vaccination coverage
13.  Serogroup C meningococci in Italy in the era of conjugate menC vaccination 
Background
To assess changes in the pattern of Invasive Meningococcal Disease (IMD) in Italy after the introduction of conjugate menC vaccine in the National Vaccine Plan 2005–2007 and to provide information for developing timely and appropriate public health interventions, analyses of microbiological features of isolates and clinical characteristics of patients have been carried out. In Italy, the number of serogroup C meningococci fell progressively following the introduction of the MenC conjugate vaccine, recommended by the Italian Ministry of Health but implemented according to different regional strategies.
Methods
IMD cases from January 2005 through July 2008 reported to the National Meningococcal Surveillance System were considered for this study. Serogrouping and sero/subtyping were performed on 179 serogroup C strains received at the National Reference Laboratory of the Istituto Superiore di Sanità. Antibiotic susceptibility testing was possible for 157 isolates. MLST (Multilocus sequence typing), porA VRs (Variable Region) typing, PFGE (Pulsed Field Gel Electrophoresis), VNTR (Variable Number Tandem Repeats) analyses were performed on all C:2a and C:2b meningococci (n = 147), following standard procedures.
Results
In 2005 and 2008, IMD showed an incidence of 0.5 and 0.3 per 100,000 inhabitants, respectively. While the incidence due to serogroup B remained stable, IMD incidence due to serogroup C has decreased since 2006. In particular, the decrease was significant among infants. C:2a and C:2b were the main serotypes, all C:2a strains belonged to ST-11 clonal complex and all C:2b to ST-8/A4. Clinical manifestations and outcome of infections underlined more severe disease caused by C:2a isolates. Two clusters due to C:2a/ST-11 meningococci were reported in the North of Italy in December 2007 and July 2008, respectively, with a high rate of septicaemia and fatal outcome.
Conclusion
Public health surveillance of serogroup C invasive meningococcal disease and microbiological/molecular characterization of the isolates requires particular attention, since the hyper-invasive ST-11 predominantly affected adolescents and young adults for whom meningococcal vaccination was not recommended in the 2005–2007 National Vaccine Plan.
doi:10.1186/1471-2334-9-135
PMCID: PMC2739211  PMID: 19698137
14.  Meningococcal disease in the republic of Korea army: incidence and serogroups determined by PCR. 
Journal of Korean Medical Science  2003;18(2):163-166.
This study was performed to determine the incidence and serogroups of meningococcal disease in the Korean Army. From August 2000 to July 2001, we identified prospective cases in the Korean Army. Meningococcal disease was confirmed by isolation of Neisseria meningitidis or detection of its antigen by latex agglutination from cerebrospinal fluid (CSF) or blood. Polymerase chain reactions (PCRs) were performed in the crgA gene to identify N. meningitidis regardless of its serogroup, and then in orf-2 (serogroup A) and siaD (serogroups B, C, Y, and W135) respectively for serogroup prediction. During the study period, twelve patients (four meningitis and eight septicaemia) were identified. The annual incidence was 2.2 per 100,000 (95% confidence interval, 1.3-3.8) among 550,000 private soldiers. Latex agglutinations were positive to A/C/Y/W135 polyvalent latex, but not to B latex in all patients. PCRs of crgA gene were positive in ten patients, whose samples (2 isolates from CSF, 2 CSFs, and 6 sera) were stored. In PCRs for serogroup prediction, one isolate was serogroup A, and one isolate and two sera were serogroup C. The need for meningococcal vaccination would be considered in the Korean Army through the cost-benefit analysis based on the result of this study.
PMCID: PMC3055030  PMID: 12692410
15.  Neisseria meningitidis Intermediately Resistant to Penicillin and Causing Invasive Disease in South Africa in 2001 to 2005▿  
Journal of Clinical Microbiology  2008;46(10):3208-3214.
Neisseria meningitidis strains (meningococci) with decreased susceptibility to penicillin (MICs, >0.06 μg/ml) have been reported in several parts of the world, but the prevalence of such isolates in Africa is poorly described. Data from an active national laboratory-based surveillance program from January 2001 through December 2005 were analyzed. A total of 1,897 cases of invasive meningococcal disease were reported, with an average annual incidence of 0.83/100,000 population. Of these cases, 1,381 (73%) had viable isolates available for further testing; 87 (6%) of these isolates tested intermediately resistant to penicillin (Peni). Peni meningococcal isolates were distributed throughout all provinces and age groups, and there was no association with outcome or human immunodeficiency virus infection. The prevalence of Peni was lower in serogroup A (7/295; 2%) than in serogroup B (24/314; 8%), serogroup C (9/117; 8%), serogroup Y (22/248; 9%), or serogroup W135 (25/396; 6%) (P = 0.02). Pulsed-field gel electrophoresis grouped 63/82 Peni isolates into nine clusters, mostly according to serogroup. The clustering of patterns from Peni isolates was not different from that of penicillin-susceptible isolates. Twelve sequence types were identified among 18 isolates arbitrarily selected for multilocus sequence typing. DNA sequence analysis of the penA gene identified 26 different alleles among the Peni isolates. Intermediate penicillin resistance is thus widespread among meningococcal serogroups, has been selected in a variety of lineages, and, to date, does not appear to be associated with increased mortality. This is the first report describing the prevalence and molecular epidemiology of Peni meningococcal isolates from sub-Saharan Africa.
doi:10.1128/JCM.00221-08
PMCID: PMC2566094  PMID: 18650361
16.  Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study 
Lancet  2013;383(9911):40-47.
Summary
Background
A serogroup A meningococcal polysaccharide–tetanus toxoid conjugate vaccine (PsA–TT, MenAfriVac) was licensed in India in 2009, and pre-qualified by WHO in 2010, on the basis of its safety and immunogenicity. This vaccine is now being deployed across the African meningitis belt. We studied the effect of PsA–TT on meningococcal meningitis and carriage in Chad during a serogroup A meningococcal meningitis epidemic.
Methods
We obtained data for the incidence of meningitis before and after vaccination from national records between January, 2009, and June, 2012. In 2012, surveillance was enhanced in regions where vaccination with PsA–TT had been undertaken in 2011, and in one district where a reactive vaccination campaign in response to an outbreak of meningitis was undertaken. Meningococcal carriage was studied in an age-stratified sample of residents aged 1–29 years of a rural area roughly 13–15 and 2–4 months before and 4–6 months after vaccination. Meningococci obtained from cerebrospinal fluid or oropharyngeal swabs were characterised by conventional microbiological and molecular methods.
Findings
Roughly 1·8 million individuals aged 1–29 years received one dose of PsA–TT during a vaccination campaign in three regions of Chad in and around the capital N'Djamena during 10 days in December, 2011. The incidence of meningitis during the 2012 meningitis season in these three regions was 2·48 per 100 000 (57 cases in the 2·3 million population), whereas in regions without mass vaccination, incidence was 43·8 per 100 000 (3809 cases per 8·7 million population), a 94% difference in crude incidence (p<0·0001), and an incidence rate ratio of 0·096 (95% CI 0·046–0·198). Despite enhanced surveillance, no case of serogroup A meningococcal meningitis was reported in the three vaccinated regions. 32 serogroup A carriers were identified in 4278 age-stratified individuals (0·75%) living in a rural area near the capital 2–4 months before vaccination, whereas only one serogroup A meningococcus was isolated in 5001 people living in the same community 4–6 months after vaccination (adjusted odds ratio 0·019, 95% CI 0·002–0·138; p<0·0001).
Interpretation
PSA–TT was highly effective at prevention of serogroup A invasive meningococcal disease and carriage in Chad. How long this protection will persist needs to be established.
Funding
The Bill & Melinda Gates Foundation, the Wellcome Trust, and Médecins Sans Frontères.
doi:10.1016/S0140-6736(13)61612-8
PMCID: PMC3898950  PMID: 24035220
17.  Implementation and impact of a meningococcal C conjugate vaccination program in 13- to 25-year-old individuals in Galicia, Spain 
Background
In response to increased case numbers of meningococcal group C disease, catch-up vaccination strategies have been shown to be successful. This paper describes the results of a repeat vaccination program in Galicia, Spain, and the strategy used for it.
Methods and results
Three vaccination waves were performed: first, in 1996/1997 with a meningococcal group A and C polysaccharide vaccine in individuals aged 18 months to 19 years; second, in 2000 with a conjugate serogroup C polysaccharide vaccine in children born since 1993 and all children and adolescents up to 19 years not previously vaccinated; third, a campaign in 2006 that became necessary because of the development of a new Neisseria strain and an increase in both the incidence and lethality of meningococcal C disease. The conjugate vaccine de-O-acetylated group C meningococcal polysaccharide coupled to tetanus toxoid was used (GCMP-TT; brand name, NeisVac-C). Results: Applying a strategy based on model calculations derived from the UK setting and focusing on a population aged 13–25 years, including students, employees of companies, and underage individuals, a total of 286,000 subjects were vaccinated, resulting in global vaccination coverage of 82.2% (all age groups over 74%). Only 17 adverse events in 17 individuals were reported, which all were mild. Incidence of meningococcal disease serogroup C by season was reduced from 0.84 cases per 100,000 in 2004/05 to 0.76 cases per 100,000 in 2005/2006 to 0.18/100,000 in 2007/08. In parallel, mortality was also decreased from 8 cases during 2005/06 (0.29 per 100,000) to 1 case in 2007/2008 (0.03 per 100,000). No cases of breakthrough disease occurred in the vaccinated population.
Conclusion
In Galicia, a series of vaccination campaigns, particularly focusing on high-risk groups, has shown high effectiveness, with a marked reduction in the disease incidence in the vaccination cohort accompanied by a relevant reduction in the overall population.
doi:10.1007/s10389-011-0403-9
PMCID: PMC3172415  PMID: 21957332
Vaccination; Meningococcal disease; Public health; Conjugated vaccines
18.  A Decade of Invasive Meningococcal Disease Surveillance in Poland 
PLoS ONE  2013;8(8):e71943.
Background
Neisseria meningitidis is a leading etiologic agent of severe invasive disease. The objective of the study was to characterise invasive meningococcal disease (IMD) epidemiology in Poland during the last decade, based on laboratory confirmed cases.
Methods
The study encompassed all invasive meningococci collected between 2002 and 2011 in the National Reference Centre for Bacterial Meningitis. The isolates were re-identified and characterised by susceptibility testing, MLST analysis, porA and fetA sequencing. A PCR technique was used for meningococcal identification directly from clinical materials.
Results
In the period studied, 1936 cases of IMD were confirmed, including 75.6% identified by culture. Seven IMD outbreaks, affecting mostly adolescents, were reported; all were caused by serogroup C meningococci of ST-11. The highest incidence was observed among children under one year of age (15.71/100,000 in 2011). The general case fatality rate in the years 2010–2011 was 10.0%. Meningococci of serogroup B, C, Y and W-135 were responsible for 48.8%, 36.6%, 1.2% and 1.2% of cases, respectively. All isolates were susceptible to third generation cephalosporins, chloramphenicol, ciprofloxacin, and 84.2% were susceptible to penicillin. MLST analysis (2009–2011) revealed that among serogroup B isolates the most represented were clonal complexes (CC) ST-32CC, ST-18CC, ST-41/44CC, ST-213CC and ST-269CC, and among serogroup C: ST-103CC, ST-41/44CC and ST-11CC.
Conclusions
The detection of IMD in Poland has changed over time, but observed increase in the incidence of the disease was mostly attributed to changes in the surveillance system including an expanded case definition and inclusion of data from non-culture diagnostics.
doi:10.1371/journal.pone.0071943
PMCID: PMC3748050  PMID: 23977184
19.  Incidence, Carriage and Case-Carrier Ratios for Meningococcal Meningitis in the African Meningitis Belt: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(2):e0116725.
Background
To facilitate the interpretation of meningococcal meningitis epidemiology in the “African meningitis belt”, we aimed at obtaining serogroup-specific pooled estimates of incidence, carriage and case-carrier ratios for meningococcal meningitis in the African meningitis belt and describe their variations across the endemic, hyperendemic and epidemic context.
Methods
We conducted a systematic review and meta-analysis of studies reporting serogroup-specific meningococcal meningitis monthly incidence and carriage in the same population and time period. Epidemiological contexts were defined as endemic (wet season, no epidemic), hyperendemic (dry season, no epidemic), and epidemic (dry season, epidemic).
Findings
Eight studies reporting a total of eighty pairs of serogroup-specific meningococcal meningitis incidence and carriage estimates were included in this review. For serogroup A, changes associated with the transition from endemic to hyperendemic incidence and from hyperendemic to epidemic incidence were 15-fold and 120-fold respectively. Changes in carriage prevalence associated with both transitions were 1-fold and 30-fold respectively. 
For serogroup W and X, the transition from endemic to hyperendemic incidence involved a 4-fold and 1•1-fold increase respectively. Increases in carriage prevalence for the later transition were 7-fold and 1•7-fold respectively. No data were available for the hyperendemic-epidemic transition for these serogroups. Our findings suggested that the regular seasonal variation in serogroup A meningococcal meningitis incidence between the rainy and the dry season could be mainly driven by seasonal change in the ratio of clinical cases to subclinical infections. In contrast appearance of epidemic incidences is related to a substantial increase in transmission and colonisation and to lesser extent with changes in the case-carrier ratio.
Conclusion
Seasonal change in the rate of progression to disease given carriage together with variations in frequency of carriage transmission should be considered in models attempting to capture the epidemiology of meningococcal meningitis and mainly to predict meningitis epidemics in the African meningitis belt.
doi:10.1371/journal.pone.0116725
PMCID: PMC4319942  PMID: 25658307
20.  An expanded age range for meningococcal meningitis: molecular diagnostic evidence from population-based surveillance in Asia 
BMC Infectious Diseases  2012;12:310.
Background
To understand epidemiologic patterns of meningococcal disease in Asia, we performed a retrospective molecular analysis of cerebrospinal fluid (CSF) specimens collected in prospective surveillance among children aged < 5 years of age in China, South Korea, and Vietnam.
Methods
A total of 295 isolates and 2,302 CSFs were tested by a meningococcal species- and serogroup-specific polymerase chain reaction (PCR) assay targeting the Neisseria meningitidis (Nm) ctrA gene. Multi-locus sequence typing (MLST) was performed in Nm gene amplification analysis and incidence rates for meningococcal meningitis were estimated.
Results
Among 295 isolates tested, 10 specimens from Vietnam were confirmed as serogroup B and all were Sequence Type (ST) 1576 by MLST. Among the 2,032 CSF specimen tested, 284 (14%) were confirmed by PCR (ctrA gene), including 67 (23.6%) from China, 92 (32.4%) from Korea, and 125 (44.0%) from Vietnam. Neonates and infants aged < 6 months of age accounted for more than 50% of Nm-PCR positive CSF. Two CSF specimens from Vietnam were identified as serogroup B using MLST. In addition, 44 specimens underwent sequencing to confirm meningococcal serogroup; of these, 21 (48%) were serogroup C, 12 (27%) were serogroup X, 9 (20%) were serogroup Y and 2 (5%) were serogroup B. The incidence rates of meningococcal meningitis among children < 5 years of age was highest in Vietnam (7.4/100,000 [95% CI, 3.6—15.3] followed by Korea (6.8/100,000 [95% CI, 3.5-13.5] and China (2.1/100,000) [95% CI, 0.7-6.2]).
Conclusions
These results suggest that there is a previously undetected, yet substantial burden of meningococcal meningitis among infants and young children. Standardized, sensitive and specific molecular diagnostic assays with Nm serogrouping capacity are needed throughout Asia to understand the true burden of N. meningitidis disease.
doi:10.1186/1471-2334-12-310
PMCID: PMC3519641  PMID: 23164061
Cerebrospinal fluid; Meningococcal meningitis; Neisseria meningitidis; Serogroup; Surveillance
21.  Meningococcal Factor H Binding Proteins in Epidemic Strains from Africa: Implications for Vaccine Development 
Background
Factor H binding protein (fHbp) is an important antigen for vaccines against meningococcal serogroup B disease. The protein binds human factor H (fH), which enables the bacteria to resist serum bactericidal activity. Little is known about the vaccine-potential of fHbp for control of meningococcal epidemics in Africa, which typically are caused by non-group B strains.
Methodology/Principal Findings
We investigated genes encoding fHbp in 106 serogroup A, W-135 and X case isolates from 17 African countries. We determined complement-mediated bactericidal activity of antisera from mice immunized with recombinant fHbp vaccines, or a prototype native outer membrane vesicle (NOMV) vaccine from a serogroup B mutant strain with over-expressed fHbp. Eighty-six of the isolates (81%) had one of four prevalent fHbp sequence variants, ID 4/5 (serogroup A isolates), 9 (W-135), or 74 (X) in variant group 1, or ID 22/23 (W-135) in variant group 2. More than one-third of serogroup A isolates and two-thirds of W-135 isolates tested had low fHbp expression while all X isolates tested had intermediate or high expression. Antisera to the recombinant fHbp vaccines were generally bactericidal only against isolates with fHbp sequence variants that closely matched the respective vaccine ID. Low fHbp expression also contributed to resistance to anti-fHbp bactericidal activity. In contrast to the recombinant vaccines, the NOMV fHbp ID 1 vaccine elicited broad anti-fHbp bactericidal activity, and the antibodies had greater ability to inhibit binding of fH to fHbp than antibodies elicited by the control recombinant fHbp ID 1 vaccine.
Conclusion/Significance
NOMV vaccines from mutants with increased fHbp expression elicit an antibody repertoire with greater bactericidal activity than recombinant fHbp vaccines. NOMV vaccines are promising for prevention of meningococcal disease in Africa and could be used to supplement coverage conferred by a serogroup A polysaccharide-protein conjugate vaccine recently introduced in some sub-Saharan countries.
Author Summary
Epidemics of meningococcal meningitis are common in sub-Saharan Africa. Most are caused by encapsulated serogroup A strains, which rarely cause disease in industrialized countries. A serogroup A polysaccharide protein conjugate vaccine recently was introduced in some countries in sub-Saharan Africa. The antibodies induced, however, may allow replacement of serogroup A strains with serogroup W-135 or X strains, which also cause epidemics in this region. Protein antigens, such as factor H binding protein (fHbp), are promising for prevention of meningococcal serogroup B disease. These proteins also are present in strains with other capsular serogroups. Here we report investigation of the potential of fHbp vaccines for prevention of disease caused by serogroup A, W-135 and X strains from Africa. Four fHbp amino acid sequence variants accounted for 81% of the 106 African isolates studied. While there was little cross-protective activity by antibodies elicited in mice by recombinant fHbp vaccines from each of the four sequence variants, a prototype native outer membrane vesicle (NOMV) vaccine from a mutant with over-expressed fHbp elicited antibodies with broad protective activity. A NOMV vaccine has the potential to supplement coverage by the group A conjugate vaccine and help prevent emergence of disease caused by non-serogroup A strains.
doi:10.1371/journal.pntd.0001302
PMCID: PMC3167780  PMID: 21909444
22.  Characterization of vaccine antigens of meningococcal serogroup W isolates from Ghana and Burkina Faso from 2003 to 2009 
F1000Research  2014;3:264.
Neisseria meningitidis is a major cause of bacterial meningitis and a considerable health problem in the 25 countries of the ‘African Meningitis Belt’ that extends from Senegal in West Africa to Ethiopia in the East. Approximately 80% of cases of meningococcal meningitis in Africa have been caused by strains belonging to capsular serogroup A. After the introduction of a serogroup A conjugate polysaccharide vaccine, MenAfriVac ™, that began in December 2010, the incidence of meningitis due to serogroup A has markedly declined in this region. Currently, serogroup W of N. meningitidis accounts for the majority of cases. Vaccines based on sub-capsular antigens, such as Generalized Modules for Membrane Antigens (GMMA), are under investigation for use in Africa. To analyse the antigenic properties of a serogroup W wave of colonisation and disease, we investigated the molecular diversity of the protein vaccine antigens PorA, Neisserial Adhesin A (NadA), Neisserial heparin-binding antigen (NHBA) and factor H binding protein (fHbp) of 31 invasive and carriage serogroup W isolates collected as part of a longitudinal study from Ghana and Burkina Faso between 2003 and 2009. We found that the isolates all expressed fHbp variant 2 ID 22 or 23, differing from each other by only one amino acid, and a single PorA subtype of P1.5,2. Of the isolates, 49% had a functional nhbA gene and 100% had the nadA allele 3, which contained the insertion sequence IS1301 in five isolates. Of the W isolates tested, 41% had high fHbp expression when compared with a reference serogroup B strain, known to be a high expresser of fHbp variant 2. Our results indicate that in this collection of serogroup W isolates, there is limited antigenic diversification over time of vaccine candidate outer membrane proteins (OMP), thus making them promising candidates for inclusion in a protein-based vaccine against meningococcal meningitis for Africa.
doi:10.12688/f1000research.3881.1
PMCID: PMC4392821  PMID: 25901274
Neisseria meningitidis; meningococcus; meningitis; serogroup W; factor H binding protein; NadA, NHBA
23.  Geotemporal Analysis of Neisseria meningitidis Clones in the United States: 2000–2005 
PLoS ONE  2013;8(12):e82048.
Background
The detection of meningococcal outbreaks relies on serogrouping and epidemiologic definitions. Advances in molecular epidemiology have improved the ability to distinguish unique Neisseria meningitidis strains, enabling the classification of isolates into clones. Around 98% of meningococcal cases in the United States are believed to be sporadic.
Methods
Meningococcal isolates from 9 Active Bacterial Core surveillance sites throughout the United States from 2000 through 2005 were classified according to serogroup, multilocus sequence typing, and outer membrane protein (porA, porB, and fetA) genotyping. Clones were defined as isolates that were indistinguishable according to this characterization. Case data were aggregated to the census tract level and all non-singleton clones were assessed for non-random spatial and temporal clustering using retrospective space-time analyses with a discrete Poisson probability model.
Results
Among 1,062 geocoded cases with available isolates, 438 unique clones were identified, 78 of which had ≥2 isolates. 702 cases were attributable to non-singleton clones, accounting for 66.0% of all geocoded cases. 32 statistically significant clusters comprised of 107 cases (10.1% of all geocoded cases) were identified. Clusters had the following attributes: included 2 to 11 cases; 1 day to 33 months duration; radius of 0 to 61.7 km; and attack rate of 0.7 to 57.8 cases per 100,000 population. Serogroups represented among the clusters were: B (n = 12 clusters, 45 cases), C (n = 11 clusters, 27 cases), and Y (n = 9 clusters, 35 cases); 20 clusters (62.5%) were caused by serogroups represented in meningococcal vaccines that are commercially available in the United States.
Conclusions
Around 10% of meningococcal disease cases in the U.S. could be assigned to a geotemporal cluster. Molecular characterization of isolates, combined with geotemporal analysis, is a useful tool for understanding the spread of virulent meningococcal clones and patterns of transmission in populations.
doi:10.1371/journal.pone.0082048
PMCID: PMC3861328  PMID: 24349182
24.  Health and Economic Outcomes of Introducing the New MenB Vaccine (Bexsero) into the Italian Routine Infant Immunisation Programme 
PLoS ONE  2015;10(4):e0123383.
Introduction
In January 2013 a novel type of multicomponent protein-based vaccine against group B meningococcal disease was licensed by the European Medicines Agency. With the widespread use of the meningococcal serogroup C conjugate vaccines, serogroup B remains now the major cause of bacterial meningitis and septicaemia in young children in Europe. The aim of this study is to investigate the health and the economic outcomes of MenB vaccine introduction into the Italian routine mass vaccination programme.
Methods
The present work is structured in two main parts. Firstly, we assess the epidemiological burden of group B meningococcal disease using official hospitalisation and notification data from two of the most populated Italian regions (Lombardia and Piemonte) during a 6-year study period (2007-2012). Secondly, we evaluate the cost-effectiveness of the immunisation programme in Italy from the public health payer perspective under base case parameters assumptions and performing a comprehensive sensitivity analysis to assess the robustness and the uncertainty of our model results.
Results
MenB serotype is responsible for 59% of the 341 cases of Invasive Meningococcal Disease in Lombardia and Piemonte. Incidence rate for MenB infection is estimated to be 0.21/100,000/y resulting at the highest level in children ≤4 years of age. Although the new MenB vaccine can potentially prevent about one third of the disease cases in the Italian population, model results show this strategy is unlikely to be cost-effective (ICER value over €350,000/QALY) with a vaccine that prevents disease only. These results are robust under most of the sensitivity scenarios except when allowing for lower discount rates.
Discussion
The introduction of the novel vaccine into the routine immunisation schedule needs to be carefully evaluated. The new MenB vaccine has the potential to reduce the disease burden at the population level. However, from the Italian Health Service perspective, the immunisation programme is unlikely to be cost-effective at the current incidence levels and vaccine price.
doi:10.1371/journal.pone.0123383
PMCID: PMC4395261  PMID: 25874805
25.  Epidemiology of Meningococcal Disease, New York City, 1989–2000 
Emerging Infectious Diseases  2003;9(3):355-361.
Study of the epidemiologic trends in meningococcal disease is important in understanding infection dynamics and developing timely and appropriate public health interventions. We studied surveillance data from the New York City Department of Health and Mental Hygiene, which showed that during 1989–2000 a decrease occurred in both the proportion of patients with serogroup B infection (from 28% to 13% of reported cases; p<0.01) and the rate of serogroup B infection (from 0.25/100,000 to 0.08/100,000; p<0.01). We also noted an increased proportion (from 3% to 39%; p<0.01) and rate of serogroup Y infection (from 0.02/100,000 to 0.23/100,000; p<0.01). Median patient age increased (from 15 to 30 years; p<0.01). The case-fatality rate for the period was 17%. As more effective meningococcal vaccines become available, recommendations for their use in nonepidemic settings should consider current epidemiologic trends, particularly changes in age and serogroup distribution of meningococcal infections.
doi:10.3201/eid0903.020071
PMCID: PMC2958530  PMID: 12643832
Neisseria meningitidis; meningitis; surveillance; serogroup; case fatality rate; New York City; research

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