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Partnership to establishaCompetitive Research Capacity in sub-Saharan Africa: MRTC as a support for malaria control Mahamadou A THERA, MD, MPH Ogobara K. Doumbo, MD, PhD Malaria Research and Training Center Department of Epidemiology of Parasitic Diseases Faculty of Medicine Pharmacy and Dentistry University of Bamako, Mali
A success story of Mali-NIAID/NIH Cooperation for Health Improvement in Mali since 1992 == the strategic vision
The National, Regional, and International Context = Creation of the MRTC • Tropical parasitic diseases are still in the 21st century important cause morbidity and DALYs in SSA: Malaria, Schistosomiasis, Filariasis, Geo-Helminths, with viruses and bacterial diseases such as HIV-Aids, Tb • Current Tools for control are efficient for most of these diseases, but need to reach >=80% of the target population and access to clinical laboratories is and issue. • They are not enough laboratory based diagnostic for case management: “all fever cases during transmission season are diagnosed malaria” = impact on patient health and family budget and risk of drug resistance (ACTs). • More certified laboratories are needed at the national, regional and district level = best patient care, evidence-based decision and diseases burden estimation and evaluation of the Implementation of strategies = knowledge research = Health care system improvement • Vaccines are the most efficient strategies in public health to reduce the burden of infectious diseases == capacity building in clinical trial in Africa == CLIA laboratory are key element for an ICH/FDA/WHO compliant trial. • Good working and research environment will reduce African Researchers and health workers’ “ brain drain “: == Creation the enabling environment!
Malaria = 3 tsunami En Afrique par an > 1,000,000 Décès
NIH MIM/TDR/WHO Government of Mali/Uni-Bko/MOH Intramural : MVDB, LMVR Extramural: NIAID/ DMID/ FIC MMV-MVI MMV-MVI AIEA CVD Maryland AUF MRTC/DEAP/FMPOS WRAIR AMANET Universities: Marseille, Angers, Bordeaux, Lyon, Paris, Oxford, Stokholm, Nijmegen, Tulane, Dakar, Ouagadougou, Abidjan, Conakry, Cotonou, Libreville USAID Institut Pasteur Grants: BioMalPar MalariaGEN EDCTP CDC FIC/NIH Pharma: Bio-Merieux,Sanofi-Aventis, GSK, Dafra, Pfizer, Mepha, Novartis
Professeur Philippe Ranque F0.1 Pr C. Soucko Pr A. Diallo Pr Y.T. Touré Pr A.Tounkara Pr O.K. Doumbo OMS- Geneva Professeur ENSUP Doyen FMPOS Vice Recteur Univ. Bko Directeur MRTC F1.1 A. Dolo O. Koita A. Djimde S. Doumbia M. Diallo M. Théra A. Touré S. Diop S. Sow F. Traoré B. Traoré Prof ag. Der FMPOS Directeur LBMA Chef Unité MEDRU Chef Unité GIS/RS Chef Unité Diag.Parat. Chef Unité MVU/BMP Expert OMS Chef Unité Anthro/Serefo Directeur CVD-Mali Directrice Phar-Priv Chef Unité PREMA F1.2 A. Dicko O.B Touré M. Diakité B.Poudiougou M S Sissoko I. Sagara K. Kayentao O. Thiero A. Bea L Sangaré Chef Unité Epi/Biosta/Data Chef Unité BioInformatic Sc Doctorant Tulane, USA Chef Unité Genomiq Expert Millienium Village PI -essai Vaccin Sotuba PI -essai Vaccin Bancoumana PI - Prema Kambila / Sikasso Biostatics Der SP FMPOS Chercheur MEDRU Chercheur LBMA F2.3 F2.4 F2.5 En formation Mali, Afrique, Europe, USA.
A. Djimdé, PharmD, PhD Chef d’Unité MEDRU F1. F1.1 O. Traoré S. Doumbo B. Fofana D. Ouologuem S. Dama M. Diakité C. Ndong A.Bea A. Kone M. Tekété PharmD 1999 Ministère Santé MD, 1999 AssistanteRecherche PREMA PharmD, 2001 Assistant Recherche MD, 2002 Formation Msc Tanzanie PharmD, 2004 Formation PhD USA PharmD, 2005 Assistant Recherche DPhil, 2007 Uk, Oxford Chef Unité Gnenomique PharmD 2007 Ministère Santé Gabon DEA, 2003 Formation PhD France DEA, 2006 Formation PhD Karolinska Institute Suede F1.2 M. Wele A. Bea D. Ouologuem O. Maiga A. Koné Formation PhD, ISFRA, Université Bamako Formation PhD , Université Paris V, France Formation PhD , Université Lyon I France Formation PhD, Université Pennsylvanie, USA Formation PhD Karolinska Institute Suede F1.3 A. Dara H. Niangaly A. Togo A. Kodio N. Diallo Internes Pharm 8 FMPOS Med 8 FMPOS Med 8 FMPOS Pharm 7 FMPOS Med 7 FMPOS
Experienced Staff (>50) • MD/PharmD + PhD • MD/PharmD + PhD candidates • PhD • PhD candidates • MD/PharmD + Master degree • MD/PharmD + Master candidates • Master • MD candidates and PharmD candidates • Project managers, drivers, lab technicians
Bandiagara Sotuba Donéguébougou Bancoumana Kangaba/Kela Bougoula Hameau
IMPACT SUR LA QUALITE DES SERVICES DE SANTE AU MALI: Normes ICH/FDA
IMPORTANCE DE LA CAPACITÉ DE FORMATION CONTINUE DES ÉQUIPES Workshop on Data Management, From 11 African countries.
Wide Area Network Description Satellite 64 kbps 128 kbps Koro 75 km Bandiagara NIH Hub SITE 128 kbps Satellite link Mopti 670 km 600 km Bamako 300 km Niono Sotuba Bamako Donéguebougou 32 km 60 km 25 km 350 km Packet Radio Banambani Bancoumana Sikasso
Major scientific contributions of the MRTC/DEAP, Mali • From 1992-2008 MRTC staff published with their international collaborators > 240 peer review papers: • NATURE • Science • PNAS • LANCET • BLOOD • JID • AJTMH • Imm. Infect • NEJM • PLoS
Current collaborative clinical research on Malaria • Malaria Vaccines Development • Molecular biology of parasites • Immunology & Immunogenetics • Biostatistics and Data Management • Vectors Ecology and Biology • GIS/RS related to malaria transmission • Epidemiology and malaria Risk factors • Drug Resistance and GRI Model for drug policies • Human Genetic and Protection against Malaria
TPIp with SP: Kayentao et al., JID, 2005 (MRTC-CDC/NIAID grant) Dose 2 Avant 38 sem Dose 1 16 sem 10 20 30 Naissance Conception Mouvement Semaine de gestation
COOH NH2 Mutation Sites in the PfCRT Transmembrane Protein R371 H97 Q271 K76 I356 N75 M74 C72 N326 A220
Molecular Diagnosis of Chloroquine Resistance in the Field
Tambacara • Doily • Cinsana • Gakoura • Segue • Banamba • Toguel • Dimbal • Kolébougou • Koulikoroba • N’Debougou • Sirakoro-Meguetana • Markacoungo • Tombola • M’Pessoba • Siékorolé • Niéna • Sincina • Kafana Map of CQR per GRI Model
New Treatment Policy • First line AS/AQ or AR-L • Severe and complicated: Quinine • RDTs validation for early case management
Improvement of case management • Bandiagara • In 1994, Traditional Healers (TT) were the main care providers for severe malaria • Approach based on respect • Maintain the principal link with community and keeping the TT influence • We also establish good capacity for diagnosis: • Improved microscopy • Available drugs for severe malarial illness treatment • Qualified staff
As a result of case management improvement in different study sites: • Reduction in incidence of severe malaria of more than 50% • Significant reduction in overall childhood mortality and dramatic reduction of malaria specific mortality • Strategies validated for the National Malaria Control Program and scaled up implementation of early case management
Clinical Malaria cases in 2006 Uncomplicated malaria cases: 2,321 Severe malaria cases: 55
Malaria Vaccine Studiesin Mali (n=10), PLoS, 2005, 2006, 2007, 2008 • 2003-2004, FMP1 trial in Bandiagara, • Phase I FMP1/AS02A vs. Rabies vaccines • Aim to assess safety and immunogenicity • 2004-2005, AMA1 trial in Doneguebougou, • Phase I AMA1-C1/Alhydrogel vs. Recombivax HB® Hepatitis B vaccine • Aim to assess safety and immunogenicity • 2004-2005, FMP2.1 trial in Bandiagara, • Phase I FMP2/AS02A vs. Rabies vaccines • Aim to assess safety and immunogenicity • 2006-2008 • AMA1: PHASE 2, BANDIAGARA + BANCOUMANA • AMA1+GpG, PHASE 1, ADULTS AND CHILDREN, DONEGUEBOUGOU. • MSP3 PHASE 2 SOTUBA
Dynamics of MSP-119 haplotypes in Mali • 100 children followed 3y • MSP-119 genotyped by Pyrosequencing • Haplotype estimation model • 18 haplotypes among 1,369 infections • Frequency distribution similar over time, season, age groups • Suggests balancing selection • 3D7 vaccine strain prevalence: 16% • Explains lack of efficacy in Kenya? • FVO = better vaccine target? Takala et. al PLoS Medicine 2007
Implications for Malaria Vaccine Design, Efficacy and Testing • Interpretation of vaccine efficacy in the context of parasite allele frequencies • Need to know frequency of vaccine target alleles • Allele-specific immunity elicited by a vaccine targeting a minor allele could result in low overall efficacy that masks high allele-specific efficacy • Power/sample size to detect allele-specific efficacy vs. overall efficacy • Identify diversity most relevant to cross-protection • 25 haplotypes—based on cluster c1L • 10 highest frequency c1L haplotypes account for 81% of infections • 3D7=13.8% and FVO=5.6%
Lesson from Mother Nature : The HbC Story in Dogon, Mali • Single point mutation • β6: Glu Lys • Originated and restricted to West Africa • Usually asymptomatic • HbC provides 80% protection against cerebral malaria • What are the mechanisms?
HbC protects Dogon from severe malariaAgarwal et al., Blood96:2358 (2000)
Rosetting and ABO blood groups in Mali case-control study : N 51 12 66 76 Median 15% 20% 12% 3%P=0.003 IQR 2-26 0-59 1-22 0-15 Kruskal Wallis test Rowe et al. PNAS 2007
Long term vision • Efficacious and safe malaria vaccine, integrated in EPI • Population where the vaccines are being tested to be among the first beneficiaries of vaccine (Ethical requirement) • Reduce the burden of malaria in Africa and in the World • Pathophysiology to develop more effective controls tools learning from Nature • Common usage of resources: high throughput technologies; NTIC, field sites etc…
Strengths of MRTC/DEAP, Mali (1) • Political/Social Environment: democracy in Mali since 1991 • Strong Support from the Malian Government • Partnerships: Mutual trust, respect • Rigorous selection procedure for trainees = Staff with clinical research experience: • F1/F2/F3 generation of researchers trained in France, USA, UK, Italy, Canada and now back at the MRTC • Large pull of juniors scientists devoted to clinical research F4/F5 generations under training • Internet connection through Satellite • Lab Space and Equipments and Tech.Transfert • Well equipped and functional field sites (5)
Strengths of MRTC/DEAP, Mali (2) • Capacity to compete for international grants with foreign collaborators • Capacity of the staff to write science and publish • Senior trainees start to become leaders in specific field of research and are building their own unit = building leadership capacity • MRTC/DEAP was selected in 2003 both by AUF and NIAID/NIH as a regional and international center of excellence on clinical research/Malaria == more funds, support and collaborations. • EDCTP- BIOMALPAR – MALARIAGEN
Strengths of MRTC/DEAP, Mali (3) • In situ Doctoral Training: DEA, PhD with ISFRA at the University of Bamako, Mali, • Over sea's training: MSc, PhD : France, UK, Canada, USA. • Regional training: Dakar, Abidjan, Ouagadougou, Tanzania (MSc in Clinical Studies). • Short terms training, workshops…. • E-learning capacities +++
Opportunities for MRTC/DEAP, Mali • NIH, EU, AUF and Other Partners commitment to support • Strong link with northern competitive scientific groups: EU, USA and southern groups in Africa • Building managerial capacities: Mali Service Center • Others research groups at the FMPOS: HIV/AIDS/TB, at the FAST and MOH, CVD Mali. • Government Policy to Strengthen Research
Acknowledgements • Government of Mali • NIAID/NIH, long term support • CVD-Maryland, USA • MIM/TDR • WAIR/GSK • USAID • AUF • EDCTP • Foundations: Mérieux, Pathfinder, Asturias • Studies sites population (Bandiagara, Doneguebougou, Bancoumana, Sikasso)