Partnership to establish a Competitive Research Capacity in sub-Saharan Africa:
MRTC as a support for malaria control
Mahamadou A THERA, MD, MPHOgobara K. Doumbo, MD, PhD
Malaria Research and Training Center Department of Epidemiology of Parasitic Diseases
Faculty of Medicine Pharmacy and DentistryUniversity 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 tsunamiEn Afrique par an
> 1,000,000 Décès
NIH
Extramural:
NIAID/ DMID/ FIC
MRTC/DEAP/FMPOSWRAIR
CDC
USAID
Government of Mali/Uni-Bko/MOH
Grants:
BioMalPar
MalariaGEN
EDCTP
CVD Maryland AUF
AMANET
Universities: Marseille, Angers, Bordeaux, Lyon, Paris, Oxford, Stokholm, Nijmegen, Tulane, Dakar, Ouagadougou, Abidjan, Conakry, Cotonou, Libreville
AIEA
Institut Pasteur
FIC/NIH Pharma: Bio-Merieux, Sanofi-Aventis, GSK, Dafra, Pfizer, Mepha, Novartis
MIM/TDR/WHO
Intramural :
MVDB, LMVR MMV-MVIMMV-MVI
Professeur Philippe Ranque
Pr C. SouckoF0.1
Professeur ENSUP
Pr A. Diallo
Vice Recteur Univ. Bko
Pr Y.T. Touré
OMS- Geneva
Pr A.Tounkara
Doyen FMPOS
Pr O.K. Doumbo
Directeur MRTC
F1.1 A. Dolo O. Koita A. Djimde S. Doumbia M. Diallo M. Théra A. Touré S. Diop F. TraoréS. Sow B. Traoré
F1.2
F2.3 F2.4 F2.5 En formation Mali, Afrique, Europe, USA.
A. Dicko O.B Touré I. SagaraM. Diakité B.Poudiougou M S Sissoko K. Kayentao O. Thiero L SangaréA. Bea
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
Chef Unité Epi/Biosta/Data
Chef Unité BioInformaticSc DoctorantTulane, USA
Chef Unité Genomiq
PI -essai Vaccin Sotuba
PI -essai Vaccin Bancoumana
Expert Millienium Village
PI - Prema Kambila / Sikasso
BiostaticsDer SPFMPOS
ChercheurLBMA
Chercheur MEDRU
A. Djimdé, PharmD, PhDChef d’Unité
MEDRU
O. Traoré S. Doumbo M. Tekété B. Fofana D. Ouologuem S. Dama C. NdongM. Diakité
M. Wele A. Bea D. Ouologuem O. Maiga
PharmD 1999Ministère Santé
MD, 1999 AssistanteRecherche PREMA
F1.
F1.1
F1.2
PharmD, 2001AssistantRecherche
MD, 2002FormationMsc Tanzanie
PharmD, 2004Formation PhDUSA
PharmD, 2005AssistantRecherche
DPhil, 2007Uk, OxfordChef Unité Gnenomique
PharmD 2007Ministère SantéGabon
A.Bea A. Kone DEA, 2003 FormationPhD France
DEA, 2006 FormationPhD KarolinskaInstituteSuede
A. Koné
FormationPhD, ISFRA, Université Bamako
FormationPhD , UniversitéLyon I France
Formation PhD, UniversitéPennsylvanie,USA
FormationPhD , UniversitéParis V, France
FormationPhD KarolinskaInstituteSuede
F1.3 A. Dara H. Niangaly A. Togo A. Kodio N. Diallo
Pharm 8FMPOS
Pharm 7FMPOS
Med 8FMPOS
Med 8FMPOS
Med 7FMPOS Internes
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
Donéguébougou
Sotuba
Bancoumana
Bougoula HameauKangaba/Kela
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
Bamako
Bamako NionoSatellite link
Bandiagara
Mopti
Satellite
Packet Radio
NIH Hub SITE
Sikasso
Sotuba
Donéguebougou
BancoumanaBanambani
Koro
300 km
350 km
670 km
60 km
600 km
25 km
32 km
75 km
128 kbps 64 kbps
128 kbps
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)
Semaine de gestation
ConceptionNaissance20 3010
Dose 116 sem
Dose 2Avant 38 sem
Mouvement
Mutation Sites in the PfCRT Transmembrane Protein
NH2
COOH
K76
N75M74
C72
H97
A220
N326
Q271 R371
I356
TCRP1
TCRP2
TCRP3
TCRP4-wTCRP4-m
Nested Mutation Specific PCR of pfcrt
Primary amplification PCR1: TCRP1 + TCRP2
Diagnostic PCR PCR2: TCRP2 + TCRP4-w or TCRP4-m
K76T
M S R S R S R S R S R
ctrl H2ODd2 3D7 106/1
pfcrt diagnostic PCR
Molecular Diagnosis of Chloroquine Resistance in the Field
Kolle
Bandiagara
Banamba
Tombola
N’Debougou
Koulikoroba Sirakoro-
Meguetana Siékor
olé
Markacoungo
Dimbal Kolébougou
Toguel
Niéna Kafana
M’Pessoba
Tambacara Doily
Segue
Sincina
Gakoura Cin
sana
Map of CQR per GRI Model
Efficacy of ACTs in Mali
0
10
2030
4050
6070
8090
100
RCPA+
AS+AQAS+SPASCoarinateCoartem
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
Bandiagara (1994)
28%
72%
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
Parasite Prevalence and Spleen rate in Bancoumana from 1996-2001
0
10
20
30
40
50
60
70
80
%
1996 1997 1998 1999 2000 2001
Years
Parasitemia
Spleen
Clinical Malaria cases in 2006
0
50
100
150
200
250
300
350
400 Cas simple
Cas grave
Uncomplicated malaria cases: 2,321Severe 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
Takala et. al PLoS Medicine 2007
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?
Dynamics of MSP-119 haplotypes in
Mali
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%
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?
Lesson from Mother Nature : The HbC Story in Dogon, Mali
HbC protects Dogon from severe malariaAgarwal et al., Blood 96:2358 (2000)
No. AA AC CC AS
Reported 3,473 81% 15% 1% 3%
Non-severe 391 80% 16% 1.5% 2.6%
Severe 67 91% 4.5%* 0 4.5%
Odds Ratios 0.22 1.91
Rosetting and ABO blood groups in Mali case-control study :
N 51 12 66 76Median 15% 20% 12% 3% P=0.003IQR 2-26 0-59 1-22 0-15 Kruskal Wallis test
Rowe et al. PNAS 2007
Future Common Plateform at the ICER: Affymetrix GeneChip® System
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)