Morbidity and mortality due to Plasmodium falciparum and Plasmodium vivax, the two predominant human malaria parasites, result during the asexual development and replication of these protozoan parasites within erythrocytes (RBCs) (44). To reduce this burden on nearly half of the world's population, several malaria vaccine strategies are being pursued (28,40,53). Blood-stage vaccines are being developed to reduce parasite load and/or prevent life-threatening complications of malaria once parasites are replicating within RBCs. The single most feasible strategy for blood-stage malaria is to immunize with subunit vaccines that induce high titers of antibodies that neutralize extracellular merozoites and prevent the invasion of erythrocytes (2,25,31,40). The multiple receptor-ligand interactions and alternate redundant pathways involved in the merozoite invasion of RBCs combined with the polymorphism of vaccine candidate antigens present a challenge for vaccine design (2,25,26).P. falciparum merozoite surface protein 1 (MSP-1)

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For the development of blood-stage malaria vaccines, there is a clear need to establish in vitro measures of the antibody-mediated and the cell-mediated immune responses that correlate with protection. In this study, we focused on establishing correlates of antibody-mediated immunity induced by immunization with apical membrane antigen 1 (AMA1) and merozoite surface protein 1 42 (MSP1 42 ) subunit vaccines. To do so, we exploited the Plasmodium chabaudi rodent model, with which we can immunize animals with both protective and nonprotective vaccine formulations and allow the parasitemia in the challenged animals to peak. Vaccine formulations were varied with regard to the antigen dose, the antigen conformation, and the adjuvant used. Prechallenge antibody responses were evaluated by enzyme-linked immunosorbent assay and were tested for a correlation with protection against nonlethal P. chabaudi malaria, as measured by a reduction in the peak level of parasitemia. The analysis showed that neither the isotype profile nor the avidity of vaccine-induced antibodies correlated with protective efficacy. However, high titers of antibodies directed against conformationindependent epitopes were associated with poor vaccine performance and may limit the effectiveness of protective antibodies that recognize conformation-dependent epitopes. We were able to predict the efficacies of the P. chabaudi AMA1 (PcAMA1) Infection with the protozoan parasites Plasmodium falciparum and Plasmodium vivax causes 300 million to 500 million clinical episodes of malaria annually (21). With at least 40% of the world's population at risk for malaria, multiple strategies are being explored to reduce this global public health problem. Progress continues to be made in the development of malaria vaccines for potential use in areas where malaria is endemic (18,28). It is encouraging that in a recent trial, the rate of severe malaria was significantly reduced in young children in Mozambique immunized with RTS,S, a P. falciparum preerythrocytic-stage vaccine (1); and it was found that RTS,S was safe, immunogenic, and efficacious in infants (1 to 3 months of age) (3). For blood-stage vaccines, the testing of vaccine safety, immunogenicity, and efficacy in human subjects has moved forward for two candidate antigens, namely, apical membrane antigen 1 (AMA1) (15,31,42) and merozoite surface protein 1 (MSP1) (30,35,47,49,56).Both AMA1 and MSP1 are expressed on the surface of extracellular, invasive merozoites and are essential for bloodstage parasite growth (17,36,50). We do not fully understand the precise functions of AMA1 and MSP1 in this invasion process, but their roles do appear to be distinct and nonoverlapping. The basic strategy for AMA1-and MSP1-based vaccines is the induction of antibodies that neutralize the merozoites released upon schizont rupture. The mechanisms of action of such neutralizing antibodies may include the blocking of key receptor-ligand interactions, inhibition of the proteolytic processing steps required for the invasion of e...