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 sensitive sites of the circumsporozoite (CS) protein, a vaccine candidate against malaria. This raised concern whether a vaccine containing the sequence of a selected strain of P. falciparum would be able to confer protection against other variant parasites. The answer to this question remained speculative, and in this study, we have formally tested the immunological impact of such natural variations within a known cytotoxic-T-cell (CTL) epitope, which is recognized by both human and murine CTLs. With a murine model, CTLs were generated against the 7G8 strain of P. falciparum. The ability of these CTLs to lyse histocompatible targets that were pulsed with synthetic peptides corresponding to polymorphic sequences of Brazilian, Papua New Guinean, and The Gambian isolates 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-specific CTL, all except one had amino acid variation in more than one residue. 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 variations in the CS protein abrogate CTL recognition. Therefore, it is important to consider the implications of these results in designing CS protein-based vaccines.