Partnership to establish a Competitive 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
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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!
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
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,