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MALARIA: Obstacles and Opportunities
nine amino acids of the CS repeat section that contained only the repetitive amino acids of the CS protein induced high levels of antisporozoite antibodies in monkeys and humans (Collins et al., 1989; Gordon et al., 1990), but these antibodies were not directed against the four-amino-acid B-cell epitope recognized by the protective monoclonal antibody (Charoenvit et al., 1991b).
Protection does not appear to be a function of the specific immunoglobulin G (IgG) subclass of antibodies, since monoclonal antibodies of the IgG1, IgG2b, and IgG3 subclasses, as well as Fab fragments (antibodies lacking their subclass-specific portion), have all been shown to transfer protection passively in mice (Potocnjak et al., 1980; Egan et al., 1987; Charoenvit et al., 1991a,b). Protection also does not appear to be explained by differences between the structure of the native sporozoite protein and the synthetic and recombinant peptide subunit vaccines, since monoclonal antibodies produced by immunization with short peptides can also confer protection when administered to animals.
Immunization undoubtedly produces polyclonal antibodies of varying affinities and specificities. To achieve consistent antibody-mediated protection, a vaccine may have to focus the immune response, or dramatically increase the overall production of antibody, to achieve appropriate concentrations of the “correct” antibodies.
PASSIVE IMMUNIZATION Because passive transfer of monoclonal antibodies is so effective in protecting against sporozoite-induced malaria in animals, some researchers are working to develop human monoclonal antibodies against the repeat regions of the human malaria CS protein. These antibodies could be used to passively immunize short-term visitors to malarious areas in the same way that gamma globulin is used to prevent hepatitis A.
CELL-MEDIATED IMMUNE RESPONSE Little is known about how to induce protective cell-mediated immune responses with subunit vaccines. Cytotoxic T lymphocytes generally are not induced by immunization with standard preparations of inactivated microbial antigens. Cytolytic T lymphocytes can be induced by immunization with recombinant live attenuated vaccines, such as those for salmonella, BCG, and vaccinia (smallpox vaccine). Work is in progress to construct recombinant live attenuated vaccines that express malaria genes and that might induce protective cell-mediated immune responses in humans.
Cytotoxic T lymphocytes can also be induced by immunization with antigens contained within liposomes (small lipid-bound vesicles that can interact with cells of the immune system), immunostimulatory complexes (particles formed by antigen complexed with the detergent saponin) (Takahashi et al., 1990), and peptides containing a cytotoxic T-lymphocyte epitope