The repetitive epitope (Asn-Ala-Asn-Pro = NANP) of the Plasmodium falciparum circumsporozoite protein is considered as the basis for the development of a recombinant or synthetic subunit vaccine against malaria. Vaccines consisting of (NANP)n molecules coupled to carrier proteins have already been tested in trials in human volunteers with partial success. In this paper we show that C57BL/6 mice, genetically responsive to carrier-free (NANP)n molecules, exhibit a secondary antibody response to (NANP) if they are primed with carrier-free (NANP)40 synthetic peptide, and then challenged with P. falciparum sporozoites. However, such a sporozoite-mediated boosting effect is not observed if C57BL/6 and BALB/c mice were previously primed with (NANP)40 peptide conjugated to carrier proteins. The genetic restriction of the murine antibody response to (NANP)n is overcome when mice bearing seven different H-2 haplotypes are immunized with entire P. falciparum sporozoites. These results may have implications for the understanding of natural or induced anti-sporozoite immunity, and show that the use of T-cell epitopes from the plasmodial antigenic repertoire would be very likely to represent an efficient approach for the development of a subunit malaria vaccine.