Vaccine candidats against malaria
Life cycle of Plasmodium
Merozoite surface antigens of Plasmodium
Erythrocyte antigens of Plasmodium falciparum

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Malaria, the most widespread parasitic disease in the world, kills more than two millions people each year. With the emergence of drug resistance in Plasmodium , the parasite responsible for malaria, the development of a vaccine has become a high priority.

Life cycle of Plasmodium

Figure. Life cycle of Plasmodium

Plasmodium infection begins with a short asymptomatic hepatic phase, followed by an erythrocytic phase that is responsible for all pathologies associated with malaria. The merozoite is the free invasive form of the parasite during the erythrocytic stage. After penetrating the red blood cell, the parasite grows and divides to produce several progeny that are released when the host cell subsequently bursts.

Merozoite surface antigens of Plasmodium

Figure. Electron micrograph and schematic representation of a Plasmodium falciparum merozoite. Some of the surface antigens that we are studying are indicated in red. (Electron micrograph kindly provided by Dr. Peter David, Unité d'Immunologie Moléculaire des Parasites, I.P.)

Some surface proteins of the merozoite, the erythrocyte-invading form of Plasmodium, are promising anti-malaria vaccine candidates. Merozoite Surface Protein 1 (MSP1) and Apical Merozoite Antigen 1 (AMA1) are among the most widely studied of the Plasmodium surface antigens in vaccine development.

(a) Merozoite Surface Protein 1 (MSP1)
(in collaboration with Dr. Shirley Longacre, Institut Pasteur)

MSP1, which is implicated in erythrocyte invasion by the parasite, is subjected to several proteolytic cleavages during maturation of the merozoite. During the first phase, it is cleaved to yield four peptide fragments, of which the 42 kDa C-terminal fragment (MSP1-42) remains fixed to the merozoite membrane. During the second phase, occurring at the moment of erythrocyte invasion, MSP1-42 itself is cleaved to yield a polypeptide of molecular weight 19 kDa (MSP1-19). The latter cleavage is essential for erythrocyte invasion, although the mechanism of this process has yet to be elucidated. In order to understand the biological role of MSP1 in the infection of erythrocytes by Plasmodium, we are studying the structure of the recombinant fragments of MSP1. Firstly, the structural comparison of MSP1-19 with MSP1-42 could help to explain the importance of the second cleavage step for the penetration of the red blood cell by the merozoite. Secondly, their three-dimensional structure would give the spatial distribution of polymorphic (dimorphic in the case of MSP1-19) residues and the position of protecting epitopes, which is essential information for the optimisation of candidate vaccine products. We have determined the structure of MSP1-19 from P. cynomolgi and MSP1-19 from P. falciparum in complex with the Fab fragment of a specific monoclonal antibody.

(b) Apical Merozoite Antigen 1 (AMA1)
(in collaboration with Drs. Alan Thomas and Clemens Kochen, B.P.R.C., Rjikswjik)

Apical Merozoite Antigen 1 is a membrane protein produced in the apical organelles of the merozoite. During invasion of erythrocytes, AMA1 redistributes over the entire surface of the parasite, and like MSP1, is proteolytically cleaved. Although the function of AMA1 is not well characterised at the molecular level, its importance in the invasion process is strongly suggested by immunisation studies in animal model systems. We have crystallised the ectoplasmic region of AMA1 and determined its 3-dimensional structure.

Erythrocyte antigens of Plasmodium falciparum

P. falciparum Erythrocyte Membrane Protein 1
(In collaboration with Dr. Odile Puijalon, Institut Pasteur; Dr. Mo Klinkert, Bernhard Nocht Institut, Hamburg; Dr. David Arnot, University of Edinburgh)

After invading the erythrocyte, Plasmodium falciparum expresses the virulence factor PfEMP1 (P. falciparum Erythrocyte Membrane Protein 1),which is transported to the surface of the red blood cell. PfEMP1 is an adhesin which confers on the infected erythrocyte the capacity to auto-agglutinate, to adhere to uninfected red blood cells or to be sequestered on vascular endothelial cells in diverse tissues. Agglutination and sequestration of infected erythrocytes are correlated with many of the pathogenic effects of malaria. We are studying the domains from a number of variants of PfEMP1 that display different receptor specificities.

Publications

Links

PAMVAC Pregnancy-Associated Malaria Vaccine Project

EUROMALVAC European Malaria Vaccine Development
Contains many links concerning world and europeans initiatives against malaria

World Health Organization

Health advices to travellers (in french)