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Abstract
BackgroundApical membrane antigen 1 (AMA1) is one of the best-studied blood-stage malaria vaccine candidates. When an AMA1 vaccine was tested in a malaria naïve population, it induced functionally active antibodies judged by Growth Inhibition Assay (GIA). However, the same vaccine failed to induce higher growth-inhibitory activity in adults living in a malaria endemic area. Vaccination did induce functionally active antibodies in malaria-exposed children with less than 20% inhibition in GIA at baseline, but not in children with more than that level of baseline inhibition.MethodsTotal IgGs were purified from plasmas collected from the pediatric trial before and after immunization and pools of total IgGs were made. Another set of total IgGs was purified from U.S. adults immunized with AMA1 (US-total IgG). From these total IgGs, AMA1-specific and non-AMA1 IgGs were affinity purified and the functional activity of these IgGs was evaluated by GIA. Competition ELISA was performed with the U.S.-total IgG and non-AMA1 IgGs from malaria-exposed children.ResultsAMA1-specific IgGs from malaria-exposed children and U.S. vaccinees showed similar growth-inhibitory activity at the same concentrations. When mixed with U.S.-total IgG, non-AMA1 IgGs from children showed an interference effect in GIA. Interestingly, the interference effect was higher with non-AMA1 IgGs from higher titer pools. The non-AMA1 IgGs did not compete with anti-AMA1 antibody in U.S.-total IgG in the competition ELISA.ConclusionChildren living in a malaria endemic area have a fraction of IgGs that interferes with the biological activity of anti-AMA1 antibody as judged by GIA. While the mechanism of interference is not resolved in this study, these results suggest it is not caused by direct competition between non-AMA1 IgG and AMA1 protein. This study indicates that anti-malaria IgGs induced by natural exposure may interfere with the biological effect of antibody induced by an AMA1-based vaccine in the target population.
Highlights
WHO estimates there were 243 million malaria cases and 0.9 million deaths in 2008; the vast majority of deaths occurred in African children less than 5-years old due to Plasmodium falciparum, which is the most virulent species of human malaria [1]
We investigated the biological activity of the AMA1specific IgGs from U.S vaccinees and Malian children by Growth Inhibition Assay (GIA)
When the data from all Apical membrane antigen 1 (AMA1)-specific IgGs from Malian children were combined, there were significant correlations between antibody levels by ELISA and percent inhibition in GIA, and each relationship followed a symmetrical sigmoid curve (r2 = 0.99 for 3D7, 0.94 for FVO). These results indicate that there was no obvious difference in biological activity of antibodies among AMA1-specific IgGs induced by an AMA1 vaccination (IgGs from U.S vaccinees), by natural infection (IgGs from D0-1, 2, 3 & 4 and Hib-1, 2 & 3 pools) and by both natural infection and vaccination (IgGs from AMA1-1, 2 & 3 pools)
Summary
WHO estimates there were 243 million malaria cases and 0.9 million deaths in 2008; the vast majority of deaths occurred in African children less than 5-years old due to Plasmodium falciparum, which is the most virulent species of human malaria [1]. In addition to the animal data, many, but not all, epidemiological studies suggest a high level of AMA1 antibodies is associated with a reduced risk of malaria [11]. Based on these findings, multiple AMA1 Phase 1 trials [14,15,16,17,18,19,20,21,22,23,24] and a Phase 2 field trial [25] have been conducted and published. Vaccination did induce functionally active antibodies in malaria-exposed children with less than 20% inhibition in GIA at baseline, but not in children with more than that level of baseline inhibition
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