Epidémiologie des Maladies Emergentes : Projets

The Emerging Diseases Epidemiology Unit was founded on July 1st, 2001.  Its mandate was to develop its own research agenda in the field of infectious diseases epidemiology, and to provide expertise in epidemiology and biostatistics to other laboratories.  Based on the potential for collaborations with the international network of Institut Pasteur, and on our past experience in international health, we decided to focus on the epidemiology of infectious and tropical diseases in resource-limited countries.  Each researcher has its own field of expertise: Arnaud Fontanet in analytical epidemiology (cohort and case-control studies), Muriel Vray in the methodology of clinical trials, Michel Garenne in demography, Tamara Giles-Vernick in social sciences, and Romulus Breban in mathematical modeling.  Main projects include hepatitis C in Egypt (see website), children diarrhea in Central African Republic, Buruli ulcer in Cameroun, acute encephalitis in Vietnam, and bacterial meningitis in Niger.  Emphasis has been put in clinical research, i.e., cohort studies and clinical trials.  In addition, four staff members, Yoann Madec, Loïc Chartier, Lénaïg Le Fouler and Laura Tondeur provide transversal support to all projects of the unit in biostatistics and data management. 
HCV research in Egypt
(Institut Pasteur, INSERM, French Hospitals, University of Cairo, University of Ain Shams, Minia University, Mansoura University; Coordination: Arnaud Fontanet & Gamal Esmat).
Funding: ANRS & EC. 

The main research objectives of this multidisciplinary network funded by the ANRS and the EC are the assessment of the burden of HCV infection and disease in Egypt, the study of factors associated with HCV transmission for designing better prevention programs, the optimization of drug regimens for the treatment of acute and chronic hepatitis C, and the study of factors associated with spontaneous HCV clearance in acute hepatitis C for vaccine development. The project has been successful in attracting twenty international research grants (from the EC, ANRS, and Wellcome Trust), and has already led to more than 25 publications in international peer-reviewed journals.  The ANRS network has been very involved in the elaboration of the 2013-2018 Egypt National Strategy for the Control of Viral Hepatitis through the National Committee against Viral Hepatitis (headed by Gamal Esmat) and the WHO Technical Advisory Group to the Ministry of Health (chaired by Arnaud Fontanet). A more detailed description of the research objectives and findings is available on the project’s website:

Description détaillée du programme de recherche
Stratégie nationale de lutte contre les hépatites virales en Egypte

Ac Mong Virus Encephalitis (AVE) Project: Investigation of unexplained acute encephalitis outbreaks in Northern Vietnam
(Collaborators: Phan Thi Nga, Hanoi; Paul Brey, IP Vientiane; Jean-Claude Manuguerra, Antoine Gessain, Marc Eloit, Matthew Albert, Olivier Lortholary, Juliette Paireau,  Arnaud Fontanet, IP Paris).
Funding : ANR, Geneviève Deyme, BNP Paribas Simplidons, ACIP.

More than 50% of acute encephalitis cases have no etiologic agent in the industrialized world (Huppatz C. et al., Emerg Infect Dis, 2009).  The advent of new high-throughput sequencing techniques and of microarrays that permit the detection of hundreds of viral sequences from a range of viruses may help us to attribute several of these unexplained acute encephalitis to an etiologic agent.  In the hope of identifying a new viral agent, we recently formed a collaborative group of epidemiologists, virologists, clinicians, immunologists, and entomologists to investigate outbreaks of pediatric acute encephalitis occurring in Northern Vietnam during the litchi harvests (months of June-July) since the end of the 1990s (AVE project, ANR MIEN-003-2008; Scientific Coordinator: Arnaud Fontanet). Epidemiological investigations performed by our group with colleagues from the National Institute of Hygiene and Epidemiology (NIHE, Hanoi) have confirmed the ecologic association between the occurrence of acute encephalitis cases and the proportion of litchi surface plantations at the commune level (n=230 communes) (Paireau et al, Emerg Infect Dis, 2012). 

This analysis was initiated to examine the local belief that these outbreaks started after the recent intensification of litchi production in the region, and after similar unexplained outbreaks of acute encephalitis took place around litchi plantations of the Bihar State in India.  The link between the litchi trees and the emergence of this new disease remains unexplained.
The clinical, biological and immunologic characteristics of patients suggest a viral etiology. No new virus has yet been identified but viral investigations on patients’ serum and cerebrospinal fluid are in progress. This project has been integrated in the general section on emerging pathogens of the recently awarded Labex IBEID (Integrative Biology of Emerging Infectious Diseases), coordinated by Pascale Cossart and Philippe Sansonnetti.

Acute Bacterial Meningitis Project: Investigation of the spatio-temporal dynamics of meningitis epidemics in Niger and the associated ecologic risk factors
Halima B. Mainassara, Jean-Paul Moulia-Pelat, Jean-François Jusot, Odile Ouwe Missi Oukem, CERMES, Niamey; Juliette Paireau, Judith Mueller, Arnaud Fontanet, IP Paris). 

Funding : DCI Monaco.

In collaboration with epidemiologists from the Centre de Recherche Médicale et Sanitaire (CERMES) in Niamey, we are using recent advances in Geographic Information Systems and statistical methodology to investigate the spatio-temporal dynamics of meningitis epidemics in Niger at a fine geographic scale (health centres) and the associated risk factors (project funded by the Office of International Cooperation of the Principality of Monaco ; Scientific Coordinator: Arnaud Fontanet).
Spatial analyses first revealed the highly localized nature of these annual epidemics, constituted by small spatial clusters of cases (Paireau et al, PLoS Negl Trop Dis, 2012). We identified heterogeneous spatio-temporal patterns, with emergence of outbreaks in different areas from year to year, followed by spread in variable geographic directions. We also showed that surveillance at a fine spatial scale would be more efficient for public health response: outbreaks would be detected earlier and reactive vaccination would be better targeted. The factors that could explain the observed spatio-temporal patterns at the health centre scale are still poorly understood and statistical models are under development in our group, integrating jointly climatic, environmental, socio-demographic and vaccination data.
Our findings should help to improve control of meningitis in sub-Saharan Africa, especially in the context of introduction of a new meningococcal A conjugate vaccine.

Epidemiology of Buruli ulcer in Cameroon
(Collaborators: Laurent Marsollier, Angers University; Jean-François Guégan, IRD; Sara Eyangoh, CPC Yaoundé; Jordi Landier, Arnaud Fontanet, IP Paris). 

Funding: ANR, Fondation Raoul Follereau, Fondation SANOFI Espoir.   

In this new research program, we will conduct for the first time the simultaneous collection of environmental (plants and insects) and human samples in two historically endemic regions located in different climates (equatorial and subtropical in Cameroon and Benin, respectively) and one newly discovered endemic focus close to a dam (in Cameroon).  Samples will be analysed for the presence of M.ulcerans, and characterised phylogenetically, to offer better understanding of the circulation of M.ulcerans across ecological niches.  Maps of M. ulcerans presence probability, as well as of M. ulcerans exposure risk, will be produced at the regional scale and tentatively expanded at the national scale, to target more efficiently diagnostic and care resources.

We will also focus on the role of peri-domestic insects in M.ulcerans transmission.  Indeed, two studies of our group suggest that individuals sleeping under mosquito nets are at a lower risk of Buruli ulcer than those who do not.  Knowing that in Australia, mosquitoes are considered as potential vectors for M.ulcerans (Lavender C.J. et al., PLoS NTD, 2011), and repellents are recommended for protection against Buruli ulcer, we seek to expand our initial studies by capturing insects around houses and using PCR to search for M.ulcerans DNA in these insects.



TORCADIA : Epidemiology of severe childhood diarrhea: A case control study in the Central African Republic (CAR)
(Collaborators: Sébastien Breurec,
Ionela Gouandjika,Thierry Frank, Caroline Martin (IP Bangui), Petulla bata, Jean Gody (Complexe pédiatrique Bangui), Tamara Giles-Vernick, Loic chartier, Muriel Vray (IP Paris)).

Funding : The fondation Total.

Diarrhea ranks as the world’s third most deadly infection in children, claiming some 2.2 million lives each year, of whom two million are under five years old. In the absence of laboratory tests, the presumptive treatment leads to an overestimation of possible bacterial diarrheas and of the overuse of antibiotic treatments, which can lead to the emergence of antibiotic resistant strains. In CAR, childhood diarrhea constitutes one of the most important public health problems, with a global prevalence estimated at 19%, and reaching 30% among children between 12 and 23 months old.

This study, which will include 600 HIV-negative children, hospitalized for severe diarrhea and a control group of 600 children, matched by sex, age, and neighborhood of residence, has the following primary objectives:
1) Identify the pathogens implicated in diarrhea;
2) Measure antibiotic resistance of different isolated bacterial strains;
3) Study over the short term the characteristics, evolution and sequellae of severe diarrhea;
4) Identify the risk factors (socio-economic, alimentary, environmental) associated with severe diarrhea;
5) Evaluate using an anthropological approach the practices and local concepts surrounding childhood diarrhea, as well as the treatment and feeding of diarrheal children.
All cases will undergo clinical examination, consisting of anthropometric measures, parasitological, virological, and bacteriological analyses of stool samples, and blood testing. For the controls, anthropometric measurements and a stool exam will be carried out.

Expected results:

This study will reinforce the knowledge of the epidemiology and etiologies of severe childhood diarrhea. In addition, it will also improve knowledge of the characteristics, evolution and sequellae of diarrhea that necessitate hospitalization. The analysis of antibiotic resistance of isolated strains and genotypical and phenotypical factors of virulence will help to strengthen algorithms for the care management of patients. The anthropological approach, which seeks to identify the understandings and practices of mothers confronted with diarrheal children, should also assist in improving the management of children’s care.

MACOMBA : Pragmatic clinical trial comparing a prophylactic treatment of cotrimoxazole (CTX) with sulfadoxine-pyriméthamine (SP) for malaria among pregnant women infected with HIV in Bangui.
(Collaborators: Alexandre Manirakiza, Sandrine Moussa, Aude Boulay, Olga Sakanga, Sébastien Breurec, Mirdad Kazanji(IP Bangui), Lenaig Le-Fouler, Muriel Vray (IP Paris)).

Funding : Fondation de France.

Accounting for HIV serological status in patients is critically important for effective malaria prevention. CTX is recommended for preventing opportunistic infections in HIV positive women with CD4 count < 350 clls/mm3. The efficacy of CTX as a prophylaxis for P. falciparum malaria is well known. A clinical trial (CTX versus SP) undertaken among children in Bandiagara, Mali reported a protective efficacy of 99.7%. The WHO and the Central African Republic (CAR) recommend intermittent SP as malaria prophylaxis for pregnant women. Therefore it is superfluous and contraindicated to provide SP and CTX together in HIV-positive persons when CD4 is <350 cells/mm3. In contrast, few studies until now have described the efficacy of CTX in the prevention of malaria among pregnant women, and particularly its efficacy in an environment in which frequent therapeutic failures of SP are on the rise, as is the case in the CAR. Finally, although existing studies have not confirmed this hypothesis, there remain persistent concerns about the possible development of cross-resistance in P. falciparum to both CTX and SP because of their similar modes of action.

The principal objective of this randomized, open label trial, carried out under real-life conditions of care, is to demonstrate the superiority of CTX (administered as a daily dose until childbirth) over SP (administered as directly observed treatment of three doses) on placental malaria parasitaemia in HIV-positive pregnant women whose CD4 count > 350 cells/mm3. This study will also permit to compare the two treatments in terms of the incidence of malaria episodes during pregnancy, profiles of resistant parasites isolated during these malaria episodes and in the placenta during childbirth, material anemia, birth weight, and infant anemia. An evaluation of adherence to the CTX treatment will be conducted at each prenatal visit; women included in the trial will be asked to report the number of pills remaining in their possession. We plan to recruit 150 women in each group.

Expected results:

The principal hypothesis is that CTX is more efficacious than SP on placental malaria parasitaemia. This result could be explained by higher plasma levels among those taking CTX. The verification of this hypothesis will permit the recommendation of CTX as a prophylactic treatment for malaria among HIV-positive women, regardless of CD4 count.  

Malaria in southwestern Burkina Faso
(Collaborators : Tamara Giles-Vernick, Abdoulaye Traoré, Sodiomon B. Sirima).
Funded by the World Health Organization, 2010-11; Wellcome Trust 2013-

The primary aim is to test the acceptability and feasibility of an intervention package for the community management of childhood malaria. The package includes rapid diagnostic testing, coartem and referral of serious cases to the nearest health care center; pre-treatment of serious cases is currently being analysed. Beginning in mid-2013, the community management strategy will be carried out by trained community health workers and medical personnel. For the qualitative part of this study, our primary interest is to investigate the changing ways that parents in southwestern Burkina Faso have understood the etiologies, treatment and control of local categories of illnesses that are related to “malaria” but not understood in precisely the same way. The aim of this research question is to tailor the use of the intervention package in such a way that it is meaningful to southwestern Burkinabe populations.


THE EMERGENCE OF HIV IN AFRICA : Ethnomedical and historical perspectives
(Collaborators :
William S Schneider, Indiana University, Guillaume Lachenal, Université de Paris Diderot Sorbonne Paris Cité,  Ch. Didier Gondola, Indiana University, Tamara Giles-Vernick, IP Paris). 
Current funding: Indiana University; pending grant proposal at the U.S. National Endowment for the Humanities

The aim of this project is to develop a more grounded, robust historical context for the emergence of HIV. While some hypotheses for the emergence of HIV have been suggested, they have been offered primarily by biomedical researchers with limited familiarity with African history. The project will offer a corrective to the errors and misconceptions concerning the historical context in which HIV emerged and developed into a global pandemic. It will subsequently develop insights from African history concerning great ape hunting, the introduction of colonial rule, urbanization, human migration, prostitution, and medical campaigns. The research group is comprised four specialists in various aspects of African history and anthropology.




Projet EPISARS : Prévention de la réémergence du SRAS (Coordinateur Scientifique : Arnaud Fontanet, IP, et HU Zhihong, Wuhan Institute, Chine)

Financement : Commission Européenne et Ministère des Affaires Etrangères

Ce projet impliquant 10 équipes de recherche européennes, et 8 chinoises, a contribué à l’identification du réservoir animal du coronavirus du SRAS, la chauve-souris (Li et coll., Science, 2005), et à la confirmation du rôle joué par les civettes comme hôte intermédiaire responsable du passage du virus vers l’homme (Song et coll., PNAS, 2005). Le projet a fait l’objet de 35 publications dans des revues internationales à comité de lecture.

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DENFRAME : ‘Innovative Diagnostic Tools and therapeutic approaches for dengue disease'. (Coordination: L Baril et P Despres)

La dengue est une pathologie virale à transmission vectorielle (Aedes) présente en milieu tropical. L’OMS estime le nombre de cas annuel autour de 100 millions et environ 50000 décès. Ce projet DENFRAME est financé par la CE (FP6-2003-INCO-DEV2) pour 3 années (Nov 2005-Oct 2008). Treize institutions sont impliquées dont 5 institutions du RIIP (IP Paris, IP Ho Chi Minh Ville, IP Cambodge, Centre Pasteur de Hong Kong et IP de la Guyane). La mise en place d’une étude clinique incluant les familles de patients ayant une dengue prouvée est en cours dans 4 pays (Cambodge, Vietnam, Brésil et Guyane). L’objectif est de connaître le profil immunologique, en particulier l’immunité innée, des personnes ayant une dengue symptomatique et des personnes infectées mais peu ou pas symptomatiques afin de mieux comprendre les mécanismes physiopathologiques qui conduisent à des formes hémorragiques létales. Le projet a également un versant qui concerne l’amélioration des outils du diagnostic virologique et une approche de développement thérapeutique antivirale.

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Essai randomisé de traitement de l'hépatite chronique B au Sénégal (Coordination : M. Vray et P.S. Mbaye)

L’infection par l’hépatite B est un problème majeur de santé publique au Sénégal avec une prévalence de sujets porteurs de l’AgHBs supérieure à 15 %. Le but du projet est d’évaluer une stratégie thérapeutique pragmatique applicable au Sénégal ou autres PED pour les patients relevant d’un traitement. L’objectif d’HEPADAK 2, étude randomisée, sans insu, est d’évaluer l’efficacité d’une stratégie thérapeutique associant LAM et vaccin thérapeutique (12 injections Engerix B en intradermique sur 6 mois) sur le contrôle de la réplication virale chez des patients porteurs d’une infection HBV réplicative avec perturbation des transaminases par rapport à un groupe sous Lamivudine seule. Les patients seront ensuite traités pendant une période de 1 an et suivis une année supplémentaire sans traitement dans le cadre du protocole puis pris en charge dans le cadre du programme national. Ce projet se fait en étroite collaboration avec l’Institut Pasteur de Dakar, et est financé par l’ANRS. L’étude a démarré en septembre 2005.


Modélisation de la transmission du VIH (Michel Garenne & Pauline Leclerc, IP, et Allan Matthews, Université du KwaZulu-Natal, Afrique du Sud)

De nombreux modèles permettent de simuler la progression de l’épidémie de SIDA dans les pays les plus touchés comme ceux du Sud de l’Afrique. Ce modèle de micro-simulation stochastique à deux sexes se distingue des précédents par une prise en compte, au-delà des paramètres démographiques et épidémiologiques classiques, des formations et dissolutions des unions stables (mariage) et temporaires (liaisons). Le modèle a été testé grâce aux données des Enquêtes Démographiques de Santé de la Zambie. Il a confirmé l’importance de la prostitution dans l’initiation de l’épidémie, et la part très élevée des transmissions au sein des couples stables une fois l’épidémie installée (Leclerc et coll., soumis). Ce modèle est maintenant prêt pour tester l’efficacité d’une grande variété d’interventions, comme le dépistage et traitement du VIH à large échelle, la généralisation de la circoncision masculine, ou l’impact d’un traitement généralisé, voire d‘un vaccin, contre les infections à herpes simplex virus 2.


Efficacité des vaccins du Programme Elargi de Vaccination chez les enfants infectés par le VIH (Laurence Baril, IP Paris, Mathurin Tejiokem, CPC Yaouné, I Gouandjika, IP de Bangui)

Cette étude menée en collaboration avec les Instituts du Réseau des IP au Cameroun et en République Centrafricaine a montré que la réponse immunitaire des enfants infectés par le VIH était de moins bonne qualité comparée à celle des enfants non infectés, notamment pour le vaccin contre la rougeole (Tejiokem et coll., PLoS ONE, 2007). Cette étude souligne l’importance des doses de rappel pour ces vaccins, notamment chez les enfants infectés par le VIH.


Diagnostic des infections opportunistes chez les patients infectés par le VIH et algorithmes de prise en charge dans les pays du Sud (M. Vray, Y. Madec et A. Fontanet, IP Paris, et IP de Dakar, Bangui, Phnom Penh et Ho Chi Minh)

Le diagnostic des infections opportunistes chez les patients infectés par le VIH en Asie et en Afrique a fait l’objet de plusieurs travaux de recherche impliquant les Instituts du Réseau des IP, et notamment ceux de Dakar, Bangui, Phnom Penh et Ho Chi Minh. Parmi les infections pulmonaires autres que la tuberculose, les pneumopathies à P.carinii ont été fréquemment retrouvées en Asie, mais très rarement en Afrique (Vray et coll., AIDS, 2008). Un algorithme permettant de différentier les pneumocystoses des tuberculoses sur des signes cliniques simples a été développé (Le Minor et coll., J AIDS, 2008). La valeur diagnostique du dépistage des antigènes cryptococciques sériques a été démontrée chez les patients très immunodéprimés au Cambodge (Micol et coll. J AIDS, 2007), et la prévalence très élevée des infections à cytomégalovirus non diagnostiquées à été également mise en évidence dans la même population de patients (Micol et coll., soumis).


Efficacité des traitements antirétroviraux des programmes de Médecins Sans Frontières (MSF) en Asie et en Afrique (Yoann Madec et Arnaud Fontanet, IP)

Au travers d’une collaboration avec MSF, nous avons pu établir l’efficacité des programmes antirétroviraux utilisés au sein de populations très immunodéprimées au Cambodge (médiane des lymphocytes CD4+ à 20/μl). En effet, la mortalité à 2 ans de 1735 patients traités par HAART n’était pas différente de celle observée dans les pays occidentaux une fois les taux de CD4 pris en compte (Madec et coll. AIDS, 2007). Nous travaillons également sur l’identification de marqueurs de suivi des patients autres que la charge virale et les taux de lymphocytes CD4+, difficiles à obtenir dans les régions les plus reculées où les antirétroviraux ont maintenant été introduits. Ainsi, sur les cohortes MSF du Cambodge (n = 2451) et du Kenya (n = 2618), nous avons pu montrer que l’absence de prise de poids supérieure à 5% du poids initial après 3 mois d’antirétroviraux était associée à une mortalité 6 fois supérieure comparée aux patients ayant récupéré 10% de leur poids initial (Madec et coll. soumis).