International Journal of Infectious Diseases 54 (2017) 103–112 X

Contents lists available at ScienceDirectX

International Journal of Infectious Diseases

journal homepage: www . elsevier . com/locate/ijidX

Review

Towards understanding the epidemiology of Neisseria meningitidis in the

African meningitis belt: a multi-disciplinary overview

a,1, b c d,e
Lydiane Agier *, Nade`ge Martiny , Oumy Thiongane , Judith E. Mueller , Juliette Paireau
e,f g h d,e i,j
, Eleanor R. Watkins , Tom J. Irving , Thibaut Koutangni , He´le`ne Broutin X

a b
Combining Health Information, Computation and Statistics, Lancaster Medical School, Lancaster University, Lancaster, UK Centre de Recherches de
Climatologie (CRC), UMR 6282 CNRS Biogeosciences, Universite´ de Bourgogne, Dijon, France
c d
Institut de Recherche pour le De´veloppement, UMR INTERTRYP IRD-CIRAD, Antenne IRD Bobo Dioulasso, Bobo, Burkina Faso EHESP French
School of Public Health, Sorbonne Paris Cite´, Rennes, France
e
Unite´ de l’Epide´miologie des Maladies Emergentes, Institut Pasteur, Paris, France

f g
Department of Ecology and Evolutionary Biology, Princeton Environmental Institute, Princeton University, Princeton, New Jersey, USA Department of
Zoology, Oxford University, Oxford, UK
h i
School of Social and Community Medicine, University of Bristol, Bristol, UK MIVEGEC, UMR 590CNRS/224IRD/UM, Montpellier, France
j
Service de Parasitologie–Mycologie, Faculte´ de Me´decine, Universite´ Cheikh Anta Diop, Fann, Dakar, Senegal
context of a the African meningitis belt.
reduction in
incidence of
serogroup A Results: Seasonal hyperendemicity is likely
ARTICLE INFO predominantly caused by increased invasion
and an
increase in rates, sporadic localized epidemics by increased
Article history: incidence of transmission rates, and larger pluri-annual
serogroups W epidemic waves by changing population
and C and of immunity. Carriage likely involves competition for
Received 24 August 2016 Streptococcus colonization and cross-immunity. The duration of
pneumoniae, a immunity likely depends on the acquisition type.
Major risk factors include dust and low humidity,
Received in revised form 21 October 2016 Accepted 29 October 2016 better
understanding and presumably human contact rates and co-
of the infections; social studies highlighted
Corresponding Editor: Eskild Petersen, determinants environmental and dietary factors, with
driving the supernatural explanations.
disease
Aarhus, Denmark
transmission Conclusions: Efforts should focus on
dynamics implementing multi-country, longitudinal
Keywords: remains seroprevalence and epidemiological studies,
crucial to validating immune markers of protection, and
improving
Bacterial meningitis
improving surveillance, including more
bacterial systematic molecular characterizations of the
meningitis bacteria. Integrating climate and social factors
control. into disease control strategies represents a high
Disease control
priority for optimizing the public health response
Methods: The and anticipating the geographic evolution of the
Research priorities African meningitis belt.
literature was
searched to
African belt provide a 2016 Published by Elsevier Ltd on behalf of
multi- International Society for Infectious Diseases.
disciplinary This is an open access article under the CC BY-
overview of
S U M MARY the NC-ND license (
determinants http://creativecommons.org/licenses/by-nc-
of meningitis
Objectives: Neisseria meningitidis is the major cause of seasonal transmission nd/4.0/). X
meningitis epidemics in the African meningitis belt. In the changing dynamics in
1. Introduction

* Corresponding author at: Adva Biosciences, CRI Rond-point de la

Current address: Institute for nced INSERM/UJF U82, Chantourne, 38700 La
Tronche, France. Tel.: +33 4 76 54 94 00. 1
Present addresses:
Lydiane Agier, Inserm
and University
Grenoble-Alpes, U823
Joint Research Center,
Grenoble, France.
Eleanor R. Watkins,
Department of
Zoology, University of
Oxford, Oxford, UK.

1.1.
Epidemiological
context

Meningococcal
meningitis is an
acute bacterial
disease
characterized by
the sudden onset
of fever, intense
headache,
nausea, stiff neck,
1
and photophobia.
The
meningococcus
Neisseria
meningitidis is
found only in
humans and is
transmitted from
E-mail address: person to person
lydiane.agier@univ- by airborne
grenoble-alpes.fr (L. droplets of
respiratory or
Agier). X throat

9712/ 2016 Inter ety for access article

Published by nati Infectious under the CC license ( http://
http://dx.doi.org/10.1016/j.ijid.201 120 Elsevier Ltd on onal Diseases. This BY-NC-ND creativecommons.org/licenses/by-nc-
6.10.032 1- behalf of Soci is an open
nd/4.0/). X
104 L. Agier et al. / International Journal of Infectious Diseases 54 (2017) 103–112
serogroup replacement, for outbreaks was considered
2 example if NmA was the not to be reached in regions
secretions. Most infections with Nm result main competitor in the with less than 300 mm of
in a period of asymptomatic pharyngeal nasopharyngeal ecological annual rainfall, due to
carriage and only occasionally lead to niche; (2) the spontaneous difficult conditions for
3
severe invasive disease. Meningococcal emergence of highly subsistence farming. The
meningitis is a serious public health invasive and transmittable southern limit (1100 mm of
problem because of its high case fatality strains given the capacity of annual rainfall) corresponds
rate and, in some regions, its propensity Nm for rapid genomic to the threshold of 50% of
4
evolution; and relative humidity.
for epidemics.

(3) population-level In 1971, an extension of the

The African meningitis belt is a region
immunity against NmA African meningitis belt to
stretching from Senegal to Ethiopia with an
waning following vaccine the eastern and southern
estimated population exceeding 400 million
introduction in the absence shores of Lake Victoria was
people. A high seasonal incidence of
of a natural booster and suggested, particularly to
meningitis has been recorded in the area
5,6 with the arrival of cover Kenya and Uganda,
for decades, with epidemic waves unvaccinated birth cohorts. countries that were
occurring periodically but irregularly every Until an effective multivalent regularly devastated by
7 28
5–12 years. Seasonal hyper-endemicity is meningococcal vaccine epidemics in 1923–1950.
observed every dry season between covering all relevant Nm In 1992, it was suggested
January and May, when weekly incidence serogroups is available to that Egypt, Tanzania, and
rates rise up to 10/100 000 population the populations and 29
Uganda be included,
throughout the African meningitis belt and pneumococcal vaccination
protects all age groups, although the local
can locally exceed 100/ 100 000
8,9 control and prevention epidemiology did not fully
population. Even with swift and match Lapeysson-nie’s
appropriate treatment, case fatality strategies need to be
adapted to the changing description. In 1996, an
10
fluctuates around 10%, and 10–15% of disease epidemiolo-gy in extension of the African
survivors suffer long-term neurological the African meningitis meningitis belt to the south
11
sequelae. While Nm serogroup A (NmA) belt.26,27 A better was suggested after
has been the main cause of large improvements in microbio-
understanding of the logical diagnostic tools
meningitis epidemics in the African determinants of bacterial
12,13 allowed the detection of
meningitis belt, serogroups W (NmW), meningitis transmission epidemic strains of NmA
C (NmC), and X (NmX) have also been, anddynamics in the African subgroup III in the Central
are still, responsible for localized epidemics meningitis belt is thus African Republic, Uganda,
and occasionally more widespread needed. Rwanda, Burundi,
13– 17
epidemic waves. Other bacteria Tanzania, and Zambia.
30
contribute to the seasonality of the disease, These studies relied on
namely Haemophilus influenzae type b and clinically suspected rather
Streptococcus pneumo-niae, the latter 1.2. Definition of the African
meningitis belt than laboratory-confirmed
having a high recorded incidence among meningitis cases (other
adults and a particularly high burden from diseases such as malaria
18
serotype 1. The definition of the African and mumps may produce
meningitis belt was similar symptoms) and did
triggered by the unique not account for the
The massive introduction of a monovalent epidemiology of bacterial
mechanisms driving the
group A polysaccha-ride–tetanus toxoid meningitis in the region; it
19 disease transmission
conjugate vaccine, known as MenAfriVac, set the stage for dynamics. There is a risk
international efforts towards that global environmental
a specific prevention and change may accelerate the
was initiated in 2010 and has successfully
public health response geographic distortion of the
reduced the incidence of NmA
13,20–23 strategy. Lapeyssonnie first African meningitis belt in
disease. To date, an estimated 217 described the African the near future.
million population meningitis belt in 1963
based on cerebrospinal
have been immunized through mass meningitis cases reported
vaccination campaigns targeting the 1–29 over 23 years in the area, 1.3. Objectives of this
years age group in 15 countries. with several serogroups of review
MenAfriVac continues to be rolled out via Nm predominantly causing
5
these mass campaigns. In 2015, long-term the epidemics. Geo- The present review aimed
strategies incorporating the vaccine into the graphic boundaries were to bring a multidisciplinary
routine Expanded Programme on established from isohyets perspective on
Immunization schedule were recom- ranging between 300 mm meningococcal meningitis
24 and 1100 mm annual
mended. Concurrently, pneumococcal disease in the African
conjugate vaccines were recently included rainfall, coinciding with this meningitis belt. Based on
in this routine immunization programme. ‘endemo-epidemic’ region, the literature, the main
However the older age groups, representing while sporadic or grouped knowledge of the
the most susceptible population, may cases of determinants of the disease
currently not be sufficiently protected to epidemiology and the
25 concepts that have
reduce the high disease burden. bacterial meningitis
occurred outside the area. emerged were synthesized,
The critical population size focusing on five main
Global Nm incidence may increase again in allowing epidemic topics: disease
the future as a result of (1) a possible transmission dynamics,
asymptomatic carriage, pathogen ecology, locations and time periods,
host immunity, and extrinsic risk factors for using variants of the case
Various electronic
the disease. In particular, the role of climate definition (suspected or
databases were searched
in driving meningitis transmission dynamics confirmed cases, with
to identify relevant
was investigated. Meningitis is clearly different lists of serogroups
literature, independently for
identified as one of the most climate- being included), aggregated
31 each topic. Details on the
sensitive diseases in Africa, with 25% of databases searched, on different spatio-temporal
the incidence variability being explained by keywords used, and scales.
32
climatic factors. It has been inclusion/exclusion criteria
recommended in recently published reviews applied are provided in the
on meningitis that major climate indicators Supplementary Material. No 2. Materials and methods
are identified for possible integration into limits were applied for
operational decision-making. Research language or publication
33
date. The records retrieved 2.1. Meningococcal disease
questions to be addressed in the future are
were first screened by title transmission dynamics and
highlighted, with the aim of gaining a better
and abstract and then by modelling
understanding of transmission dynamics
examination of the full text.
and developing appropriate long-term
Studies that clearly did not
vaccination strategies to reduce the burden A set of statistical methods
meet the inclusion criteria
of this disease in Africa. were investigated to
were discarded. The
analyze the spatio-temporal
publications that were
transmission dynamics of
retained investigated
meningitis epidemics
meningitis in various
1.4. Literature search methodology
L. Agier et al. / International Journal of Infectious Diseases 54 (2017) 103–112
105

of reported cases were genotype.

57
and case emergence, spread, and laboratory tested, and
outbreaks on different spatial and time most large-scale 2.4. Host immunity
scales, including simple epidemiological retrospective studies relied
34,35 on suspected cases defined
description, and more advanced The immunological assays
by clinical criteria rather
modelling techniques such as wavelet that are currently available
7 than laboratory-confirmed
analysis, cross-correlation between time 58 for population-based
cases. Phenotypic
36
series, Kulldorff’s spatial scan serological studies of
approaches to antigenic meningococcal disease
37,38
statistic, principal component analysis, typing using serotyping and (i.e., IgG concentration and
39
and cluster analysis. Mechanistic serosubtyping were most serum bactericidal antibody
commonly used until the assays) do not allow
susceptible–infected–recovered (SIR)
mid-2000s. These distinction between
transmission
techniques were used to naturally acquired immunity
identify epidemic clones of following carriage or
modelling was used to explore and test Nm (e.g. Kwara et al. ,
59
disease, and vaccine-
40–42
potential disease processes. Ouedraogo-Traore et al. ).
60 induced immunity. This is
Nowadays, the identification currently limiting the
2.2. Asymptomatic carriage techniques routinely used interpretation of results,
are sequence-based mostly for studies
methods relying on conducted in areas with
Most existing carriage studies were cross- cerebrospi-nal fluid both high endemicity and
sectional or series of cross-sectional obtained through lumbar high vaccination
43–51 45,64
surveys, with only one published cohort puncture. They include coverage. No
standard microbiology with serological correlate of
52 culture isolation and protection is known for NmA
approach. All studies aimed to rely on serological identification of disease or carriage in the
representative population samples, and serogroup, latex African meningitis belt. The
when reported, recommended agglutination testing, and serum bactericidal assay is
nasopharyngeal swabbing via the mouth 61 the accepted correlate of
PCR testing. Beyond
behind the uvula (with or without protection for
53,54 bacterial isolation and
tonsils). An evaluation of PCR analysis identification of serogroups, meningococcal disease,
65
of enriched swab suspension compared to there is now a wide range but thresholds of protection
usual culture analysis found low sensitivity of molecular typing are only established for
of conventional microbiology methods for techniques available to serogroup C meningococcal
55
carriage studies, which had already been genetically characterize disease.
45,66
In addi-tion,
suggested in a study comparing swabbing meningococcal strains, from most Nm seroprevalence
with immunohistochemistry after invasive cases to carriage. studies in the African
tonsillectomy. It is therefore likely that all Among these, multi-locus
56
meningitis belt have used
existing meningococcal carriage studies sequence typing (MLST) cross-sectional study
have underestimated true carriage and multi-locus enzyme designs to quantify
prevalence. electrophoresis (MLEE) immunity at specific time
have frequently been used points, and at best cohort
to characterize strains in studies to quantify changes
2.3. Pathogen ecology the African meningitis during one meningitis
62,63
belt. Sequence types season.
50,52
Laboratory testing was not performed are grouped into clonal
systematically in the African meningitis belt complexes according to
over the last 40 years. Approximately 10% their similarity with a central 2.5. Risk factors
 gives a qualitative rather
than quantitative estimate
Risk factor analyses were assessed both at
of the number of dusty days
the individual level (e.g., in case–control
and the atmospheric
studies) and at an aggregated ecological
turbidity in a given location).
level (e.g., in geographical correlation
studies). The most frequently
Risk factors were primarily
investigated using
investigated factors for infection were
32,67–73 regression methods to
environmental and climatic factors, estimate their association
with a few studies including other risk with the disease. The other
37,38,74
factors such as population density, approaches investigated
household socio-demographic char- included disease
47,75–77 6,81
acteristics and lifestyle, or other co- mapping, hypotheti-cal
78,79 25,82
infections. Al- explanatory models,
and mathematical
80
though climate was long suspected to modeling. The
influence the transmission dynamics of characteristics of the
5 publications relating
meningococcal disease in Africa, meningococcal menin-gitis
researchers only began to test these to environmental and
associations in the 2000s when long-term
climatic risk factors are
remote sensing data became available.
Before this, climate and health associations detailed in Table 1,
were investigated on a local scale using in including the list of factors
situ meteorological data (e.g., air investigated, the methods
68 69 used for analysis, and a
temperature and humidity, or rainfall ).
The advances made in remote sensing summary of the results.X
enabled the effects to be investigated on a
larger scale.
Few studies have
investigated the social
Regarding the specific role of desert dust in science viewpoint on the
epidemics, a high diversity of existing dust disease and on vaccination.
products were investigated, from remote In the African meningitis
sensing products (generally indices that are belt, these studies relied on
proxies for the aerosol quantity over the qualitative data collected
whole atmospheric column, some of which through in-depth
need
interviews and/or focused
to be refined or corrected from various group discussions in
complex effects before being used for several ethnic groups in
health impact studies, e.g. aerosol Burkina Faso,
83–85
80 69,80
index ) to in Niger,
86,87
and Benin.
88
They
situ aerosol measurements (e.g., the PM10
mass concentration, which is available from investigated the knowledge
a limited number of meteorological stations and perceptions of the
across the African meningitis belt, or disease and its risk factors.
visibility, which is more widely available but
3. Knowledge and concepts
3.1. Pathophysiology of
meningitis in the African
meningitis belt
Laboratory-based
surveillance studies on
meningococcal disease in
the African meningitis belt
usually rely on suspected
cases of acute bacterial
meningitis and the analysis
of cerebro-spinal fluid.
Based on the usual
pathophysiology requiring
invasion of the blood
stream before invasion of
the central nervous
89
system, epidemics of
meningococcal meningitis
should come with high
morbidity and mortality due
to meningococcal
septicaemia. For example,
assuming that 28% of
cases of invasive
meningococcal disease are
accompanied by clinical
signs of septicaemia, as
90
was observed in France,
one would have expected
around 400 cases of
septicaemia in Niger in
2015, when 1435 cases of
Nm were confirmed in the
91
laboratory. However, the
surveillance of febrile
syndromes, which requires
wide inclusion criteria and
blood culture for evaluation,
is rarely conducted in the
92
African meningitis belt,
and no published data are
available on the incidence
of septicaemia in the
region. A possibly high ratio
of meningitis to septicaemia
cases could be due
106 L. Agier et al. / International Journal of Infectious Diseases 54 (2017) 103–112

Table 1
Characteristics of the publications relating meningococcal meningitis to environmental and climatic risk factors.

First author/year
Location
Period
Epidemiological data
Risk factors investigated
Methods of analysis
Space/time

scale

80
Agier 2013
Niger
1986–2007
Suspected cases
Dust, wind direction and
Wavelets
District/week

force, relative humidity,

temperature

Agier 201339
Niger, Mali, and
1986–2007
Suspected cases
(Incidence only was
Cluster analysis,
District/week

Burkina Faso
investigated)
principal component

analysis

Besancenot
Benin
1965–1992
Biologically confirmed
Temperature, relative
Simple linear
Region/month
199768

cases and suspected

humidity, vapour
regression

cases of Nm
pressure, dust haze

Bharti 2012128
Niger
1995–2004
Suspected cases
Human density, daily
Cox proportional
District/year

rainfall
hazard regression

model

Broutin 20077
Mali, Burkina Faso,
1939 – 1999
Suspected cases
(Incidence only was
Wavelet analysis
Country/year
Ghana, Togo, Benin,

investigated)

Niger, Nigeria, Chad,

and Sudan

Dukic´ 201279
Navrongo in Ghana
1998–2008
Biologically confirmed
Rainfall, temperature,
Poisson generalized
Month (no

cases
relative humidity, wind
additive model,
space scale)

speed, dusty days, carbon

possibly with lagged

dioxide emissions from

risk factors

fires
Greenwood
Zaria area in
1977–1979
Biologically confirmed
Temperature, absolute
Pearson correlation
Two weeks (no
198467
Northern Nigeria

cases of Nm
humidity, rainfall,

space scale)

Harmattan intensity

Hodgson 200175
Kassena-Nankana
1997
Suspected cases (case–
Socio-economic factors,
Computation of
Odds ratio

District in northern

control study)
housing and household
Mantel–Haenszel odds

Ghana

overcrowding, smoking
ratios

and exposure to smoke,

and close contact with a

case

Irving 201140
(this simulation
(this simulation
(this simulation study
Model parameters: (1)
Deterministic
District–week

study did not require

study did not
did not require real
rate of progression from
compartmental model

real data)
require real data)
data)
asymptomatic carriage to
susceptible–carrier–

invasive disease is
ill– recovered

seasonally forced; (2)

carriers and cases are

infectious, same
transmission rate; (3) no

immunity, immunity due

to disease, immunity due

to disease and carriage

Jackou-Boulama
Niger
1996–2002
Suspected cases
Rainfall: monthly
Pearson correlation
Country/month
200569

cumulative rainfall from

four meteorological

stations

Maı¨nassara
Niger
2002–2008
Biologically confirmed
(Incidence only was
Spatial scan statistics
Canton/year
201037

cases of Nm
investigated)

Niger
2002–2008
Biologically confirmed
Population density
Pearson correlation
Department/

cases of Nm

year
Martiny 201371
Niger and Mali
2004–2009
Suspected cases
Dust, absolute humidity
Comparisons between
Country/week

mean standardized

annual regimes in

dust, absolute
humidity, and

meningitis; Pearson

correlation

Molesworth
Africa
1841–1999
Meningitis epidemics
Absolute humidity,
Principal component
District (no time
200374

published (PubMed)
absorbing aerosols,
analysis, clustering,
scale)

and unpublished
rainfall, land-cover type,
logistic regression

(institutional reports)
population density

Mueller 200876
Bobo-Dioulasso City
February to
Carriers of Nm during
Socio-demographic
Multivariate mixed
Individual scale

in Burkina Faso
June 2003
hyperendemic period
information (medical
Poisson regression
(5 monthly visits:
history, smoke exposure,

pharyngeal swabs)
crowding, etc.),

meteorological data

Cox proportional
Individual scale

hazard model

Three rural villages

2006
Carriers of Nm during
Socio-demographic
Multivariate mixed
Individual scale

in Burkina Faso

NmA epidemic period

information (medical
logistic regression

history, smoke exposure,

crowding, etc.),

meteorological data
L. Agier et al. / International Journal of Infectious Diseases 54 (2017) 103–112

107
Table 1 (Continued )

First author/year
Location
Period
Epidemiological data
Risk factors investigated
Methods of analysis
Space/time

scale

Mutonga
West Pokot District
December
Suspected cases (case–
Characteristics of the
Conditional
Individual scale
77
2009
in Kenya
2005–April 2006
control study)
household, lifestyle,
multivariate logistic

recent travel, exposure to

regression
sick people, upper

respiratory tract infection,

socio-economic status,

level of education

38
Paireau 2012
Niger
2003–2009
Biologically confirmed
(Incidence only was
Spatial scan statistics
Health area/

cases of Nm
investigated)
and local Moran’s I test
year

for spatial

autocorrelation

Niger
2003–2009
Biologically confirmed
Distance to road and
Pearson correlation
Health area/
cases of Nm
population density

year
Philippon
Mali
1992–2003
Suspected cases
(Incidence only was
Cross-correlation of
Region/week,
36
2009

investigated)
times series of cases
district/week,

and village/

week
Raghunathan
Burkina Faso, two
2002
5–25-year-olds,
Demographic
Logistic regression
Individual scale
47
2006
districts vaccinated

carriage and
information, household

against NmA and NmC

seroprevalence
conditions, recent medical

history, and self-reported

previous meningococcal
vaccination: exposure to

meningitis in the

household, travel to

Mecca

Sultan 2005
73
X
Mali
1994–2002
Suspected cases
Winter maximum
Linear regression
Country/week
34
Tall 2012
Six districts of
2004–2008
Suspected cases
(Incidence only was
Pearson correlation
Health centre/

Burkina Faso

investigated)

week
70
Thomson 2006
Burkina Faso
1997–2001
Suspected cases
Dust, rainfall, normalized
Multivariate linear
District/year

Niger
1993–2001

difference vegetation
regression
Parts of Mali
1989–1998

index, cold cloud duration

Togo
1990–1997

32
Yaka 2008
Niger and Burkina
1966–2005
Suspected cases
Wind velocity, surface
Multivariate linear
Country/year

Faso

temperature, specific/
regression

relative humidity near the

surface

Nm, Neisseria meningitidis; NmA, N. meningitidis serogroup A; NmC, N. meningitidis serogroup C.

of localized epidemics within a
34
country or broader scale, pluri- district.
annual cycles of 5 to 12 years are
to the direct spread of bacteria from the nasopharynx to the central 7,39,57
nervous system along the olfactory nerve, which is supported by a few observed. No systematic It was hypothesized that the
93,94 spatial diffusion pattern was transition to seasonal hyper-
animal studies. 7
observed at the country, region, endemicity, localized epidemics,
36 and larger pluri-annual epidemic
3.2. Meningitis transmission dynamics district, village, or health waves are distinct phenomena
with their own respective mecha-
centre levels. However, it was
38 nisms, which could be explained
In the African meningitis belt, seasonal meningitis outbreaks
by an increased risk of invasion
shown that large outbreaks were
given nasopharyngeal
associated with early epidemic
are localized both in time and space when monitored on a scale smaller 32,39 colonization (possibly due to a dry
34,37,38 onset, and with large and dusty climate), epidemic co-
than the district. When data are aggregated on a
numbers factors increasing meningococcal
transmis-sion and colonization during short periods (such as viral 97–
adolescents and young adults.
respiratory infections), and changing population immunity (e.g., due to 99
There is growing evidence that
the evolution of the predominant circulating meningococcal strains),
8
respectively. The suggested roles of an increased risk of invasion in the
seasonal hyperendemicity and of increased transmission in driving carriage of the epidemic strain is
localized epidemics were reinforced by the findings of a systematic substantially increased during an
95 44,48,95
review on surveillance and carriage in the African meningitis belt. epidemic. The season and
immunization with polysaccha-
ride vaccine appear to have little
The transmission dynamics of infectious diseases are primarily explained effect on carriage, but being in
by vaccine or disease-induced immunity. For epidemic meningitis in the 97,100
contact with a case has.
African meningitis belt, vaccination coverage data were not
systematically reported before the introduction of MenAfriVac, and few
seroprevalence estimates were available, such that the effect of In industrialized countries,
vaccination on the disease transmission dynamics could not be hyperinvasive Nm clones are
investigated before 2010. rarely identified in carriers, and
carriage populations are highly
96
3.3. Asymptomatic carriage genetically diverse. In the
African meningitis belt, a low
carriage
The estimated prevalence of Nm carriage varies between 5% and
96,97
30%, and was shown to be low in young children and higher in
rate of Nm and extensive genetic
diversity of carriage strains was
101–103
also found, except in one
study.
43
The carriage of less
virulent clones may help to
prevent hypervirulent clones
spreading through induced
104
immunity (indirect competition),
or the physical presence of a
clone in the nasopharyngeal
niche may hamper colonization by
other strains (direct interaction).
Carriage of meningococci with a
capsular null locus or FetA null
locus, which cannot produce a
capsule, was also reported
frequently in the African
101,102,105
meningitis belt. While
these
108 L. Agier et al. / International Journal of Infectious Diseases 54 (2017) 103–112

unencapsulated strains may establish long- 1950s and prior to the but they have reported an
43 introduction of MenAfriVac, increase in other
term carriage relation-ships with the host,
sporadic cases of meningitis due to these the majority of meningitis serogroups and/or
105 cases were caused by
meningococci have been reported. 113,114
Nm, mainly serogroup pathogen incidence, mainly
12,13
A. NmA outbreaks were NmW, NmC, and S.
Little is known about the duration of 16,20,23,120–122
caused by the sequence pneumo-niae.
carriage episodes in the African meningitis
type ST-1, ST-4, and ST-5 A few years of additional
belt. Carriage can be transient or can last 57,62,115
up to clonal complexes. In data are needed to
particular, ST-5 was linked evaluate the long-term
effectiveness of the
several months before being cleared MenAfriVac vaccine.
naturally, and this duration is likely to vary to three successive
99
107 pandemic waves in the
by strain and by age of the host. One African meningitis belt; the 3.5. Host immunity
study latest occurred in 1996–
1997 and resulted in more Disease and vaccination
51 than 250 000 cases and 50 both induce immunity;
estimated a half-life of 3 months, and 000 deaths. The ST-5 however carriage can
another estimated a carriage episode complex persisted in Africa
102 promote bactericidal activity
duration of 30 days on average. until MenAfriVac was as well, and repeated
introduced. Serogroup W
strains were circulating at
It is unclear what triggers the transition from carriage episodes may offer
low levels in the African
asymptomatic carrier status to disease some immunity against
meningitis belt (mostly in
development, and what the impact is of the future carriage and
duration of carriage on the process. 123,124
Hypothetical models have suggested that a Chad, Cameroon, Niger, disease, including
systematic and widespread increase in the Togo, and Senegal) before cross-strain
44,66,125
carriage rate during the dry season is not 2000, until clone ST-11 immunity. Some
likely, although it is required locally for an caused epidemics in
8 Burkina Faso and
epidemic to occur. The first point evidence has been given
57,116,117
contradicts Greenwood’s hypothetical Niger. The for such serogroup-specific
67 44,47,50
model and the conclusion of the first SIR relation-ships, but
simulation models, which stated that a NmW ST-2881 clone was 50
not systematically. It is,
seasonal increase in transmission was occasionally reported. No however, coherent with
necessary to obtain uneven annual NmC epidemic was
40
incidences. reported in the region for
over 30 years, until studies that have found
epidemics occurred in antibody concentrations to
3.4. Pathogen ecology 16 125
2013–2015 in Nigeria and increase with age, and
in Niger, due to a previously that living in a district with
Many of the observed genotypes in the unknown NmC strain ST emerging serogroup W
African meningitis belt are escape variants with unique antigenic disease is a predictor of
(in terms of antigenic typing or in other 16 higher immunity antibody
108–111 properties. The incidence 47
outer membrane antigens ) resulting of serogroup X has levels. The duration of
from positive selection, which may be increased in recent years; immunity is unknown, but
attributed to herd immunity. Competition this represents a major likely depends on the route
between fit genotypes results in dramatic concern, as there is of acquisition (through
changes in population composition over currently no available vaccination, asymptomatic
short time periods. Most often, clonal 15,118 carriage, or by developing
vaccine. The
complexes comprise a dominant genotype the disease).
surveillance of these non-A
and closely related variants. Most escape
serogroups is important due
variants are less fit than their parents and
to their epidemic potential in Some studies have found
are lost because of competition and
the context of the wide- an inverse relationship
bottlenecks during spread from country to
scale introduction of between immunity and
country. Yet, new variants with heightened
MenAfriVac, which has incidence (low NmW
fitness may arise, allowing antigenic escape
eliminated epidemics due to immunity during a hyperen-
and spread when the antigenic char-
NmA so far. Since Nm demic season and high
acteristics are partially distinct from the
shows a great capacity to NmA immunity with no
parents. Although this is unlikely to happen
change its genome, the detectable circulation of the
in the presence of cross-immunity, it may 52
emergence of a new and bacteria ), but others have
occasionally result in the emergence of a
108 possibly highly virulent not. A positive association
novel epidemic strain. Epidemics are serogroup cannot be was found between age-
usually triggered by concomitant short-term 119
excluded. Recent studies specific NmA immunity and
changes in the pathogen’s genetics, host 44,45
112 of the post-vaccination meningitis incidence,
immunity, and the environment. epidemiology of meningitis and higher antibody titres
have all found that NmA were recorded (1) in Sudan
Little is known regarding the strains that cases have disappeared (even in unvaccinated
caused the disease in the first part of the from vaccinated countries populations)
twentieth century in Africa. However, from and that the global number
the of meningitis suspected
cases has decreased, compared to other regions
outside the African meningitis belt, although between immunity, carriage, negatively associated with
this did not prevent epidemics from and disease is limited, 69,70,74
incidence, while
104,126 especially as immunity and
occurring; (2) temperature showed a
carriage are likely to 79
positive association. Low
change greatly over time.
for NmW in endemic areas of Burkina Faso Yet, long-term and repetitive humidity appeared to
compared to non-endemic areas (even carriage episodes may prevent acquisition and
47
bring some immunity to the increase clearance of the
when an epidemic had just occurred). 76
Immunity possibly does not have a direct host. non-groupable bacteria,
effect, but rather an interaction effect with and to be a necessary but
another risk factor affecting the disease not sufficient condition for
3.6. Risk factors
transmission dynamics (a climatic factor for meningitis outbreaks to
71
instance), so that no clear relationship can occur. Carbon monoxide
be found with incidence. The first suspicion of 79
emission and land cover
climate largely impacting 74
Nm transmis-sion dynamics type were also found to
One major limitation in serological studies is was inspired by the finding be associated with the
the absence of a correlate of protection for that the seasonal profile for magnitude of the
most relevant serogroups in the African meningitis coincided with epidemics; yet no
45
meningitis belt. The high prevalence of the core of the dry season, hypothetical causal effect
putatively protective serogroup A serum when the was suggested. Despite a
bactericidal antibody (SBA) titres >1:8 or negative association
>1:128 in the population even before the between dust and
Harmattan regime is well 70
introduction of the MenAfriVac1 suggests meningitis in one study,
settled, and ended with the
that the standard SBA either does not more recent studies have
arrival of the African
measure functional antibody, or that these 5,6,71,82 shown a positive correlation
antibodies are not functional in this monsoon.
between dust and
45
region. meningitis incidence,
72,79
At spatially aggregated with a 1- to 2-week delay
levels, evidence suggested between dust and
Overall, our knowledge of the relationship
that humidi-ty/rainfall was meningitis seasonal
L. Agier et al. / International Journal of Infectious Diseases 54 (2017) 103–112
109

79 the aetiological risk factors

in Ghana, yet the 2-month
71,80,127 delay was likely too long to of meningitis were
components. This time-lag is examined and highlighted
be biologically relevant.
consistent with the biologi-cally plausible environmental factors with
Smoking was shown to
hypothesis that dust particles and dry air supernatural explanations
favour bacterial invasion into the blood in all West African societies.
stream by damaging the host’s mucosal be a risk factor for NmW One sort of wind in
barrier or by inhibiting mucosal immune 47
disease and NmY particular is believed to be
82
defenses, with an incubation period of carriage,
76
but not for NmA pathological, i.e., to be a
<14 days.
123
Wind was also found to impact carriage or disease.44,75,77 sorcery entity purportedly
86
32,73 bringing disease. In Niger,
meningitis incidence, but it may rather Different measures of
this entity is expected to be
be a correlate of a true risk factor, such as proximity
met in the bush and cause
dust or humidity. with asymptomatic carriers
agitations and delirium
or meningitis cases were 87
found to during the disease phase.
Regarding non-climatic risk factors, the Meningitis is also viewed as
reoccurrence rate of epidemics was higher an airborne disease in
36,128 increase the risk of both
in highly populated districts, but the Burkina Faso,
130
in
47,76
carriage (except for one northern Benin where it is
contradictory result) and believed to be caused by
association between annual incidence and 75,77
population density was not proven infection. Being a winds carrying waste, and
37,74 student lowers the risk of in the Mosse
significant. Human contact associated
with primary roads might largely contribute
to local spatial transmis-sion dynamics and 75 groups where it is
contracting the disease.
128 considered the ‘disease of
spread of the disease. Exposure to kitchen fire
At the individual level, symptoms of upper smoke was found to inflate the sun’ or ‘disease of the
84,88
respiratory tract the risk of meningitis during wind’. In both Benin
44,75 and Burkina Faso, staying
epidemics, but
under the
infection appeared to favour NmA and NmW the evidence is not
47,76 77
carriage during localized epidemics, conclusive.
while this and previous symptoms of flu sun during the hot season
is believed to increase the
None of the studies risk of developing the
were found to be associated with investigating quantitative illness, particularly among
subsequent meningococcal meningitis socio-economic factors 83
children.
This may found significant
44,77
during localized epidemics.
associations with carriage
relate to immune depression following viral
or with developing the Meningitis is also believed
infections, as is known for influenza virus
129 disease. to have dietary causes,
and pneumococci. Similarly, the monthly
such as malnutrition in the
incidence of meningitis was shown to be Hausa groups, or green
associated with the incidence of pneumonia The social perceptions of
foods in Burkina Faso, e.g. green mangoes countries of the African meningococcal strains
mostly when consumed by children, during meningitis belt. would help to determine
the hot season, or when ingested with Mathematical and statistical and foresee the emergence
83 models that draw upon and spread of new strains
dust. People with a predisposition for
meningitis in Burkina Faso activate the these aspects, along with and the succession of
disease by eating prohibited green climatic and sociological invasive strains in the
83 factors, should be further African meningitis belt.
mangoes and green food, and those with adapted and developed so Ecological factors within the
a predisposition for meningitis in Niger have as to better explain the nasopharyngeal
weak souls and develop the disease by patterns of the disease environment and strain
87
looking at a sick person. observed, anticipate future competition are not well
outbreaks and vaccine understood at present, but
impact, and help likely play an important role
These West African representations of the
characterize the changing in the epidemic wave
aetiology of meningitis display similarities
boundaries of the African phenomenon. Competition
with the risk factors identified in
meningitis belt. Ultimately, can be indirect (mediated
epidemiological studies, mostly with
this would allow better through immunity) or direct
environmental factors. Yet, different
adaptation of prevention (through interactions in the
mechanistic assumptions are described in
and control strategies and a nasopharynx, via either
these two viewpoints, which deserve further
more efficient response to exploitative or interference
exploration, as this may be crucial to 27
localized outbreaks. mechanisms). Both
integrate more social science into
Several important immunological
operational tools.
considerations and limiting
factors that need to be and direct competitive
4. Perspectives on research to date and the addressed are discussed
interactions have been
way forward below. suggested to be potentially
important in high-income
Despite research efforts over the last countries,
134,135
but no
decades, gaps in the understanding of
several key aspects of meningococcal 4.1. Meningococcal
disease meningitis risk factors in the observation has been made
African meningitis belt in the context of the African
meningitis belt. The
epidemiology and ecology in the African nasopharyngeal
meningitis belt have prevented better Population-level changes in
microbiome should indicate
control of the occurrence of seasonal natural and vaccine-
the pathogen interactions
outbreaks and optimization of the public induced immunity over time
and their role in epidemic
health response. Specifically, these gaps have not been investigated
waves in a context of multi-
include (1) clarifying the role of climatic risk systematically in the African vaccine implementation
factors, carriage, and immunity in driving meningitis belt. Innovative
(i.e., MenAfriVac and
meningitis transmission dynamics; (2) seroprevalence studies with
pneumococcal conjugate
understanding why large-scale meningitis repeated immunogenic vaccines), including the role
epidemics occur only in a few Sahelian samples, ensuring more
of S. pneumoniae, which is
countries, and the possible role of extensive geographic and
also responsible for local
behavioural and socio-cultural factors; (2) temporal coverage, are meningitis epidemics.
elucidating how insights into the molecular needed. Such studies
epidemiology of meningococcus may help would require immune
prevent epidemics; and (4) defining markers to be fully validated In addition to the biological
populations at risk and better characterizing as surrogates of protection factors, further
the boundaries of the African meningitis belt against the most commonly investigations, possibly
and its potential evolution in the future in a reported serogroups in the combined, into climatic
context of climate change. African meningitis belt. factors (especially humidity
They would also benefit and dust in the dry season)
from comparing clones at and social factors
In order to advance the field of the whole genome level (especially resource
meningococcal meningitis epidemiology in using novel molecular inequalities, migration, and
the African meningitis belt, efforts should techniques so as to identify seasonal population
focus on developing the infrastructure, differences in virulence, movements) and their
methods, and approaches to systematically transmissibility, or relationships with
collect high-quality, population- 109,131–133 meningococcal disease
representative longitudinal data on carriage, antigenicity. A
would be valuable
immunity, disease incidence, social factors, better understanding of the
and key molecular characteristics in genetic evolution of
110 L. Agier et al. / International Journal of Infectious Diseases 54 (2017) 103–112
in developing plans to prevent and mitigate
the spread of this disease.
4.2. Mathematical and statistical modelling
of meningococcal disease in Africa
In terms of statistical and mechanistic
models, more precise data would allow (1)
narrow spatial heterogeneities in disease
transmission dynamics to be detected; (2)
risk factors to be better detected and their
impact to be estimated; (3) this knowledge
to be built on to obtain a clearer idea of the
mechanisms underlying the disease. In this
regard, mathematical mechanistic SIR
models have great potential, but need to be Conflict of interest: None.
developed further, with reliable parameter
estimates being plugged in. Scaling down
the spatial resolution of analyses to the
health centre level would require that the
ministries of health of the countries of
interest report cases at the health centre
level and keep up-to-date records of the
evolution of the health centres’ spatial
definition. More timely reporting of
meningitis incidence would reduce the time
for decisions and allow reactive vaccination Rosenstein N, Perkins B, Stephens D, Popovic T,
strategies to be opti-mized, which remain Hughes J. Meningococcal disease. N Engl J
crucial for global meningitis control. In
contrast, the current delay in the
dissemination of information and
aggregation of data at the district level
reduces the vaccination campaign efficacy Stephens DS, Greenwood B, Brandtzaeg P. Epidemic
27
in preventing cases. Finally, as the
epidemiol-ogy of bacterial meningitis is
currently changing in the African meningitis
belt following the introduction of
MenAfriVac, the national surveillance
systems could subsequently be adapted if Lancet 2012;380:1623–4 . http://dx.doi.org/10.1016/S0140-
all stakeholders and partners prioritize this
undertaking.
In conclusion, the priorities identified here
for future research ultimately aim at
understanding the observed patterns of the
disease, anticipating meningitis epidemic
outbreaks, forecasting the effects of
possible public health policies, and
determining the geographical evolution of
the African meningitis belt. Despite the
imminent introduction of a multivalent
meningococcal vaccine and the use of
pneumococcal vaccine in routine childhood
immunization, no time should be wasted
and efforts should be made towards better
understanding bacterial meningitis in the
African meningitis belt and in particular the
links between climate, pathogens, and
hosts, so as to be prepared for suboptimal
disease elimination following vaccine
introduction.
Acknowledgements
This review was conducted by members of
the international consortium MAMEMA
(Multidisciplinary Approach for Meningitis
Epidemiology and Modeling in Africa).
MAMEMA was initiated in 2011 as part of
the MERIT (Meningitis Environmental Risk
Information Technologies) activities, a
multidisciplinary group Greenwood BM. Meningococcal meningitis in
focusing on understanding
Africa. Trans R Soc Trop Med Hyg
the epidemiology and
transmission dynamics of 1999;93:341–53. X
meningococcal disease in
the African meningitis belt.
We thank all MERIT and Boisier P, Maı¨nassara HB, Sidikou F, Djibo S,
MAMEMA participants for
Kairo KK, Chanteau S. Case-fatality ratio of
the thorough discussions
on the topic. bacterial meningitis in the African meningitis
belt: we can do better. Vaccine
Funding: This research did
not receive any specific 2007;25(Suppl 1):A24–9. X
grant from funding
agencies in the public,
Smith AW, Bradley AK, Wall RA, McPherson B,
commercial, or not-for-profit
sectors. Secka A, Dunn DT, et al. Sequelae of epidemic
meningococcal meningitis in Africa. Trans R
Soc Trop Med Hyg 1988;82:312–20.
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