Molecular epidemiology of meningococcal disease in Northern Ghana

Meningococcal disease remains a major public health concern, especially in the
African Meningitis Belt where large meningitis epidemics with attack rates of up to
500/100,000 recur every 8-12 years. The factors precipitating epidemics are largely
unknown. Epidemics are therefore unpredictable which often leads to control
measures being initiated too late to be effective. Following a major meningitis
epidemic that occurred in northern Ghana in 1997, a collaborative research project
was developed between the Swiss Tropical Institute and the Navrongo Health
Research Center, in order to address several research questions relevant to the
epidemiology of meningococcal disease in Ghana. This research partnership built the
framework of the present thesis, which concentrated on the molecular epidemiological
aspects of the project. During the dry season of 1998, there was a second meningitis outbreak in the
Kassena-Nankana district (KND) of northern Ghana. All suspected meningitis
patients were recruited at the local health facilities, lumbar punctures carried out
before treatment and the cerebrospinal fluid (CSF) specimen sent to the field
laboratory for analysis. In 50 of 92 CSF samples analyzed, serogroup A Neisseria
meningitidis were detected. All serogroup A N. meningitidis isolates recovered were
of the A:4:P1.9,20 phenotype. Analysis of representative isolates by multilocus
sequence typing (MLST) and by restriction fragment length polymorphism (RFLP) of
opa, iga and ingA genes showed that they belonged to subgroup III (sequence type 5)
of N. meningitidis and had RFLP patterns characteristic of serogroup A subgroup III
bacteria isolated in Africa after the 1987 Mecca epidemic. RFLP analysis of six
polymorphic loci in a global collection of 502 isolates of subgroup III, serogroup A N.
meningitidis identified nine ‘genoclouds’, consisting of genotypes that were isolated
repeatedly, plus 48 less frequent descendent genotypes. Starting during the second outbreak, a series of five 6-monthly carriage surveys
of 37 randomly selected households were carried out in KND. As serogroup A N.
meningitidis carriage decreased, that of X meningococci increased dramatically to
reach 18% (53/298) of the people sampled during the dry season of 2000. This
coincided with a further outbreak of disease, this time caused by serogroup X. The
Ghanaian serogroup X strains were analyzed by MLST and pulsed-field gel
electrophoresis (PFGE) along with other serogroup X isolates from different countries of Africa, Europe and North America. The European and American isolates were
highly diverse. However, one clonal grouping was identified among sporadic disease
and carrier strains isolated over the last two decades in the UK, The Netherlands,
Germany and the USA. In contrast to the diversity among the European and American
isolates, most carrier and disease isolates recovered in Ghana and other countries of
the African Meningitis Belt over the last thirty years belong to a second clonal
grouping. Based on the PFGE results, two genoclouds were identified within the
second clonal grouping, one of which caused an outbreak in Niger in 1997 and the
other of which caused the outbreak in KND in 2000. Patterns of carriage of N. lactamica in KND were unrelated to those of N.
meningitidis. Non-serogroupable (NG) strains of N. meningitidis were infrequent.
This contrasts with industrialized countries where asymptomatic nasopharyngeal
carriage of N. meningitidis is common and up to 50% of the strains carried are NG. The nine genoclouds of subgroup III meningococci have caused three pandemic
waves of disease since the mid-1960’s, with the 1997-8 outbreaks in KND forming
part of the second wave. The third wave was imported from East Asia to Europe and
Africa in the mid-1990s, and may well lead to renewed epidemic serogroup A disease
in Europe and the Americas. The finding that a serogroup X meningococcal clonal
grouping has caused outbreaks in Africa, supports concerns that polysaccharide
vaccines, which have been in use for more than a decade might be selecting for nonvaccine
serogroups and argues for the development of a comprehensive conjugate
vaccine including serogroup X polysaccharide. The dynamics of meningococcal
carriage that were observed in KND suggest that in the African meningitis belt, the
populations become colonized in waves of different meningococcal strains, and the
occurrence of epidemics of disease depends on the virulence of these strains. Carriage
of NG meningococci may protect against meningococcal disease by eliciting crossreactive
immunity against pathogenic strains and the low levels of carriage of such
organisms in the African meningitis belt may thus increase susceptibility to
epidemics.