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December 15th 2007, Lisbon Federation of the European Academy of Medicine Epidemiology, genetics and control of Plasmodium falciparum malaria in sub-Saharan.

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Presentation on theme: "December 15th 2007, Lisbon Federation of the European Academy of Medicine Epidemiology, genetics and control of Plasmodium falciparum malaria in sub-Saharan."— Presentation transcript:

1 December 15th 2007, Lisbon Federation of the European Academy of Medicine Epidemiology, genetics and control of Plasmodium falciparum malaria in sub-Saharan Africa David Modiano david.modiano@uniroma1.it Department of Public Health Sciences

2 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Rogers DJ et al. Nature. 2002. 415: 710-715 Satellite-derived predictions of Entomological Inoculation Rates (EIR) in sub-Saharan Africa

3 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Mortality About 2.7 million people die from malaria each year, most of whom are children

4 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 2.2 billion people at risk 515 (range 300–660) million episodes of clinical Plasmodium falciparum malaria in 2002 70% of clinical events concentrated in sub- Saharan Africa 25% in South East Asia Morbidity

5 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 These global estimates are up to 50% higher than those reported by the WHO and 200% higher for areas outside Africa Morbidity

6 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Reasons for malaria re-emergence Drug resistance (parasite) Insecticide resistance (vector) Climate change Deterioration of National Malaria Control Programs

7 Distribution of Drug Resistance Chloroquine resistance Sulfadoxine-Pyrimethamine resistance Mefloquine resistance

8 December 15th 2007, Lisbon First cause of poverty in Sub-Saharan Africa (WHO) Loss of 1.3% of GNP in Sub-Saharan (SS) Africa Some countries lose up to 6% of GNP $12 billion lost annually 40% of all health care expenditures in SS Africa are spent on malaria 40% of absences from school or work in SS Africa are due to malaria The Socio-economic Burden of Malaria Malaria control is a strategy for reducing poverty

9 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Available control tools are not able to block transmission Artemisinin-based combination therapies (ACTs) artemether/lumefantrine artesunate plus amodiaquine artesunate plus mefloquine (Insufficient safety data to recommend its use in Africa) artesunate plus sulfadoxine/pyrimethamine Long-lasting

10 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Vaccine highly needed Funding for malaria vaccines has increased recently from below US$50 million to around $60–70 million but remains an order of magnitude below that for HIV vaccine development

11 December 15th 2007, Lisbon Data indicating that malaria vaccine are feasible RADIATION ATTENUATED SPOROZOITES

12 Malaria vaccines December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 are classified according to the parasite stages that are targeted Thomas L. Richie & Allan Saul; Nature; 415; 2002

13 Pre-erythrocytic vaccines December 15th 2007, Lisbon Designed to prevent blood-stage infection; to avoid all manifestations of disease (anti-infection vaccines) Vaccines directed against sporozoites and/or liver stages Possible Immune Pathways 1.Antibodies to block sporozoite invasion of liver cells Possible Immune Pathways 2. T cell responses against infected liver cells (IFNg and CTL) Thomas L. Richie & Allan Saul; Nature; 415; 2002

14 Asexual blood stages vaccines December 15th 2007, Lisbon designed to reduce clinical severity (anti-morbidity/mortality vaccines) Possible Immune Pathways 1.Antibodies against merozoite surface antigens to block invasion of red blood cells Possible Immune Pathways 2.Antibodies against malaria proteins expressed on surface of infected RBC Thomas L. Richie & Allan Saul; Nature; 415; 2002

15 Transmission-blocking vaccines December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 designed to halt development in the mosquito Vaccines directed against mosquito stages Possible Immune Pathways: Antibodies to gametes and ookinetes Thomas L. Richie & Allan Saul; Nature; 415; 2002

16 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Miller LH et al. Nature. 2002 Why only 2% of clinical malaria cases evolve into severe forms of the disease ? The challenge of human genetics Greenwood B et al. Parasitology Today. 1991

17 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Descriptive Genetic epidemiology Mechanism/s Malaria protective genes NEW TOOLS ?? The road map

18 MalariaGEN December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Global network for genomic epidemiology of malaria $16.4 million funding from Grand Challenges for Global Health Funded by the Bill and Melinda Gates Foundation, through the Foundation for the National Institute for Health, and the Wellcome Trust

19 MalariaGENs goal December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Identify specific genes that are critical for protective immunity against malaria Strategy The billion genotype study of severe malaria 675,000 SNPs in 8000 cases and 8000 ethnically matched controls from Burkina Faso, Cameroon, Ghana, Kenya, Malawi, Mali, Tanzania,Sudan, Papua New Guinea and Vietnam)

20 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 1. Intra-ethnic case-control studies (severe malaria, non complicated malaria, healthy population); vs Descriptive genetic epidemiology Three populational approaches 3. Inter-ethnic studies (Fulani vs sympatric populations in West Africa) Fulani Mossi vs 2. Intra-ethnic cross-sectional surveys (healthy population: Susceptibility/resistance to infection)

21 December 15th 2007, Lisbon The description …. the role of haemoglobin C Reduction in risk of clinical malaria: AC heterozygotes: 29% CC homozygotes: 93% Reduction in risk of clinical malaria: AS heterozygotes: 73% SS homozygotes: lethal

22 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 The mechanism ?

23 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Why only in West Africa ?? Haemoglobin C (GA SNS) (β6 GluLys) MALARIA Haemoglobin S (AT SNS) (β6 GluVal)

24 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 THE AGE OF C and S Haplotypic variability of the C and S alleles in the Mossi of Burkina Faso The estimates of their absolute ages ranged between: 50-100 generations for β C 25-35 generations for β S Benin

25 December 15th 2007, Lisbon Models of geographic diffusion of haemoglobin C (left) and haemoglobin S (right) Haemoglobin S and haemoglobin C: quick but costly versus slow but gratis genetic adaptations to Plasmodium falciparum malaria. Modiano D. et al. Human Molecular Genetics, 2007

26 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 The description …. The Fulani resistance against malaria

27 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 The mechanism Lower expression of genes determinant for Treg activity (TGF, TGF Rs, CTLA4, FOXP3) in Fulani compared to both Mossi and Europeans Proc. Natl. Acad. Sci. USA, in press Pathway-focused microarray analysis on T regulatory cells

28 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 The mechanism Serum levels of T regulatory cytokines in Mossi and Fulani TGF and IL-10: markers of Treg activity CCL22 attracts DCs and T cell (TH2 marker) CXCL10 attracts T cell (TH1 marker) Proc. Natl. Acad. Sci. USA, in press

29 December 15th 2007, Lisbon Lisbon Conference, 15 December 2007 Descriptive Genetic epidemiology Mechanism/s Malaria protective genes NEW TOOLS ?? The road map

30 INSTITUTIONS AND FUNDING Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom Valentina Mangano Kirk Rockett Dominic Kwiatkowski Centre National de Recherche et Formation sur le Paludisme, Ministère de la Santé, Burkina Faso Issa Nebié Edith Bougma Bienvenu Sodiomon Sirima Dipartimento di Biologia, Università "Tor Vergata" Rome, Italy Guido Modiano Bianca Ciminelli Dipartimento di Fisiopatologia Clinica Università degli Studi di Firenze, Italy Gabriella Torcia Federico Cozzolino Dipartimento di Medicina Interna Università degli Studi di Firenze, Italy Lorenzo Cosmi Francesco Annunziato Sergio Romagnani Dipartimento di Scienze di Sanità Pubblica, Università La Sapienza Rome, Italy Federica Verra Germana Bancone Valentina Mangano Mario Coluzzi David Modiano Centre Medical Saint-Camille, Burkina Faso Jacques Simporé Italian Ministry of Education FP6, BioMalPar NoE MalariaGEN Grand Challenges for Global Health Bill and Melinda Gates Foundation Wellcome Trust


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