Malaria continues to be one of the greatest public health problems in the world. Between 300 and 500 million people are affected annually, which leads to 1.5 to 2.5 million deaths, mainly in children less than 5 years old.[1, 2] Immunoprophylactic method development is the only cost-effective control alternative [3] and currently several malarial vaccines including our SPF-66 have been tested and shown to have limited (but significant)[4] or no efficacy in humans.[5] The Plasmodium falciparum merozoite surface protein-1 (MSP-1) is one of this parasite× s most abundant merozoite membrane molecules. It plays a key role in merozoite invasion of human erythrocytes, and is therefore regarded as a promising vaccine candidate.[6] Our objective is to induce an immune response able to block the receptor±ligand interaction responsible for human red blood cell (RBC) invasion.

Our first step was to identify MSP-1 sequences involved in the invasion process; such sequences were then used (unmodified or with single or multiple substitutions) in immunization studies. The changes induced in the lead peptide threedimensional structure (determined by using NMR spectroscopy) were analyzed by correlating the substitution with the degree of protective immunity in Aotus monkeys. Relevant MSP-1 sequences have previously been identified by their interaction with human RBCs.[7] One of these sequences, located in the N-terminal portion of the 42-kDa MSP-1 fragment (peptide1585: EVLYLKPLAGVYRSLKKQLE), binds to RBC with an affinity constant of 180 nm. We have chosen the peptide1585 (which has a conserved sequence in all parasite strains) to avoid the wide genetic variability of P. falciparum.[8, 9] Evidence to date suggests that the conserved protein sequence in P. falciparum has poor or no antigenicity (capacity to induce immune response after infection) nor immunogenicity (capacity to induce immune response when used as a vaccine) in humans.[7] The first step in the design of analogues was to recognize those amino acids critical to the RBC binding process and to determine if residue substitution induced immunogenicity and protectivity. Determination of these residues [10, 11] showed that