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)