Prediction of Merozoite Surface Protein 1 and Apical Membrane Antigen 1 Vaccine Efficacies againstPlasmodium chabaudiMalaria Based on Prechallenge Antibody Responses

Abstract

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...

High Antibody Titer against Apical Membrane Antigen-1 Is Required to Protect against Malaria in the Aotus Model

“…Recombinant AMA1 of the P. chabaudi rodent malaria parasite also protected vaccinated mice against lethal challenge with a homologous strain of P. chabaudi , but no protection was observed against a heterologous strain [11] . As above in primate models, the vaccine efficacy in the rodent models correlated with antibody titers [12] and protection was also conferred upon passive transfer of IgG. Antibodies against conformational epitopes were critical for this protective response [11] .…”

“…As above in primate models, the vaccine efficacy in the rodent models correlated with antibody titers [12] and protection was also conferred upon passive transfer of IgG. Antibodies against conformational epitopes were critical for this protective response [11].…”

Immunosignatures can predict vaccine efficacy

“…Neutralizing antibodies against pathogens such as HIV are predominantly directed against conformational epitopes, and, in Plasmodium chabaudi malaria, antibody titers to linear epitopes were associated with poor vaccine efficacy whereas the antibodies raised against properly folded proteins were associated with protection (33). Given the difficulties in producing properly folded protein, peptide mimetics are an ideal means to define antibodies to conformational epitopes.…”

Boosting antibody responses toPlasmodium falciparummerozoite antigens in children with highly seasonal exposure to infection

“…While IgG3 antibodies have a shorter half life than IgG1 antibodies, the relative affinity of different antibody subclasses to malaria antigens has not been defined. A P. chabaudi murine vaccine study showed no differences between antibody avidities to AMA1 or MSP1 conformation-dependent and conformation-independent epitopes ( 27 ; MSP2 could not be compared as that antigen is not present in rodent malaria parasites). Less persistent antibody responses were observed to MSP2 than to AMA1, EBA175, MSP1 19 and schizont extract antigens during the dry season amongst children in this cohort ( 10 ).…”