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

Abstract

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.