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Comparison of functional assays used in the clinical development of a placental malaria vaccine

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BACKGROUND: Malaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. Plasmodium falciparum infected erythrocytes (IE) express VAR2CSA that mediates binding to chondroitin sulphate A (CSA) in the placenta. Two VAR2CSA-based vaccines for placental malaria are in clinical development. The purpose of this study was to evaluate the robustness and comparability of binding inhibition assays used in the clinical development of placental malaria vaccines.

METHODS: The ability of sera from animals immunised with different VAR2CSA constructs to inhibit IE binding to CSA was investigated in three in vitro assays using 96-well plates, petri dishes, capillary flow and an ex vivo placental perfusion assay.

RESULTS: The inter-assay variation was not uniform between assays and ranged from above ten-fold in the flow assay to two-fold in the perfusion assay. The intra-assay variation was highest in the petri dish assay. A positive correlation between IE binding avidity and the level of binding after antibody inhibition in the petri dish assay indicate that high avidity IE binding is more difficult to inhibit. The highest binding inhibition sensitivity was found in the 96-well and petri dish assays compared to the flow and perfusion assays where binding inhibition required higher antibody titers.

CONCLUSIONS: The inhibitory capacity of antibodies is not easily translated between assays and the high sensitivity of the 96-well and petri dish assays stresses the need for comparing serial dilutions of serum. Furthermore, IE binding avidity must be in the same range when comparing data from different days. There was an overall concordance in the capacity of antibody-mediated inhibition, when comparing the in vitro assays with the perfusion assay, which more closely represents in vivo conditions. Importantly the ID1-ID2a protein in a liposomal formulation, currently in a phase I trial, effectively induced antibodies that inhibited IE adhesion in placental tissue.

Original languageEnglish
JournalVaccine
Volume35
Issue number4
Pages (from-to)610-618
Number of pages9
ISSN0264-410X
DOIs
Publication statusPublished - 23 Jan 2017

    Research areas

  • Animals, Antibodies, Protozoan, Antigens, Protozoan, Cell Adhesion, Chondroitin Sulfates, Cytological Techniques, Drug Discovery, Erythrocytes, Female, Malaria Vaccines, Malaria, Falciparum, Mice, Inbred C57BL, Placenta Diseases, Pregnancy, Rabbits, Rats, Wistar, Reproducibility of Results, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't

ID: 52820997