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.