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MALARIA: Obstacles and Opportunities
Antigens That Induce Protective Immunity in Animal Models A number of animal malarias, such as those caused by P. chabaudi and P. yoelii in mice, P. lophurae in ducklings, and P. fragile and P. knowlesi in rhesus monkeys, have been used to identify antigens that can induce protective immunity. The hope is that homologous molecules from human malaria parasite species will make good vaccine candidates. Experimental immunization with merozoite surface antigen 1 (MSA-1) in various animal models supports this hope (Holder and Freeman, 1981; Schmidt-Ullrich et al., 1983; Patarroyo et al., 1987; Siddiqui et al., 1987).
P. falciparum has been adapted to grow in aotus and saimiri monkeys, and partially purified parasite antigens that confer protection have been identified (Patarroyo et al., 1987). A number of blood-stage proteins were purified and tested individually for protective efficacy in aotus monkeys. The sequence of proteins that induced a degree of protection was determined, and synthetic peptides were made and used to immunize aotus monkeys. A combination of peptides from three proteins induced a protective immune response that resulted in survival from an otherwise lethal infection, often with little or no parasitemia.
Pathogenic Immune Factors Efforts to produce vaccines that prevent the most severe symptoms and signs of malaria disease represent an exciting new approach to malaria vaccine development. The impetus for research in this area comes from the observation that older children and repeatedly infected adults in endemic areas may harbor significant parasite concentrations without showing symptoms of disease. This tolerance is lost fairly quickly after exposure to malaria ceases. There is also similarity between the symptoms of malaria and the symptoms produced in nonmalarious individuals by treatment with TNF, interferons, and some of the interleukins. There is also a correlation between the severity of symptoms in severe malaria and the level of circulating TNF (see Chapter 4).
Soluble exoantigens of bloodstage P. yoelii, P. berghei, and P. falciparum, probably released at the time of schizont rupture, induce the secretion of TNF from mouse peritoneal macrophages and human peripheral blood lymphocytes in vitro (Bate et al., 1988; Taverne et al., 1990). These exoantigens, which appear to be phospholipids, also induce TNF production in vivo and can kill mice made sensitive to it (Bate et al., 1989). When exoantigens are used as immunogens, they induce a T-cell-independent IgM antibody response (Bate et al., 1990) that protects mice from dying from what would ordinarily be a lethal malaria infection (Playfair et al., 1990). This antibody response also blocks the ability of exoantigens to induce TNF production in vitro. Exoantigens appear to be conserved across animal species, since antisera against rodent malaria exoantigens recognize human exoantigens, and vice versa.