An Outbreak of Serotype 1 Streptococcus pneumoniae Meningitis in Northern Ghana with Features That Are Characteristic of Neisseria meningitidis Meningitis Epidemics

BackgroundThe Kassena-Nankana District (KND) of northern Ghana lies in the African meningitis belt, where epidemics of bacterial meningitis have been reoccurring every 8-12 years. These epidemics are generally caused by Neisseria meningitidis an organism that is considered to be uniquely capable of causing meningitis epidemics MethodsWe recruited all patients with suspected meningitis in the KND between 1998 and 2003. Cerebrospinal fluid samples were collected and analyzed by standard microbiological techniques. Bacterial isolates were subjected to serotyping, multilocus sequence typing (MLST), and antibiotic-resistance testing ResultsA continual increase in the incidence of pneumococcal meningitis was observed from 2000 to 2003. This outbreak exhibited strong seasonality, a broad host age range, and clonal dominance, all of which are characteristic of meningococcal meningitis epidemics in the African meningitis belt. The case-fatality rate for pneumococcal meningitis was 44.4%; the majority of pneumococcal isolates were antibiotic sensitive and expressed the serotype 1 capsule. MLST revealed that these isolates belonged to a clonal complex dominated by sequence type (ST) 217 and its 2 single-locus variants, ST303 and ST612 ConclusionsThe S. pneumoniae ST217 clonal complex represents a hypervirulent lineage with a high propensity to cause meningitis, and our results suggest that this lineage might have the potential to cause an epidemic. Serotype 1 is not included in the currently licensed pediatric heptavalent pneumococcal vaccine. Mass vaccination with a less complex conjugate vaccine that targets hypervirulent serotypes should, therefore, be considere

Clonal Waves of Neisseria Colonisation and Disease in the African Meningitis Belt: Eight- Year Longitudinal Study in Northern Ghana

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

Clonal waves of meningococcal and pneumococcal meningitis in a region of the meningitis belt of Sub-Saharan Africa

Bacterial meningitis remains one of the major health problems in Sub-Saharan Africa and contributes significantly to childhood morbidity and mortality. The three most important agents are Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. All three pathogens are common colonizers of the human nasopharynx, invasive disease is usually a rare event. While meningitis caused by Haemophilus influenzae (Hib) and Streptococcus pneumoniae (pneumococcus) is mostly endemic and affects certain risk groups, Neisseria meningitidis (meningococcus) is known for its potential to cause meningitis epidemics especially in Sub-Saharan Africa. In the so called African Meningitis Belt, epidemics of meningococcal meningitis reccur every 8-12 years with incidence rates of up to 1% in the affected population, typically caused by serogroup A. Recently, outbreaks of serogroup W135 have raised general concern. The dynamics of these epidemic cycles is uncompletely understood. As meningitis cases in the early phase of epidemics usually fulminantly shoot up, outbreaks are often only detected when the epidemic is already on course. Also a lack of functional infrastructure in the respective countries, contributes to the delayed initiation of intervention measures, to prevent the majority of cases such as emergency immunization of the affected population with meningococcal polysaccharide vaccine . After a major meningitis epidemic in Northern Ghana in 1998 a long-term colonisation and disease study was initiated in the Kassena Nankana District (KND), by a joined collaboration of the Navrongo Health Research Center and the Swiss Tropical Institute. The study aims to enhance the understanding of the dynamics of meningococcal meningitis epidemics in the African Meningitis Belt for early outbreak detection and improved intervention. This thesis as part of the long term study, concentrates on epidemiological characteristics of colonisation and disease and the association of the population of meningococcal carriage- and patient-isolates. Furthermore, the impact of emerging clones (e.g. serogroup W135) and other bacterial species (in particular S. pneumoniae) causing acute bacterial meningitis in Northern Ghana was investigated. During eight years study period completed so far, we observed sequential waves of colonisation with pathogenic and apathogenic meningococcal genoclouds that typically lasted for three to four years. Epidemiological trends were profoundly different from those observed in industrialized countries. The carried populations of meningococci were i) less stable in genotype composition, ii) less diverse during the peaks of colonization waves, iii) non-groupable (NG) strains were comparatively rare and iv) the hyperinvasive genoclouds responsible for all culture-reconfirmed meningococcal meningitis cases were not a minority, but dominated, representing 71% of the colonisation isolates. Serogroup A meningococci caused two outbreaks during the study period. Sequence Type (ST) 5 bacteria were detected during a post-epidemic outbreak in 1998 and colonisation persisted until 1999. While A ST5 meningococci have never been isolated again in the KND, closely related A ST7 meningococci emerged in 2001, causing substantial outbreaks between 2002 to 2004 before disappearing from the district in late 2005. In between, an outbreak of serogroup X bacteria occured in 2000 and 2001, with colonisation rates of up to 20%, but only a limited number of cases. Even though the meningococcal population observed in the KND over eight years exhibited a low genetic diversity, constant microevolution was observed in the different genoclouds. W135 meningococci, exhibiting epidemic potential in neighbouring Burkina Faso only caused sporadic meningitis cases in Ghana and no major wave of colonisation and disease. However, W135 strains isolated from single meningitis patients were indistinguishable from Burkinian epidemic isolates by PFGE analysis and in certain patient communities efficient clonal colonisation with carriage rates of up to 20% was observed. Hib meningitis was recorded only infrequently in the KND since routine vaccination with the Hib polysaccharide-protein conjugate vaccine had been implemented in Ghana in 2000. In contrast, S. pneumoniae caused an outbreak of pneumococcal meningitis in the KND between 2000 and 2003, that revealed features characteristic for meningococcoal meningitis such as seasonality, clonality and a broad age spectrum of the patients. Serotyping and MLST analysis showed the dominance of a serotype 1 clonal complex, which has repeatedly been isolated in various African countries. PFGE analysis and pspAsequencing of the outbreak strains in comparison with reference strains representing three serotype 1 lineages, confirmed the clonal relationship of the Ghanaian isolates and indicated a phylogenetic association of the three serotype 1 lineages. The observed lack of a temporally stable and genetically diverse resident pharyngeal flora of meningococci might contribute to the susceptibility of the population in the African meningitis belt to meningococcal disease epidemics. 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. Furthermore the emergence of new genoclouds of non-vaccine serogroups with epidemic potential or other species such as S. pneumoniae needs to be carefully examined to evaluate the need for other vaccines or a change of the intervention strategies

Genetic diversification of Neisseria meningitidis during waves of colonization and disease in the meningitis belt of sub-Saharan Africa

Although Neisseria meningitidis is a highly variable organism, most invasive disease is caused by a minority of genotypes. Hypervirulent lineages have been identified and their pandemic spread has been traced. During a longitudinal meningococcal colonization study in a district of northern Ghana clonal waves of carriage and disease were observed. Genetic diversification of genoclouds was analysed by pulsed field gel electrophoretic (PFGE) analysis of isolates from healthy carriers and from meningitis patients. Even during the limited time of persistence in the district, microevolution of the dominating genoclouds took place. Population genomic analyses are required to understand the genetic basis for the emergence of new lineages with epidemic potential, which is of crucial importance for the development of long-term global vaccination strategies against meningococcal disease

An outbreak of serotype 1 Streptococcus pneumoniae meningitis in northern Ghana with features that are characteristic of Neisseria meningitidis meningitis epidemics

The Kassena-Nankana District (KND) of northern Ghana lies in the African meningitis belt, where epidemics of bacterial meningitis have been reoccurring every 8-12 years. These epidemics are generally caused by Neisseria meningitidis, an organism that is considered to be uniquely capable of causing meningitis epidemics.; We recruited all patients with suspected meningitis in the KND between 1998 and 2003. Cerebrospinal fluid samples were collected and analyzed by standard microbiological techniques. Bacterial isolates were subjected to serotyping, multilocus sequence typing (MLST), and antibiotic-resistance testing.; A continual increase in the incidence of pneumococcal meningitis was observed from 2000 to 2003. This outbreak exhibited strong seasonality, a broad host age range, and clonal dominance, all of which are characteristic of meningococcal meningitis epidemics in the African meningitis belt. The case-fatality rate for pneumococcal meningitis was 44.4%; the majority of pneumococcal isolates were antibiotic sensitive and expressed the serotype 1 capsule. MLST revealed that these isolates belonged to a clonal complex dominated by sequence type (ST) 217 and its 2 single-locus variants, ST303 and ST612.; The S. pneumoniae ST217 clonal complex represents a hypervirulent lineage with a high propensity to cause meningitis, and our results suggest that this lineage might have the potential to cause an epidemic. Serotype 1 is not included in the currently licensed pediatric heptavalent pneumococcal vaccine. Mass vaccination with a less complex conjugate vaccine that targets hypervirulent serotypes should, therefore, be considered

Waves of Colonisation and Disease in the KND from April 1998 until November 2005

<div><p>Carriage rates recorded during 16 colonisation surveys (April and November each year) and monthly numbers of confirmed meningitis cases of <i>N. meningitidis.</i></p> <p>(A) Genoclouds of serogroup A ST5 and ST7 meningococci are shown.</p> <p>(B) Genoclouds of serogoup X ST851 and NG ST192 meningococci are shown.</p> <p>(C) Carriage rates of other serogroups and meningococci unrelated to the A, X, or NG ST192 genoclouds are shown.</p> <p>(D) Carriage rates of N. lactamica are shown.</p></div

Age and Sex Patterns of Colonisation and Disease

<div><p>(A) Carriage of meningococci (all serogroups and NG; cumulation of all surveys) in the different age groups of the male (light grey bars) and female (dark grey bars) population are shown. 95% CIs are indicated. These CIs do not allow for repeated sampling.</p> <p>(B) Carriage of N. lactamica in the different age groups (mean over all surveys) of the male (light grey bars) and the female population (dark grey bars) are shown. 95% CIs are indicated. These CIs do not allow for repeated sampling.</p> <p>(C) Age spectrum of IR of meningococcal meningitis in the male (circles) and female (triangles) population of the KND in the epidemic of 1996–1997 (dark grey) versus the interepidemic period 2001–2005 (light grey). Denominator is the district population 1995–1999. On the primary y-axis the epidemic IRs and on the secondary y-axis the interepidemic IRs are indicated.</p></div