ANTIGENIC DIVERSITY IN THE CIRCUMSPOROZOITE PROTEIN OF PLASMODIUM-FALCIPARUM ABROGATES CYTOTOXIC-T-CELL RECOGNITION

Genetic analysis of field isolates of Plasmodium falciparum has shown selective accumulation of point mutations within the immunologically s ensitive sites of the circumsporozoite (CS) protein, a vaccine candida te against malaria. This raised concern whether a vaccine containing t he sequence of a selected strain of P. falciparum would be able to con fer protection against other variant parasites. The answer to this que stion remained speculative, and in this study, we have formally tested the immunological impact of such natural variations within a known cy totoxic-T-cell (CTL) epitope, which is recognized by both human and mu rine CTLs. With a murine model, CTLs were generated against the 7G8 st rain of P. falciparum The ability of these CTLs to lyse histocompatibl e targets that were pulsed with synthetic peptides corresponding to po lymorphic sequences of Brazilian, Papua New Guinean, and The Gambian i solates was determined. While these CTLs were able to recognize three of the four variant CS sequences found in Brazil and Papua New Guinea, they failed to recognize four of the five variant CS sequences found in The Gambia. Among the peptides that lost their reactivity to 7G8-sp ecific CTL, all except one had amino acid variation in more than one r esidue. On the other hand, only one of the four peptides that showed a positive reaction had amino acid substitutions in more than a single residue. Thus, our findings demonstrate that natural amino acid variat ions in the CS protein abrogate CTL recognition. Therefore, it is impo rtant to consider the implications of these results in designing CS pr otein-based vaccines.