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MALARIA: Obstacles and Opportunities
parasites (Chulay, 1989), which facilitates the testing of vaccines in various animal model systems.
The CS proteins of all malaria parasites studied thus far are similar in size and overall structure but vary considerably in specific composition. All have a central region consisting of tandem repeats of species-specific amino acids (Dame et al., 1984). After immunization with irradiated sporozoites, most of the antibodies that develop are directed against the repetitive region of the CS protein (Zavala et al., 1983). Antibodies directed against the CS repetitive region inhibit sporozoite invasion into cultured liver cells (Mazier et al., 1986), and administration of such antibodies can completely protect against sporozoite-induced malaria in mouse and monkey model systems (Potocnjak et al., 1980; Egan et al., 1987; Charoenvit et al., 1991a,b). In P. falciparum, the repetitive region contains a series of four amino acids (asparagine-alanine-asparagine-proline) that has been detected in all isolates analyzed (Zavala et al., 1985). Thus, protective immunity directed against the repetitive region of P. falciparum would be expected to be species specific but not isolate specific.
Antibodies against non-repetitive regions of the CS protein have also been shown to inhibit sporozoite invasion into cultured liver cells (Aley et al., 1986; D. M. Gordon, Department of Immunology, Walter Reed Army Institute of Research, personal communication, 1990).
The CS protein is also a target of cell-mediated immunity. Mice and humans immunized with irradiated sporozoites develop cytotoxic T lymphocytes directed against portions of the CS protein (Kumar et al., 1988; Romero et al., 1989; Weiss et al., 1990; Malik et al., 1991). Such cytotoxic T lymphocytes can destroy malaria-infected liver cells in culture (Weiss et al., 1990), and administration of cloned T lymphocytes specific for portions of the CS protein can protect mice against sporozoite-induced malaria (Romero et al., 1989; Del Giudice et al., 1990).
The CS protein also contains epitopes recognized by helper T lymphocytes. These T helper epitopes are present in both the repetitive and flanking non-repetitive regions of the CS protein (Good et al., 1987).
Sporozoite Surface Protein 2 A second sporozoite surface protein (SSP2) that is a target of protective immunity has recently been identified in P. yoelii (Charoenvit et al., 1987; Hedstrom et al., 1990). Antibodies against SSP2 partially inhibit sporozoite invasion into liver cells in culture (S. Mellouk, unpublished), and administration of a cloned T lymphocyte that recognizes SSP2 can protect mice against sporozoite-induced malaria (S. Khusmith, unpublished). Immunization of mice with either a CS protein vaccine alone or an SSP2 vaccine alone can protect a proportion of mice against sporozoite-induced malaria, while concurrent immunization with both vaccines protects all mice (Khusmith et al., 1991). This synergistic effect emphasizes one of the advantages of including multiple antigens from a single parasite stage in a multicomponent malaria vaccine.