(attenuated) confers protection against subsequent sporozoite-induced malaria infection in mice, monkeys, and humans (Nussenzweig et al., 1967; Clyde et al., 1973a,b, 1975; Rieckmann et al., 1974, 1979; Gwadz et al., 1979). In the human studies, mosquitoes infected with malaria sporozoites were exposed to x-rays, and the resulting radiation-attenuated sporozoites were introduced into human volunteers during the mosquitoes ' blood meal.

Immunization with radiation-attenuated sporozoites induces protection unlike that found after natural infection. Naturally acquired immunity seems to be directed primarily against the erythrocytic stages of the parasite, so that infection per se is not prevented, but people are protected from severe disease and death. Individuals who have lived for 20 or more years in endemic regions still become infected, although they may have few or no symptoms (Hoffman et al., 1987). In contrast, volunteers immunized with irradiated sporozoites do not develop any detectable blood-stage infection. The differences may be due in part to the fact that even in areas of the highest malaria transmission, naturally exposed individuals are bitten by relatively few infective mosquitoes (fewer than 50 per month) (Beier et al., 1990). Thus they may not receive sufficient stimulation by sporozoite antigens to induce the protective immune responses achieved by repeated exposure to many hundreds of irradiated, infected mosquitoes over a few weeks or months (Clyde et al., 1973a,b, 1975; Rieckmann et al., 1974, 1979).

Vaccinating people with irradiated sporozoites cannot be routinely done. No culture system capable of producing large numbers of sporozoites is available or perhaps even feasible. Dissecting sporozoites from infected mosquitoes is far too labor intensive, and exposing people to mosquitoes containing irradiated sporozoites is not a tenable strategy. Given these limitations, the only hope for a pre-erythrocytic vaccine lies in the construction of a subunit vaccine, and researchers have been focusing on this objective. Identifying the mechanisms of protective immunity and the parasite antigens against which these protective immune responses are directed is a prerequisite to the development of this type of vaccine. Both antibodies and cellular immune responses contribute to this protection.

Antibody-Mediated Immunity Mice and humans immunized with irradiated sporozoites develop antibodies directed against sporozoites. When administered to animals, some of these antisporozoite antibodies can protect against sporozoite-induced malaria infection (Potocnjak et al., 1980; Egan et al., 1987; Charoenvit et al., 1991a,b). Protective antisporozoite antibodies generally react with only a single species of malaria parasite and thus confer protection only against that species. This is similar to the species-specific immunity induced by immunization with irradiated sporozoites (Clyde et al., 1975).



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