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The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine

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Harvard

Nielsen, MA, Resende, M, De Jongh, WA, Ditlev, SB, Mordmüller, B, Houard, S, Ndam, NT, Agerbæk, MØ, Hamborg, M, Massougbodji, A, Issifou, S, Strøbæk, A, Poulsen, L, Leroy, O, Kremsner, PG, Chippaux, J-P, Luty, AJF, Deloron, P, Theander, TG, Dyring, C & Salanti, A 2015, 'The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine', P L o S One, vol. 10, no. 9, pp. e0135406. https://doi.org/10.1371/journal.pone.0135406

APA

Nielsen, M. A., Resende, M., De Jongh, W. A., Ditlev, S. B., Mordmüller, B., Houard, S., Ndam, N. T., Agerbæk, M. Ø., Hamborg, M., Massougbodji, A., Issifou, S., Strøbæk, A., Poulsen, L., Leroy, O., Kremsner, P. G., Chippaux, J-P., Luty, A. J. F., Deloron, P., Theander, T. G., ... Salanti, A. (2015). The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine. P L o S One, 10(9), e0135406. https://doi.org/10.1371/journal.pone.0135406

CBE

Nielsen MA, Resende M, De Jongh WA, Ditlev SB, Mordmüller B, Houard S, Ndam NT, Agerbæk MØ, Hamborg M, Massougbodji A, Issifou S, Strøbæk A, Poulsen L, Leroy O, Kremsner PG, Chippaux J-P, Luty AJF, Deloron P, Theander TG, Dyring C, Salanti A. 2015. The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine. P L o S One. 10(9):e0135406. https://doi.org/10.1371/journal.pone.0135406

MLA

Vancouver

Author

Nielsen, Morten A ; Resende, Mafalda ; De Jongh, Willem Adriaan ; Ditlev, Sisse B ; Mordmüller, Benjamin ; Houard, Sophie ; Ndam, Nicaise Tuikue ; Agerbæk, Mette Ø ; Hamborg, Mette ; Massougbodji, Achille ; Issifou, Saddou ; Strøbæk, Anette ; Poulsen, Lars ; Leroy, Odile ; Kremsner, Peter G ; Chippaux, Jean-Philippe ; Luty, Adrian J F ; Deloron, Philippe ; Theander, Thor G ; Dyring, Charlotte ; Salanti, Ali. / The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine. In: P L o S One. 2015 ; Vol. 10, No. 9. pp. e0135406.

Bibtex

@article{566a2c1e3323439e8ba848dc8951cd89,
title = "The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine",
abstract = "The disease caused by Plasmodium falciparum (Pf) involves different clinical manifestations that, cumulatively, kill hundreds of thousands every year. Placental malaria (PM) is one such manifestation in which Pf infected erythrocytes (IE) bind to chondroitin sulphate A (CSA) through expression of VAR2CSA, a parasite-derived antigen. Protection against PM is mediated by antibodies that inhibit binding of IE in the placental intervillous space. VAR2CSA is a large antigen incompatible with large scale recombinant protein expression. Vaccines based on sub-units encompassing the functionally constrained receptor-binding domains may, theoretically, circumvent polymorphisms, reduce the risk of escape-mutants and induce cross-reactive antibodies. However, the sub-unit composition and small differences in the borders, may lead to exposure of novel immuno-dominant antibody epitopes that lead to non-functional antibodies, and furthermore influence the folding, stability and yield of expression. Candidate antigens from the pre-clinical development expressed in High-Five insect cells using the baculovirus expression vector system were transitioned into the Drosophila Schneider-2 cell (S2) expression-system compliant with clinical development. The functional capacity of antibodies against antigens expressed in High-Five cells or in S2 cells was equivalent. This enabled an extensive down-selection of S2 insect cell-expressed antigens primarily encompassing the minimal CSA-binding region of VAR2CSA. In general, we found differential potency of inhibitory antibodies against antigens with the same borders but of different var2csa sequences. Likewise, we found that subtle size differences in antigens of the same sequence gave varying levels of inhibitory antibodies. The study shows that induction of a functional response against recombinant subunits of the VAR2CSA antigen is unpredictable, demonstrating the need for large-scale screening in order to identify antigens that induce a broadly strain-transcending antibody response.",
author = "Nielsen, {Morten A} and Mafalda Resende and {De Jongh}, {Willem Adriaan} and Ditlev, {Sisse B} and Benjamin Mordm{\"u}ller and Sophie Houard and Ndam, {Nicaise Tuikue} and Agerb{\ae}k, {Mette {\O}} and Mette Hamborg and Achille Massougbodji and Saddou Issifou and Anette Str{\o}b{\ae}k and Lars Poulsen and Odile Leroy and Kremsner, {Peter G} and Jean-Philippe Chippaux and Luty, {Adrian J F} and Philippe Deloron and Theander, {Thor G} and Charlotte Dyring and Ali Salanti",
year = "2015",
doi = "10.1371/journal.pone.0135406",
language = "English",
volume = "10",
pages = "e0135406",
journal = "PLOS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

RIS

TY - JOUR

T1 - The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine

AU - Nielsen, Morten A

AU - Resende, Mafalda

AU - De Jongh, Willem Adriaan

AU - Ditlev, Sisse B

AU - Mordmüller, Benjamin

AU - Houard, Sophie

AU - Ndam, Nicaise Tuikue

AU - Agerbæk, Mette Ø

AU - Hamborg, Mette

AU - Massougbodji, Achille

AU - Issifou, Saddou

AU - Strøbæk, Anette

AU - Poulsen, Lars

AU - Leroy, Odile

AU - Kremsner, Peter G

AU - Chippaux, Jean-Philippe

AU - Luty, Adrian J F

AU - Deloron, Philippe

AU - Theander, Thor G

AU - Dyring, Charlotte

AU - Salanti, Ali

PY - 2015

Y1 - 2015

N2 - The disease caused by Plasmodium falciparum (Pf) involves different clinical manifestations that, cumulatively, kill hundreds of thousands every year. Placental malaria (PM) is one such manifestation in which Pf infected erythrocytes (IE) bind to chondroitin sulphate A (CSA) through expression of VAR2CSA, a parasite-derived antigen. Protection against PM is mediated by antibodies that inhibit binding of IE in the placental intervillous space. VAR2CSA is a large antigen incompatible with large scale recombinant protein expression. Vaccines based on sub-units encompassing the functionally constrained receptor-binding domains may, theoretically, circumvent polymorphisms, reduce the risk of escape-mutants and induce cross-reactive antibodies. However, the sub-unit composition and small differences in the borders, may lead to exposure of novel immuno-dominant antibody epitopes that lead to non-functional antibodies, and furthermore influence the folding, stability and yield of expression. Candidate antigens from the pre-clinical development expressed in High-Five insect cells using the baculovirus expression vector system were transitioned into the Drosophila Schneider-2 cell (S2) expression-system compliant with clinical development. The functional capacity of antibodies against antigens expressed in High-Five cells or in S2 cells was equivalent. This enabled an extensive down-selection of S2 insect cell-expressed antigens primarily encompassing the minimal CSA-binding region of VAR2CSA. In general, we found differential potency of inhibitory antibodies against antigens with the same borders but of different var2csa sequences. Likewise, we found that subtle size differences in antigens of the same sequence gave varying levels of inhibitory antibodies. The study shows that induction of a functional response against recombinant subunits of the VAR2CSA antigen is unpredictable, demonstrating the need for large-scale screening in order to identify antigens that induce a broadly strain-transcending antibody response.

AB - The disease caused by Plasmodium falciparum (Pf) involves different clinical manifestations that, cumulatively, kill hundreds of thousands every year. Placental malaria (PM) is one such manifestation in which Pf infected erythrocytes (IE) bind to chondroitin sulphate A (CSA) through expression of VAR2CSA, a parasite-derived antigen. Protection against PM is mediated by antibodies that inhibit binding of IE in the placental intervillous space. VAR2CSA is a large antigen incompatible with large scale recombinant protein expression. Vaccines based on sub-units encompassing the functionally constrained receptor-binding domains may, theoretically, circumvent polymorphisms, reduce the risk of escape-mutants and induce cross-reactive antibodies. However, the sub-unit composition and small differences in the borders, may lead to exposure of novel immuno-dominant antibody epitopes that lead to non-functional antibodies, and furthermore influence the folding, stability and yield of expression. Candidate antigens from the pre-clinical development expressed in High-Five insect cells using the baculovirus expression vector system were transitioned into the Drosophila Schneider-2 cell (S2) expression-system compliant with clinical development. The functional capacity of antibodies against antigens expressed in High-Five cells or in S2 cells was equivalent. This enabled an extensive down-selection of S2 insect cell-expressed antigens primarily encompassing the minimal CSA-binding region of VAR2CSA. In general, we found differential potency of inhibitory antibodies against antigens with the same borders but of different var2csa sequences. Likewise, we found that subtle size differences in antigens of the same sequence gave varying levels of inhibitory antibodies. The study shows that induction of a functional response against recombinant subunits of the VAR2CSA antigen is unpredictable, demonstrating the need for large-scale screening in order to identify antigens that induce a broadly strain-transcending antibody response.

U2 - 10.1371/journal.pone.0135406

DO - 10.1371/journal.pone.0135406

M3 - Journal article

C2 - 26327283

VL - 10

SP - e0135406

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 9

ER -

ID: 45788231