Scholarly article on topic 'Towards understanding the epidemiology of Neisseria meningitidis in the African meningitis belt: a multi-disciplinary overview'

Towards understanding the epidemiology of Neisseria meningitidis in the African meningitis belt: a multi-disciplinary overview Academic research paper on "Biological sciences"

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Abstract of research paper on Biological sciences, author of scientific article — Lydiane Agier, Nadège Martiny, Oumy Thiongane, Judith E. Mueller, Juliette Paireau, et al.

Summary Objectives Neisseria meningitidis is the major cause of seasonal meningitis epidemics in the African meningitis belt. In the changing context of a reduction in incidence of serogroup A and an increase in incidence of serogroups W and C and of Streptococcus pneumoniae, a better understanding of the determinants driving the disease transmission dynamics remains crucial to improving bacterial meningitis control. Methods The literature was searched to provide a multi-disciplinary overview of the determinants of meningitis transmission dynamics in the African meningitis belt. Results Seasonal hyperendemicity is likely predominantly caused by increased invasion rates, sporadic localized epidemics by increased transmission rates, and larger pluri-annual epidemic waves by changing population immunity. Carriage likely involves competition for colonization and cross-immunity. The duration of immunity likely depends on the acquisition type. Major risk factors include dust and low humidity, and presumably human contact rates and co-infections; social studies highlighted environmental and dietary factors, with supernatural explanations. Conclusions Efforts should focus on implementing multi-country, longitudinal seroprevalence and epidemiological studies, validating immune markers of protection, and improving surveillance, including more systematic molecular characterizations of the bacteria. Integrating climate and social factors into disease control strategies represents a high priority for optimizing the public health response and anticipating the geographic evolution of the African meningitis belt.

Academic research paper on topic "Towards understanding the epidemiology of Neisseria meningitidis in the African meningitis belt: a multi-disciplinary overview"

Accepted Manuscript

Title: Towards understanding the epidemiology of Neisseria Meningitidis in the African meningitis belt: a multi-disciplinary overview.

Author: Lydiane Agier Nadege Martiny Oumy Thiongane Judith E. Mueller Juliette Paireau Eleanor R. Watkins Tom J. Irving Thibaut Koutangni Helene Broutin

PII: DOI:

Reference:

S1201-9712(16)31218-8 http://dx.doi.Org/doi:10.1016/j.ijid.2016.10.032 IJID 2764

To appear in:

International Journal of Infectious Diseases

Received date: Revised date: Accepted date:

24-8-2016

21-10-2016

29-10-2016

Please cite this article as: Agier L, Martiny N, Thiongane O, Mueller JE, Paireau J, Watkins ER, Irving TJ, Koutangni T, Broutin H, Towards understanding the epidemiology of Neisseria Meningitidis in the African meningitis belt: a multi-disciplinary overview., International Journal of Infectious Diseases (2016), http://dx.doi.org/10.1016Zj.ijid.2016.10.032

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Review article

Towards understanding the epidemiology of Neisseria Meningitidis in the African meningitis belt: a multi-disciplinary overview.

Lydiane Agiera1*lydiane.agier@univ-grenoble-alpes.fr, Nadège Martinyb, Oumy Thionganec, Judith E. Muellerd'e, Juliette Paireaue'f, Eleanor R. Watkinsg2, Tom J. Irvingh, Thibaut Koutangnid'e, Hélène Broutini,j

a Combining Health Information, Computation and Statistics, Lancaster Medical School, Lancaster University,Lancaster, UK.

b Centre de Recherches de Climatologie (CRC), UMR 6282 CNRS BIOGEOSCIENCES, Université de Bourgogne, 6 Bd Gabriel, 21000 Dijon, France.

c Institut de Recherche pour le Développement, UMR INTERTRYP IRD-CIRAD, Antenne IRD Bobo Dioulasso, 01 BP 171 Bobo, Burkina Faso.

d EHESP French School of Public Health, Sorbonne Paris Cité, Rennes, France.

e Unité de l'épidémiologie des maladies émergentes, Institut Pasteur, Paris, France.

Department of Ecology and Evolutionary Biology, Princeton Environmental Institute, Princeton University, Princeton, NJ 08544 USA.

g Department of Zoology, Tinbergen Building, Oxford University, Oxford, OX1 3PS, UK. h School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.

i MIVEGEC, UMR 590CNRS/224IRD/UM, 910 avenue Agropolis, 34000 Montpellier cedex 5, France.

j Service de Parasitologie-Mycologie, Faculté de Médecine, Université Cheikh Anta Diop, Fann, Dakar, Senegal.

<PA>Institute for Advanced Biosciences, CRI INSERM/UJF U82, Rond-point de la Chantourne, 38700 La Tronche, France, Tel.: (0033) 4 76 54 94 00

<AF>1Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Inserm and University Grenoble-Alpes, U823 Joint Research Center, Grenoble, France

<AF>2Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK

Highlights

Better understanding the determinants of bacterial meningitis dynamics is crucial Improving surveillance and implementing large scale, longitudinal studies is needed Improving markers of protection and comparing clones' molecular characteristics is needed Integrating climate and social factors into control strategies is a priority Investigating the disease dynamics at a smaller spatial scale would be beneficial

Abstract

Objectives: Neisseria meningitidis is the major cause of meningitis seasonal epidemics in the African meningitis belt. In the changing context of serogroup A incidence reduction and serogroups W and C and Streptococcus pneumoniae incidence increase, a better understanding of the determinants driving the disease transmission dynamics remains crucial to improve bacterial meningitis control.

Design and methods: We searched the literature to provide a multi-disciplinary overview of the determinants of meningitis transmission dynamics in the African meningitis belt.

Results: Seasonal hyperendemicity is likely predominantly caused by increased invasion rates, sporadic localized epidemics by increased transmission rates and larger pluri-annual epidemic waves by changing population immunity. Carriage likely involves competition for colonization and cross-immunity. The duration of immunity likely depends on the acquisition type. Major risk factors include dust and low humidity, and presumably human contacts rates and co-infections; social studies highlighted environmental and dietary factors, with supernatural explanations.

Conclusions: Efforts should focus on implementing multi-countries, longitudinal seroprevalence and epidemiological studies, validating immune markers of protection and improving surveillance, including more systematic molecular characterizations of the bacteria. Integrating climate and social factors into disease control strategies represents a high priority for optimizing the public health response and anticipating the geographic evolution of the African meningitis belt.

Keywords: bacterial meningitis, disease control, research priorities, African belt.

INTRODUCTION Epidemiological context

Meningococcal meningitis is an acute bacterial disease characterized by the sudden onset of fever, intense headache, nausea, stiff neck and photophobia.1 The meningococcus Neisseria meningitidis (Nm) is found only in humans and is transmitted from person to person by airborne droplets of respiratory or throat secretions.2 Most infections with Nm result in a period of asymptomatic pharyngeal carriage and only occasionally lead to severe invasive disease.3 Meningococcal meningitis is a serious public health problem because of its high case fatality rate4 and, in some regions, its propensity for epidemics.

The African meningitis belt is a region stretching from Senegal to Ethiopia with an estimated population exceeding 400 million people. A high seasonal incidence of meningitis was recorded in the area for decades,5,6 with epidemic waves occurring periodically but irregularly every 5-12 years.7 Seasonal hyperendemicity is observed every dry season between January and May, when weekly incidence rates rise up to 10/100,000 population throughout the African meningitis belt and can locally exceed 100/100,000 population.8,9 Even with swift and appropriate treatment, case fatality fluctuates around 10%,10 and 10-15% of survivors suffer long-term neurological sequelae.11 While Nm serogroup A (NmA) was the main cause for large meningitis epidemics in the African meningitis belt,12,13 serogroups W (NmW), C and X were also, and are still, responsible for localized epidemics and occasionally more widespread epidemic waves.13-17 Other bacteria contribute to the seasonality of the disease, namely Haemophilus influenzae type b and Streptococcus pneumoniae which records high incidences among adults and a particularly high burden from serotype 1.18

The massive introduction of a monovalent group A polysaccharide-tetanus toxoid conjugate vaccine, known as MenAfriVac®,19 was initiated in 2010 and has successfully reduced the

1 ^ Oft

incidence of NmA disease. , - To date, an estimated 217 million population were immunized through mass vaccination campaigns targeting the 1-29 year age group in 15 countries. MenAfriVac® continues to be rolled out via these mass campaigns. In 2015, long term strategies incorporating the vaccine into the routine Expanded Program of Immunization schedule were recommended.24 Concurrently, pneumococcal conjugate vaccines were recently included in this routine Immunization Program; but old age groups, which represent the most susceptible population, may currently not be sufficiently protected to reduce the high disease burden.25

Global Nm incidence may increase again in the future as a result (i) of a possible serogroup replacement, for example, if NmA was the main competitor in the nasopharyngeal ecological niche; (ii) of spontaneous emergence of highly invasive and transmittable strains given Nm capacity for rapid genomic evolution; and (iii) of population-level immunity against NmA waning following vaccine introduction in the absence of a natural booster and with the arrival of unvaccinated birth cohorts. Until an effective multivalent meningococcal vaccine covering all relevant Nm serogroups is available to the populations and pneumococcal vaccination protects all age groups, control and prevention strategies need to be adapted to the changing disease epidemiology in the African meningitis belt.26,27 It is thus needed to better understand the determinants of bacterial meningitis transmission dynamics in the African meningitis belt.

Definition of the African meningitis belt

The definition of the African meningitis belt was triggered by the unique epidemiology of bacterial meningitis in the region; it set the stage for international efforts towards specific prevention and public health response strategy. Lapeyssonnie first described the African

meningitis belt in 1963 based on cerebrospinal meningitis cases reported over 23 years in the area, with several serogroups of Nm predominantly causing the epidemics.5 Geographic boundaries were established from isohyets ranging between 300 and 1100 mm annual rainfall, coinciding with this "endemo-epidemic" region while sporadic or grouped cases of bacterial meningitis occurred outside the area. The critical population size allowing epidemic outbreaks was considered not to be reached in regions with less than 300 mm of annual rainfall, due to difficult conditions for subsistence farming. The Southern limit (1100mm of annual rainfall) corresponds to the threshold of 50% of relative humidity. In 1971, an extension of the African meningitis belt to the eastern and southern shores of Lake Victoria was suggested, particularly Kenya and Uganda that were regularly devastated by epidemics in 1923-1950.28 In 1992, it was suggested to include Egypt, Tanzania and Uganda,29 although the local epidemiology did not fully match Lapeyssonnie's description. In 1996, an extension of the African meningitis belt to the south of the African meningitis belt was suggested after the improvement of microbiological diagnostic tools allowed the detection of epidemic strains of NmA subgroup III in Central African Republic, Uganda, Rwanda, Burundi, Tanzania and Zambia.30 These studies relied on clinically suspected rather than laboratory-confirmed meningitis cases (other diseases such as malaria or mump may produce similar symptoms) and did not account for the mechanisms driving the disease transmission dynamics. There is a risk for global environmental change to accelerate the geographic distortion of the African meningitis belt in the near future.

Objectives of this review

The present review aims at bringing a multidisciplinary perspective on meningococcal meningitis disease in the African meningitis belt. Based on the literature, we synthesized the main knowledge of the determinants of the disease epidemiology, and the concepts that have emerged, focusing on 5 main topics: disease transmission dynamics, asymptomatic carriage,

pathogen ecology, host immunity, and extrinsic risk factors for the disease. In particular, the role of climate in driving meningitis transmission dynamics was investigated. Meningitis is clearly identified as one of the most climate sensitive diseases in Africa,31 with 25% of the incidence variability being explained by climatic factors.32 It was recommended by recently published reviews on meningitis to identifying major climate indicators to be possibly integrated into operational decision-making.33 We finally highlighted research questions to be addressed in the future so as to better understand transmission dynamics and to develop appropriate long-term vaccination strategies aiming at reducing the burden of the disease in Africa.

Literature Search Methodology

We searched various electronic databases to identify relevant literature, independently for each topic. Details on searched databases, keywords and inclusion/exclusion criteria are provided in eAppendix 1. No limits were applied for language or publication date. The retrieved records were first screened by title and abstract; then by examination of the full text. Studies that clearly did not meet the inclusion criteria were discarded. The publications that were retained investigated meningitis in various locations and time periods, using variants of the case definition (suspected or confirmed cases, with different lists of serogroups being included) aggregated at different spatio-temporal scales.

METHODS AND MA TERIALS

Meningococcal disease transmission dynamics and modeling

A set of statistical methods were investigated to analyze the spatio-temporal transmission dynamics of meningitis epidemics and cases emergence, spread and outbreaks at different spatial and time scales, including simple epidemiological description,34,35 and more advanced

modeling techniques such as wavelet analyses,7 cross-correlation between time series,36 Kulldorffs spatial scan statistic, ' principal component and cluster analysis. Mechanistic Susceptible-Infected-Recovered (SIR) transmission modeling were used to explore and test potential disease processes.40-42

Asymptomatic Carriage

Most existing carriage studies were cross-sectional or series of cross-sectional surveys,43-51 with only one published cohort approach.52 All studies aimed to rely on representative population samples, and when reported, recommended nasopharyngeal swabbing via the mouth behind the uvula (with or without tonsils).53,54 An evaluation of polymerase chain reaction (PCR) analysis of enriched swab suspension compared to usual culture analysis found low sensitivity of conventional microbiology methods for carriage studies,55 which was already suggested in a study comparing swabbing with immuno-histography after tonsillectomy.56 It is therefore likely that all existing meningococcal carriage studies underestimated true carriage prevalence.

Pathogen ecology

In the last 40 years, laboratory testing was not systematically carried out in the African meningitis belt: approximately 10% of reported cases were laboratory tested,57 such that most large-scale retrospective studies relied on suspected cases defined by clinical criteria rather than laboratory-confirmed cases.58 Phenotypic approaches to antigenic typing using serotyping and serosubtyping were most commonly used until the mid-2000s. These techniques were used to identify epidemic clones of Nm (e.g. 59,60). Nowadays, routinely used identification techniques are sequence-based methods relying on cerebro-spinal fluid obtained through lumbar puncture. They include standard microbiology with culture isolation and serological identification of serogroup, latex agglutination testing, and PCR testing.61 Beyond

bacterial isolation and identification of serogroups, there is now a wide range of molecular typing techniques available to genetically characterize meningococcal strains, be it from invasive cases or carriage. Among these, multi-locus sequence typing (MLST) and multi-locus enzyme electrophoresis (or MLEE) were frequently used to characterize strains in the African meningitis belt,62,63 Sequence types are grouped into clonal complexes according to their similarity with a central genotype.

Host Immunity

The immunological assays that are currently available for population-based serological studies of meningococcal disease (i.e. IgG concentration and serum bactericidal antibody assays) do not allow distinction between naturally acquired immunity following carriage or disease, and vaccine-induced immunity. This is currently limiting the interpretation of results, mostly for studies conducted in areas with both high endemicity and high vaccination coverage.45,64 No serological correlate of protection is known for NmA disease or carriage in the African meningitis belt. The serum bactericidal assay is the accepted correlate of protection for meningococcal disease,65 but thresholds of protection are only established for serogroup C meningococcal disease.45,66 In addition, most Nm seroprevalence studies in the African meningitis belt used cross-sectional study designs to quantify immunity at specific time points, at best cohort studies to quantify changes during one meningitis season.50,52

Risk Factors

Risk factor analyses were performed both at the individual level (e.g. in case-control studies) and at an aggregated ecological level (e.g. in geographical correlation studies). The most frequently investigated factors for infection are environmental and climatic factors,32,67-73 with

-3-7 -50 -7/1

a few studies including other risk factors such as population density, ' ' household socio-

ATI 7^ 77 78 70

demographic characteristics and lifestyle, , - or other co-infections. , Though climate

was suspected for long to influence the transmission dynamics of meningococcal disease in Africa,5 researchers only began to test these associations in the 2000s when long-term remote sensing data became available. Before this, climate and health associations were investigated at a local scale using in situ meteorological data (e.g. air temperature and humidity68 or rainfall69). The remote sensing advances enabled to investigate effects on a larger scale.

Regarding the specific role of desert dust in epidemics, a high diversity of existing dust products were investigated, from remote sensing products (generally indices which are proxies of the aerosol quantity over the whole atmospheric column, some of which need to be refined or corrected from various complex effects before being used for health impact studies, e.g. aerosol index,80)69,80 to in-situ aerosol measurements (e.g. PM10 mass concentration that is available from limited number of meteorological stations across the African meningitis belt, or visibility that is more widely available but give a qualitative rather than quantitative estimate of the number of dusty days and the atmospheric turbidity in a given location).

Risk factors were primarily investigated using regression methods to estimate their

association with the disease. The other approaches investigated include disease mapping,6,81

25,82 80

hypothetical explanatory models, and mathematical modeling. Characteristics of the publications are detailed in Table 1, including the list of factors investigated, the methods used for the analysis, and a summary of the results.

Few studies investigated the social science viewpoint on the disease and on vaccination. In the African meningitis belt, these studies relied on qualitative data collected through in depth interviews or/and focused group discussions in several ethnic groups in Burkina Faso,83-85

86,87 88

Niger, ' and Benin. They investigated the knowledge and perceptions of the disease and its risk factors.

KNOWLEDGE and CONCEPTS

Pathophysiology of meningitis in the African meningitis belt

Laboratory-based surveillance studies of meningococcal disease in the African meningitis belt usually rely on suspected cases of acute bacterial meningitis and analysis of cerebrospinal fluid. Based on the usual pathophysiology requiring invasion of the blood stream before invasion of the central nervous system,89 epidemics of meningococcal meningitis should come with high morbidity and mortality due to meningococcal septicemia. For example, assuming that 28% of cases of invasive meningococcal disease are accompanied by clinical signs of septicemia as it was observed in France,90 one would have expected around 400 cases of septicemia in Niger in 2015, when 1435 cases of Nm91 were confirmed in laboratory. However, surveillance of febrile syndromes, which requires large inclusion criteria and hemoculture for evaluation, is rarely conducted in the African meningitis belt92 and no published data is available on septicemia incidence in the region. A possibly high ratio of meningitis over septicemia number of cases could be due to a direct ascension of the bacteria from the nasopharynx along the olfactory nerve, which is supported by a few animal

studies.93,94

Meningitis transmission dynamics

In the African meningitis belt, seasonal meningitis outbreaks are localized both in time and

34,37,38

space when monitored at a scale finer than the district. ' ' When data is aggregated at a country or broader scale, pluri-annual cycles of 5 to 12 years are observed.7,39,57 No systematic spatial diffusion pattern was observed at any of the country,7 region, district, village,36 or health centre levels.38 However, it was shown that large outbreaks were associated with early

"2Q ^ <

epidemic onset, ' and with large number of localized epidemics within a district.

It was hypothesized that the transition to seasonal hyperendemicity, localized epidemics and larger pluri-annual epidemic waves were distinct phenomena with their respective mechanisms, which could be explained respectively by an increased risk of invasion given nasopharyngeal colonization (possibly due to dry and dusty climate), epidemic co-factors increasing meningococcal transmission and colonization during short periods (such as viral respiratory infections), and changing population immunity (e.g., due to the evolution of the predominant circulating meningococcal strains).8 The suggested roles of increased risk of invasion in the seasonal hyperendemicity and of increased transmission in driving localized epidemics were reinforced by the findings of a systematic review on surveillance and carriage in the African meningitis belt.95

The transmission dynamics of infectious diseases are primarily explained by vaccine or disease-induced immunity. For epidemic meningitis in the African meningitis belt, vaccination coverage data was not systematically reported before the introduction of MenAfriVac®, and only little seroprevalence estimates were available, such that the effect of vaccination on the disease transmission dynamics could not be investigated before 2010.

Asymptomatic carriage

The estimated prevalence of Nm carriage varies between 5% and 30%,96,97 and was shown to be low in young children and higher in adolescents and young adults.97-99 There is growing evidence that carriage of the epidemic strain is substantially increased during an epidemic.44,48,95 Season and immunization with polysaccharide vaccine appear to have little effect on carriage, but being in contact with a case has.97,100.

In industrialized countries, hyperinvasive Nm clones are rarely identified in carriers and carriage populations are highly genetically diverse.96 In the African meningitis belt, it was also found a low carriage rate of Nm and an extensive genetic diversity of carriage strains, 101-

except in one study.43 The carriage of less virulent clones may help to prevent hypervirulent clones to spread through induced immunity (indirect competition),104 or if the physical presence of a clone in the nasopharyngeal niche hampered colonization by other strains (direct interaction). Carriage of meningococci with capsular null locus or FetA null locus, which cannot produce a capsule, was also being frequently reported in the African meningitis belt.102,105,106 While these unencapsulated strains may establish long-lived carriage relationships with the host,43 sporadic cases of meningitis due to these meningococci have been reported.105

Little is known about the duration of carriage episodes in the African meningitis belt. Carriage can be transient, or can last up to several months before being cleared naturally,99 and this duration is likely to vary by strain,107 and by age of the host. Two studies respectively estimated a half-life of 3 months,51 and a carriage episode duration of 30 days on average.102

It is unclear what triggers the transition from asymptomatic carrier to developing the disease, and what is the impact of the duration of carriage in the process. Hypothetical models have suggested that a systematic and widespread increase in the carriage rate during the dry season is not likely; despite it is required locally for an epidemic to occur.8 The first point contradicts Greenwood's hypothetical model,67 and the conclusion of the first SIR simulation models, which stated that seasonal increase in transmission was necessary for obtaining uneven annual incidences.40

Pathogen ecology

Many of the observed genotypes in the African meningitis belt are escape variants (in terms of antigenic typing or in other outer membrane antigens108,109,110,111) resulting from positive selection that may be attributed to herd immunity. Competition between fit genotypes results in dramatic changes in population composition over short time periods. Most often, clonal

complexes comprise a dominating genotype and closely related variants. Most escape variants

are less fit than their parents and are lost because of competition and bottlenecks during

spread from country to country. Yet, new variants with heightened fitness may arise, allowing

antigenic escape and spread when its antigenic characteristics are partially distinct from its

parents. Although this unlikely happens in the presence of cross-immunity, it may

occasionally result in the emergence of a novel epidemic strain.108 Epidemics are usually

triggered by concomitant short-term changes in the pathogen genetic, the host immunity and 112

its environment.

Little is known regarding the strains that caused the disease in the first part of the 20th century in Africa. However, from the 1950s and prior to MenAfriVac® introduction, the majority of meningitis cases were caused by Nm,113,114, mainly serogroup A. 12,13 NmA outbreaks were caused by the ST-1, ST-4 and ST-5 clonal complexes. 115,57,62, In particular, ST-5 was linked to three successive pandemic waves in the African meningitis belt; the latest occurred in 1996-1997 and resulted in more than 250,000 cases and 50,000 deaths. ST-5 complex persisted in Africa until MenAfriVac® was introduced. Serogroup W strains were circulating at low levels in the African meningitis belt (mostly in Chad, Cameroon, Niger, Togo and Senegal) before 2000, until the clone ST-11 caused epidemics in Burkina Faso and

57116 117

Niger. , , The NmW ST-2881 clone was occasionally reported. No Nm serogroup C epidemic was reported in the region for over 30 years; until epidemics occurred in 2013-2015 in Nigeria16 and in Niger, due to a previously unknown Nm C strain sequence type with unique antigenic properties.16 Serogroup X incidence increased in recent years, which represents a major concern, as there is currently no vaccine available.15,118 The surveillance of these non-A serogroups is important due to their epidemic potential in the context of the wide-scale introduction of MenAfriVac® that eliminated epidemics due to NmA so far. Since Nm shows a great capacity to change its genome, the emergence of a new and possibly highly

virulent serogroup cannot be excluded.119 Recent studies of the post-vaccination epidemiology of meningitis all found that NmA cases disappeared from vaccinated countries and that the global number of meningitis suspected cases decreased but they reported an increase in other serogroups and/or pathogen incidence, mainly NmW, C and Streptococcus

16 20 23 120 122

pneumoniae. , , , - a few years of additional data is needed for evaluating the long-term effectiveness of the MenAfriVac® vaccine.

Host Immunity

Disease and vaccination both induce immunity; but carriage can promote bactericidal activity as well and repeated carriage episodes may offer some immunity against future carriage and disease,123,124 including cross-strain immunity.44,66,125 Some evidence was given for such serogroup-specific relationships,44,47,126 but not systematically.126 It is however coherent with studies finding that antibody concentration increased with age,125 and that living in a district with emerging serogroup W disease was a predictor of higher immunity antibody levels.47 The duration of immunity is unknown, but likely depends on the acquisition type (through vaccination, asymptomatic carriage or by developing the disease).

Some studies found an inverse relationship between immunity and incidence (low NmW immunity during a hyper-endemic season and high NmA immunity with no detectable circulation of the bacteria,52) but others have not. Positive association was found between age-specific NmA immunity and meningitis incidence,44,45 and higher antibody titers were recorded (i) in Sudan (even in unvaccinated populations) compared to other regions outside the African meningitis belt, although this did not prevent epidemics occurrence;104,127 (ii) for NmW in endemic areas of Burkina Faso compared to non-endemic areas (even when an epidemic just occurred).47 Immunity possibly does not have a direct effect, but rather an

interaction effect with another risk factor affecting the disease transmission dynamics (a climatic factor for instance), so that no clear relationship can be found with incidence.

One major limitation in serological studies is the absence of a correlate of protection for most relevant serogroups in the African meningitis belt.45 The high prevalence of putatively protective serogroup A serum bactericidal antibody (SBA) titers >1:8 or >1:128 in the population even before PsA-TT introduction suggest that standard SBA does either not measure functional antibody, or that these antibodies are not functional in this region.45

Overall, our knowledge of the relationship between immunity, carriage, and disease is limited, especially as immunity and carriage are likely to be highly changing over time. Yet, long-term and repetitive carriage episodes may bring some immunity to the host.

Risk factors

The first suspicion of climate largely impacting Nm transmission dynamics was inspired by the seasonal profile for meningitis that coincides with the core of the dry season when the Harmattan regime is well settled, and ends with the arrival of the African monsoon.5,6,71,82

At spatially aggregated levels, evidence suggested that humidity/rainfall was negatively associated with incidence,69,70,74 while temperature showed a positive association.79 Low humidity appeared to restrain acquisition and increases clearance of the non-groupable bacteria,76 and to be a necessary but not sufficient condition for meningitis outbreaks to

7 1 70 HA.

occur. Carbon monoxide emission, and land cover type, were also found to be associated with the magnitude of the epidemics; yet no hypothetical causal effect was suggested. Despite a negative association between dust and meningitis in one study,70 more recent studies have shown a positive correlation between dust and meningitis incidence,72,79 with a 1 to 2-week delay between dust and meningitis seasonal components.71,80,128 This time-lag is consistent

with the biologically-plausible hypothesis that dust particles and dry air favor bactericidal invasion into the blood stream by damaging the host's mucosal barrier or by inhibiting mucosal immune defenses,82 with an incubation period of <14 days.123 Wind was also found to impact meningitis incidence,32,73 but it may rather be a correlate of a true risk factor, such as dust or humidity.

Regarding non-climatic risk factors, the reoccurrence rate of epidemics is higher in highly populated districts,36,129 but the association between annual incidence and population density was not proven significant.37,74 Human contact associated with primary roads might largely contribute to local spatial transmission dynamics and spread of the disease.129

At the individual level, symptoms of upper respiratory tract infections appear to favor NmA and NmW carriage during localized epidemics,47,76 while this and previous symptoms of flu were found to be associated with subsequent meningococcal meningitis during localized epidemics.44,77 This may relate to immune depression following viral infections, such as known for influenza virus and pneumococci.130 Similarly, monthly incidence of meningitis was shown to be associated with incidence of pneumonia in Ghana,79 yet the 2-month delay is likely too long to be biologically relevant. Smoking was shown to be a risk factor for NmW disease,47 and Nm Y carriage,76 but neither for NmA carriage nor disease.44,75,77 Different measures of proximity with asymptomatic carriers or meningitis cases were found to increase

A'n 'H/z c 77 _

the risk for both carriage, , (except for one contradictory result) and infection. , Being a student lowers the risk of contracting the disease.75 Exposure to kitchen fire smoke was found to inflate the risk of meningitis during epidemics,44,75 but the evidence is not conclusive.77

None of the studies investigating quantitative socio-economic factors found significant associations with carriage or with developing the disease.

The social perceptions of meningitis etiologic risk factors were examined and highlighted environmental factors with supernatural explanations in all West African societies. One sort of wind in particularly is believed to be pathologic, i.e. to be a sorcery entity purportedly bringing disease.86 In Niger, this entity is expected to be met in the bush and cause agitations and delirium during the disease phase.87 Meningitis is also viewed as an airborne disease in Burkina Faso;131 in northern Benin where it is believed to be caused by winds carrying waste; and in the Mosse groups where it is considered the "disease of the sun" or "disease of the wind".84,88 Both in Benin and Burkina Faso, staying under the sun during the hot season is believed to increase the risk of developing the illness, particularly among children.83

Meningitis is also believed to have dietary reasons, such as malnutrition in the Hausa groups, or green foods in Burkina Faso, e.g. green mangoes mostly when consumed by children, during the hot season, or when ingested with dust.83 People having a predisposition for meningitis (i) in Burkina Faso, activate the disease by eating prohibited green mangoes and green food;83 (ii) in Niger, have weak souls and develop the disease by looking at a sick

person.

These West African representations of the etiology of meningitis display similarities with the risk factors identified in epidemiological studies, mostly with environmental factors. Yet, different mechanistic assumptions are described in these two viewpoints, which deserve further exploration, as it may be crucial to integrate more social science into operation tools.

PERSPECTIVES on Research to Date/Way Forward

Despite research efforts over the last decades, gaps in the understanding of several key aspects of meningococcal disease epidemiology and ecology in the African meningitis belt prevent from better controlling the occurrence of seasonal outbreaks and from optimizing the public health response. Specifically, these gaps include (i) clarifying the role of climatic risk factors,

of carriage, and of immunity in driving meningitis transmission dynamics; (ii) understanding why large-scale meningitis epidemics occur only in a few Sahelian countries, and the possible role of behavioral and socio-cultural factors; (iii) elucidating how insights into the molecular epidemiology of the meningococcus may help preventing epidemics; and (iv) defining populations at risk and better characterizing the boundaries of the African meningitis belt and its potential evolution in the future in a context of climate change.

In order to advance the field of meningococcal meningitis epidemiology in the African meningitis belt, efforts should focus on developing infrastructures, methods, and approaches to systematically collect high-quality, population-representative longitudinal data on carriage, immunity, disease incidence, social factors and key molecular characteristics in countries of the African meningitis belt. Mathematical and statistical models that draw upon these aspects along with climatic and sociological factors should be further adapted and developed, so as to better explain the observed patterns of the disease, anticipate future outbreaks and vaccine impact, and help characterizing the changing boundaries of the African meningitis belt. Ultimately, this would allow better adapting prevention and control strategies, and responding more efficiently to localized outbreaks.27 Several important considerations and limiting factors that need to be addressed are discussed below.

Meningococcal meningitis risk factors in the African meningitis belt

Population-level changes in natural and vaccine-induced immunity over time have not been systematically investigated in the African meningitis belt. Innovative seroprevalence studies with repeated immunogenic samples ensuring more extensive geographic and temporal coverage are needed. Such study would require to fully validate immune markers as surrogates of protection against most commonly reported serogroups in the African meningitis belt; and to pursue comparison of clones at the whole genome level using novel molecular techniques so as to spot differences in virulence, transmissibility or antigenicity.109,132-134

Better understanding the genetic evolution of meningococcal strains would help with understanding and foreseeing the emergence and spread of new strains and the succession of invasive strains in the African meningitis belt. Ecological factors within the nasopharyngeal environment and strain competition are not well understood at present, but likely play an important role in the epidemic wave phenomena. Competition can be indirect (mediated through immunity) or direct (through interactions in the nasopharynx, via either exploitative or interference mechanisms). Both immunological and direct competitive interactions were suggested to be potentially important in the high income countries,135,136 but no observation was made in the context of the African meningitis belt. Nasopharyngeal microbiome should inform the pathogens interactions and their role in epidemic waves in a context of multi-vaccines implementation (i.e. MenAfriVac® and pneumococcal conjugate vaccines), including the role of Streptococcus pneumoniae, which is also responsible for local meningitis epidemics.

In addition to the biological factors, further investigation into (possibly combined) climatic (especially humidity and dust in the dry season) and social factors (especially resource inequalities, migrations and seasonal population movements) and their relation with meningococcal disease would be valuable in developing plans to prevent and mitigate disease spread.

Mathematical and statistical modeling of meningococcal disease in Africa

In terms of statistical and mechanistic models, more precise data would allow (i) detecting thin spatial heterogeneities in disease transmission dynamics; (ii) better detecting risk factors and estimating their impact; (iii) building on this knowledge to get a clearer idea of the underlying mechanism of the disease. In this regard, mathematical mechanistic SIR models have a great potential but need to be further developed with reliable parameters 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 center level and keep up to date a record of the evolution of the health centers spatial definition. More timely reporting of meningitis incidence would allow reducing the time for decision and optimizing the reactive vaccination strategies, which remain crucial for a global meningitis control. In contrast, current delay in information diffusion and data aggregation at the district level reduces the vaccination campaign efficacy in preventing cases.27 Finally, as the epidemiology of bacterial meningitis is currently changing in the African meningitis belt following the introduction of MenAfriVac®; the national surveillance systems could be subsequently adapted if all stakeholders and partners prioritized this undertaking.

To conclude, the priorities we have identified for future research ultimately aim at understanding observed patterns of the disease, anticipating meningitis epidemics outbreaks, forecasting the effects of possible public health policies and 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 link 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 focusing on understanding the epidemiology and the transmission dynamics of meningococcal disease in

the African meningitis belt. We thank all MERIT and MAMEMA participants for the thorough discussions on the topic.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest: None

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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

Agier 201380 Niger 1986-2007 Suspected cases Dust, Wind direction and force, Relative Humidity, Temperature wavelets district - week

Agier 201339 Niger, Mali and Burkina Faso 1986-2007 Suspected cases cluster analysis, principal component analysis district - week

Besancenot 199768 Benin 1965-1992 Biologically confirmed cases and suspected cases of Nm Temperature, relative humidity, vapor pressure, dust haze Simple linear regression region -month

Bharti 2012129 Niger 1995-2004 Suspected cases Human density, daily rainfall Cox proportional hazard regression model district - year

Broutin 20077 Mali, Burkina Faso, Ghana, Togo, Benin, Niger, Nigeria, Chad and Sudan 1939 - 1999 Suspected cases Wavelet analysis country - year

Dukic 201279 Navrongo in Ghana 1998-2008 Biologically confirmed cases Rainfall, temperature, relative humidity, wind speed, dusty days, carbon dioxide emissions from fires Poisson generalized additive model, possibly with lagged risk factors Month (no space scale)

Greenwood 198467 Zaria area in Northern Nigeria 1977-1979 Biologically confirmed cases of Nm Temperature, absolute humidity, rainfall, Harmattan intensity Pearson correlation two weeks (no space scale)

Hodgson 200175 Kassena-Nankana district in northern Ghana 1997 Suspected cases (case-control study). socio-economic factors, housing and household overcrowding, smoking and exposure to smoke and close contact with a case Computation of Mantel-Haenszel odds ratios. odd ratio

Irving 2011 40 model parameters: 1/ rate of progression from asymptomatic carriage to invasive disease is seasonally forced; 2/ carriers and cases are infectious, same transmission rate; 3/ no immunity, immunity due to disease, immunity due to disease and carriage Deterministic compartmental model Susceptible-Carrier-Ill- Recovered

Jackou-Boulama 200569 Niger 1996-2002 Suspected cases Rainfall: monthly cumulative rainfall from 4 meteorological stations Pearson correlation country -month

Mainassara 201037 Niger 2002-2008 Biologically confirmed cases of Nm Spatial scan statistics canton - year

Niger 2002-2008 Biologically confirmed cases of Nm Population density Pearson correlation departement -year

Martiny 201371 Niger and Mali 2004-2009 Suspected cases Dust, Absolute humidity Comparisons between mean standardized annual regimes in dust, absolute humidity and meningitis. Pearson correlation country -week

Molesworth 200374 Africa 1841-1999 Meningitis epidemics published (Pubmed) and unpublished (institutional reports) Absolute humidity, absorbing aerosols, rainfall, land-cover type, population density Principal component analysis, clustering, logistic regression district (no time scale)

Mueller 200876 Bobo- Dioulasso city in Burkina Faso February to June 2003 Carriers of Nm during hyperendemic period (5 monthly visits: pharyngeal swabs) Socio-demo info (medical history, smoke exposure, crowding...), meteorological data Multivariate mixed Poisson regression Individual scale

Cox proportional hazard model Individual scale

Three rural villages in Burkina Faso 2006 Carriers of Nm during NmA epidemic period Socio-demo info(medical history, smoke exposure, crowding.), meteorological data Multivariate mixed logistic regression Individual scale

Mutonga 200977 West Pokot district in Kenya December 2005-April 2006 Suspected cases (case-control study) Characteristics of the household, lifestyle, recent travel, exposure to sick people, upper respiratory tract infection, socio-economic status, level of education Conditional multivariate logistic regression Individual scale

Paireau 201238 Niger 2003-2009 Biologically confirmed cases of Nm Spatial scan statistics and local Moran's I test for spatial autocorrelation Health area -year

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

Philippon 200936 Mali 1992-2003 Suspected cases Cross-correlation of times series of cases Region-week, district-week and village-week

Ragunathan 200647 Burkina Faso, 2 districts vaccinated against NmA and NmC 2002 5-25 years old carriage and seroprevalence Demographic information, household conditions, recent medical history, and self-reported previous meningococcal vaccination: exposure to meningitis in the household, travel to Mecca Logistic regression Individual scale

Sultan 200573 Mali 1994-2002 Suspected cases Winter maximum Linear regression country -week

Tall 201234 Six districts of Burkina Faso 2004-2008 Suspected cases Pearson correlation Health centre - week

Thomson 200670 BF Niger parts of Mali Togo 1997-2001 1993-2001 1989-1998 1990-1997 Suspected cases Dust, rainfall, NDVI, CCD (cold cloud duration) Multivariate linear regression district - year

Yaka 200832 Niger and Burkina Faso 1966-2005 Suspected cases wind velocity, surface temperature, specific/relative humidity near the surface Multivariate linear regression country-year