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

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Pehrson, Caroline ; Heno, Kristine K ; Adams, Yvonne ; Resende, Mafalda ; Mathiesen, Line ; Soegaard, Max ; de Jongh, Willem A ; Theander, Thor G ; Salanti, Ali ; Nielsen, Morten A. / Comparison of functional assays used in the clinical development of a placental malaria vaccine. I: Vaccine. 2017 ; Bind 35, Nr. 4. s. 610-618.

Bibtex

@article{6830a5885eb34ab6af60c17c115fbf50,
title = "Comparison of functional assays used in the clinical development of a placental malaria vaccine",
abstract = "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.",
keywords = "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",
author = "Caroline Pehrson and Heno, {Kristine K} and Yvonne Adams and Mafalda Resende and Line Mathiesen and Max Soegaard and {de Jongh}, {Willem A} and Theander, {Thor G} and Ali Salanti and Nielsen, {Morten A}",
note = "Copyright {\circledC} 2016. Published by Elsevier Ltd.",
year = "2017",
month = "1",
day = "23",
doi = "10.1016/j.vaccine.2016.12.028",
language = "English",
volume = "35",
pages = "610--618",
journal = "Vaccine",
issn = "0264-410X",
publisher = "Elsevier Ltd",
number = "4",

}

RIS

TY - JOUR

T1 - Comparison of functional assays used in the clinical development of a placental malaria vaccine

AU - Pehrson, Caroline

AU - Heno, Kristine K

AU - Adams, Yvonne

AU - Resende, Mafalda

AU - Mathiesen, Line

AU - Soegaard, Max

AU - de Jongh, Willem A

AU - Theander, Thor G

AU - Salanti, Ali

AU - Nielsen, Morten A

N1 - Copyright © 2016. Published by Elsevier Ltd.

PY - 2017/1/23

Y1 - 2017/1/23

N2 - 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.

AB - 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.

KW - Animals

KW - Antibodies, Protozoan

KW - Antigens, Protozoan

KW - Cell Adhesion

KW - Chondroitin Sulfates

KW - Cytological Techniques

KW - Drug Discovery

KW - Erythrocytes

KW - Female

KW - Malaria Vaccines

KW - Malaria, Falciparum

KW - Mice, Inbred C57BL

KW - Placenta Diseases

KW - Pregnancy

KW - Rabbits

KW - Rats, Wistar

KW - Reproducibility of Results

KW - Comparative Study

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.vaccine.2016.12.028

DO - 10.1016/j.vaccine.2016.12.028

M3 - Journal article

VL - 35

SP - 610

EP - 618

JO - Vaccine

JF - Vaccine

SN - 0264-410X

IS - 4

ER -

ID: 52820997