Scientists of the Bio-Medical Parasitology Unit at the Institut Pasteur, headed by Pierre DRUILHE, have just described the validation of " humanized " mice for the screening of vaccine candidates against malaria. In this work, published in the last issue of the Journal of Experimental Medicine, the researchers further confirmed the vaccine potential of the antigen MSP3. Scientists at the Institut Pasteur had initiated studies on MSP3 a number of years ago, and human clinical trials should start soon.
According to the World Health Organization, two billions people are exposed to malaria world wide, and each year there are 300 to 500 millions clinical cases, and 2 to 4 millions deaths are recorded, principally in tropical countries. The search for weapons, and especially a vaccine, against this major public health problem, has been severely hampered by the lack of a suitable in vivo model.
The Bio-Medical Parasitology Unit thus focused part of its work on the development of a non-primate in vivo malaria model in order to evaluate the protective effect of vaccine candidates. This work was supported by the European Community (INCO-DEV- International Cooperation with Developing countries- program) and the WHO Tropical Diseases Research department (TDR).
The aim was first to obtain the development of Plasmodium falciparum, the main parasite responsible for malaria, in human erythrocytes grafted into the BXN mice. During this phase of the infection, the parasite penetrates red blood cells where multiplication occurs. After two days, daughter parasites are released from the burst red blood cells, which leads to clinical manifestations of the disease. The parasites free in the blood then rapidly infect new red blood cells, and the cycle is repeated. This critical step of the malarial infection has been reproduced in immunocompromised mice (BXN) in which normal and Plasmodium-infected human red blood cells were grafted. Previous clinical and laboratory studies carried out by the scientists has established that the protective effect of human antibodies from clinically immune subjects required the presence of human blood mononuclear cells. In the BXN mice grafting of these cells was also shown to be necessary to mimic the protective human immune response to infection: i.e. the antibodies need to cooperate with cytotoxic cells in order to induce a reduction in the parasitemia. In the "humanized" mice obtained, the level of parasitemias (the quantity of parasites in the blood ) was similar to that usually observed in humans, and the reduction in parasitemias after injection of the human protective antibodies was also similar to that observed in immune humans. Thus the Bio-Medical Parasitology Unit, in collaboration with the Faculty of Medicine in Amsterdam (The Netherlands) and SEDAC-Therapeutics, established an animal model of great value to evaluate rapidly the protective effect of vaccine candidates.
Using the BXN model the team assessed the effect of human antibodies which are specific to MSP3, one of the vaccine candidates they study. The injection of human anti-MSP3 antibodies into these mice induced a rapid and total clearance of parasitemia. Through a unique immuno-epidemiological follow-up over many years of individuals living in an endemic area, Dielmo village in Senegal, the Bio-Medical Parasitology Unit have also demonstrated (manuscript in preparation) that natural immunity against malaria was strongly associated with anti-MSP3 antibodies. This large scale study, and other investigations by scientists at the Institut Pasteur, support setting-up human clinical trials, with funding from The European Malaria Vaccine Initiative (EMVI), where immunization with the MSP3 antigen (phase I) will be conducted. These trials should be initiated in a few weeks.
The experiments with "humanized" mice have other important implications for malaria vaccine development. Pierre Druilhe's group also demonstrated that in the BXN mice the injection of anti-MSP3 antibodies alone, immuno-purified from total antibodies present in the sera of human subjects protected against malaria, led to a stronger and faster decrease of parasitemia than that observed when the total antibodies were injected. This observation indirectly implies that other antibodies might partially block the inhibitory effect of anti-MSP3 antibodies. This would indicate that immunization by carefully selected malarial antigens may elicit stronger protective responses than those resulting from exposure to the parasite. In other words, it might be possible to induce a stronger protection than that observed in subjects naturally exposed to the parasite. This emphasizes the importance of pursuing rational investigations of protective molecules, where the in vivo model described here should be accelerate.
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- "Human Malaria in Immunocompromised Mice : An In Vivo Model
to Study Defense Mechanisms angainst Plasmodium falciparum", Journal
of Experimental Medicine, December 2000, the 4th
Edgar BADELL (1), Claude OEUVRAY (1), Alicia MORENO (1), Soe
SOE (1), Nico van ROOIJEN (2), Ahmed BOUZIDI (3), Pierre DRUILHE (1)
(1) Unité de Parasitologie Biomédicale, Institut
Pasteur, Paris, France
(2) Département de Biologie cellulaire et Immunologie, Faculté
de Médecine, Université de Vrije, Amsterdam, Pays-Bas
(3) SEDAC-Therapeutics SA, Lille, France
- Pierre Druilhe, Bio-Medical Parasitology Unit, tel : 33 1 45 68 85 78, e-mail : druilhe@pasteur.fr
- Press Office of the Institut Pasteur, tel : 33 1 45 68 81 46, e-mail : presse@pasteur.fr