A Vaccine Effective Against Both the Sexual and Asexual Stages of Plasmodium knowlesi

With malaria a resurging public health problem in much of the tropical world, the search for newer methods to combat this disease has been intensified. Current research is multifaceted, directed toward the development of better means of mosquito control, new chemotherapeutic drugs, and an effective vaccine. Malaria is caused by a protozoan parasite with a complex life cycle and several different forms and stages (Fig. 1). Infection in the mammalian host is initiated with the injection by mosquitoes of sporozoites that invade hepatic parenchymal cells. Here, each sporozoite can develop into 20,000 or more merozoites; each merozoite, after leaving the liver, is capable of infecting an erythrocyte. Within erythrocytes, merozoites asexually reproduce to form schizonts which in turn produce more merozoites; after cell rupture these then reinvade other erythrocytes. It is this cycle of cell rupture and reinvasion by asexual parasites that causes the clinical disease. The sexual cycle of the parasite is equally complex. Some merozoites invade erythrocytes and instead of forming schizonts, develop into male or female sexual forms, the gametocytes. When these are ingested by a blood-feeding mosquito, gametocytes give rise to either sperm-like male microgametes or nonmotile female macrogametes in the gut of the mosquito. These gametes fuse and the resulting ookinetes (zygotes) penetrate through the gut epithelium of the mosquito and produce oocysts. It is the oocyst which ultimately produces the sporozoites found in the salivary gland of the mosquito and which are capable of infecting the vertebrate host to complete the cycle of transmission when the mosquito feeds again. Malaria parasites are intracellular for most of their existence within the vertebrate host. However, for short periods, different forms of the parasites are extracellular; merozoites are free briefly in the plasma after rupture of the schizont and before erythrocyte reinvasion, sporozoites are free from the time of injection by the mosquito until they invade a liver cell. Gametes are also free from cells in the gut of the mosquito. It is thought that during these brief extracellular periods merozoites, sporozoites, and gametes are vulnerable to immune factors that affect their infectivity, and it is on this vulnerability that anti-merozoite (1), anti-sporozoite (2), and antigamete (3) vaccines are based. Interference with sexual development of the malarial parasite would have an obvious effect on the transmission of the organism from host to host and could act to limit the spread of the disease. Such a scheme for interference with sexual development and transmission has already been demonstrated with the avian malaria, Plasmodium gallinaceum, in chickens (3, 4). After immunization by intravenous injections of Xirradiated or killed sexual parasites, chickens remain susceptible to infection with