coupled to a lipid structure (Deres et al., 1989). These offer additional possible approaches to induction of protective cell-mediated immune responses.
Antigenic Diversity Most malaria antigens appear to have significant antigenic diversity. Much of this diversity may be an adaptive response of the parasite to host immunity, and it is theoretically possible that an initially effective malaria vaccine might select for parasite variants, leading to vaccine-resistant strains.
For example, there are at least two major variants of the repetitive region of the CS protein of P. vivax, and antibodies that recognize one variant do not react with the other (and vice versa) (Rosenberg et al., 1989; Wirtz et al., 1990). Extensive variation in the CS protein repetitive region occurs in the monkey malaria parasites P. knowlesi and P. cynomolgi (Sharma et al., 1985; Galinski et al., 1987). For vaccines intended to induce antibodies directed against the CS repetitive epitope, variability in the repetitive region would complicate vaccine formulation, since a useful vaccine must protect against all variants. For P. falciparum, variation in the repeat region of the CS protein has thus far been limited to minor changes in the numbers of repeating units and, occasionally, changes in a few of the individual repetitive epitopes. All P. falciparum isolates obtained from different parts of the world are recognized by monoclonal antibodies directed against the predominant repetitive epitope (Zavala et al., 1985).
Variability in T-cell epitopes may also be important. For example, the DNA sequence of the CS protein gene from several different isolates has been determined. It is highly conserved, and the variations that do occur are clustered within regions that code for T-cell epitopes (Good et al., 1987; Kumar et al., 1988; Lockyer and Schwarz, 1987). Variation in helper T-cell epitopes may potentially limit the ability of sporozoites to boost the antibody response to CS protein B-cell epitopes, and variations in cytotoxic T-lymphocyte epitopes may allow liver-stage parasites to evade killing by cytotoxic T lymphocytes.
Genetic Restriction of the Immune Response T lymphocytes recognize fragments of antigens that are presented as a complex with host MHC proteins on the surface of cells (see above). The antigen fragments (T-cell epitopes) are formed by the action of cellular enzymes that digest the antigen into small pieces of about 8 to 12 amino acids.
The interaction of T-cell epitopes with MHC proteins is highly specific. Changing a single amino acid in either the T-cell epitope or the region of the MHC protein that binds to the T-cell epitope can completely prevent the interaction. There is tremendous variability among individuals in the genetically determined amino acid sequence of the region of the MHC