december 15th 2007, lisbon federation of the european academy of medicine epidemiology, genetics and...

December 15th 2007, Lisbon

Federation of the European Academy of Medicine

Epidemiology, genetics and control of Plasmodium falciparum malaria in sub-Saharan Africa

David [email protected]

Department of Public Health Sciences


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



Mortality

About 2.7 million people die from malaria each year, most of whom are children



• 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



These global estimates are up to 50% higher than those reportedby the WHO and 200% higher for areas outside Africa

Morbidity



Reasons for malaria re-emergence

• Drug resistance (parasite)

• Insecticide resistance (vector)

• Climate change

• Deterioration of National Malaria Control Programs

Distribution of Drug Resistance

Chloroquine resistance

Sulfadoxine-Pyrimethamine resistanceMefloquine resistance


• 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



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



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


Data indicating that malaria vaccine are feasible

• RADIATION ATTENUATED SPOROZOITES

Malaria vaccines



are classified according to the parasite stages that are targeted

Thomas L. Richie & Allan Saul; Nature; 415; 2002

Pre-erythrocytic vaccines


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


2. T cell responses against infected liver cells (IFNg and CTL)


Asexual blood stages vaccines


designed to reduce clinical severity(anti-morbidity/mortality vaccines)


1. Antibodies against merozoite surface antigens to block invasion of red blood cells


2. Antibodies against malaria proteins expressed on surface of infected RBC


Transmission-blocking vaccines



designed to halt development in the mosquito

Vaccines directed against mosquito stagesPossible Immune Pathways:

Antibodies to gametes and ookinetes




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



Descriptive Genetic epidemiology

Mechanism/s

Malaria protective genes

NEW TOOLS ??

The road map

MalariaGEN



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

MalariaGEN’s goal



• 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)



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)

FulaniMossi

vs

M MM

R

F

FF

F

F

FF

FF

FF

F

R

RR

R

RRR

MM

M MM M M

MR

RR R

R

F

Barkoundouba

Barkoumbilen

MALI NIGER

CÔTE

GHANABENIN

100

Km

D'IVOIRE

BURKINAFASOOuagadougou

BoboDioulasso

Study area

Km

0 0.5 1

F = FulaniM = MossiR = Rimaibé

Kaya

Ouagadougou

2. Intra-ethnic cross-sectional surveys (healthy population: Susceptibility/resistance to infection)

Sample N Relative and (absolute) genotype frequencies Relative and (absolute) allele frequencies

AA AC AS CC SC SS A C S Healthy subjects 3513 0.6641

(2333) 0.2172 (763)

0.0954 (335)

0.0165 (58)

0.0065 (23)

0.0003 (1)

0.8204 (5764)

0.1284 (902)

0.0512 (360)

Severe malaria 359 0.8078 (290)

0.1755 (63)

0.0111 (4)

0.0028 (1)

0.0028 (1)

0 (0)

0.9011 (647)

0.0919 (66)

0.0070 (5)

Non-complicated malaria 476 0.8004 (381)

0.1555 (74)

0.0399 (19)

0 (0)

0.0042 (2)

0 (0)

0.8981 (855)

0.0798 (76)

0.0221 (21)

Malaria patients (total) 835 0.8036 (671)

0.1641 (137)

0.0275 (23)

0.0012 (1)

0.0036 (3)

0 (0)

0.8994 (1502)

0.0850 (142)

0.0156 (26)

Comparisons Odds ratio (95% confidence interval) and P values *

Healthy subjects vs. Malaria patients 2.07 (1.71-2.50)

<<0.001

0.71 (0.58-0.87)

0.0008

0.27 (0.17-0.42)

<<0.001

0.07 (0.00-0.48)

0.0011

n.s.

n.s.

<<0.001

<<0.001

<<0.001

Severe malaria vs. non-severe malaria n.s. n.s 0.27 (0.08-0.86)

0.021

n.s. n.s. n.s. n.s. n.s. 0.023


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



The mechanism ?



Why only in West Africa ??

Haemoglobin C(G→A SNS)

(β6 Glu→Lys) MALARIA

Haemoglobin S(A→T SNS)

(β6 Glu→Val)



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 βC

25-35 generations for βS Benin


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



The description …. The Fulani resistance against malaria



The mechanism

Lower expression of genes determinant for Treg activity (TGF, TGFRs, 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



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



Descriptive Genetic epidemiology

Mechanism/s

Malaria protective genes

NEW TOOLS ??

The road map

INSTITUTIONS AND FUNDING

Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

Valentina ManganoKirk Rockett

Dominic Kwiatkowski

Centre National de Recherche et Formation sur le Paludisme, Ministère de la Santé,

Burkina FasoIssa 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 VerraGermana Bancone

Valentina ManganoMario Coluzzi

David Modiano

Centre Medical Saint-Camille, Burkina FasoJacques Simporé

Italian Ministry of Education FP6, BioMalPar NoE

MalariaGEN Grand Challenges for Global HealthBill and Melinda Gates Foundation

Wellcome Trust

december 15th 2007, lisbon federation of the european academy of medicine epidemiology, genetics and...

Documents

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africa morbidity slide

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africa artesunate