Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants

Lea Barfod; Tina Dobrilovic; Pamela Magistrado; Pongsak Khunrae; Firmine Viwami; Jonas Bruun; Madeleine Dahlbäck; Nadia L Bernasconi; Michal Fried; Davis John; Patrick E Duffy; Ali Salanti; Antonio Lanzavecchia; Chwee Teck Lim; Nicaise Tuikue Ndam; Matthew K Higgins; Lars Hviid

doi:10.4049/jimmunol.1002390

Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants

Lea Barfod, Tina Dobrilovic, Pamela Magistrado, Pongsak Khunrae, Firmine Viwami, Jonas Bruun, Madeleine Dahlbäck, Nadia L Bernasconi, Michal Fried, Davis John, Patrick E Duffy, Ali Salanti, Antonio Lanzavecchia, Chwee Teck Lim, Nicaise Tuikue Ndam, Matthew K Higgins, Lars Hviid

43 Citations (Scopus)

Abstract

Acquired protection from Plasmodium falciparum placental malaria, a major cause of maternal, fetal, and infant morbidity, is mediated by IgG specific for the P. falciparum erythrocyte membrane protein 1 variant VAR2CSA. This protein enables adhesion of P. falciparum-infected erythrocytes to chondroitin sulfate A in the intervillous space. Although interclonal variation of the var2csa gene is lower than that among var genes in general, VAR2CSA-specific Abs appear to target mainly polymorphic epitopes. This has raised doubts about the feasibility of VAR2CSA-based vaccines. We used eight human monoclonal IgG Abs from affinity-matured memory B cells of P. falciparum-exposed women to study interclonal variation and functional importance of Ab epitopes among placental and peripheral parasites from East and West Africa. Most placental P. falciparum isolates were labeled by several mAbs, whereas peripheral isolates from children were essentially nonreactive. The mAb reactivity of peripheral isolates from pregnant women indicated that some were placental, whereas others had alternative sequestration foci. Most of the mAbs were comparable in their reactivity with bound infected erythrocytes (IEs) and recombinant VAR2CSA and interfered with IE and/or VAR2CSA binding to chondroitin sulfate A. Pair-wise mAb combinations were more inhibitory than single mAbs, and all of the mAbs together was the most efficient combination. Each mAb could opsonize IEs for phagocytosis, and a combination of the eight mAbs caused phagocytosis similar to that of plasma IgG-opsonized IEs. We conclude that functionally important Ab epitopes are shared by the majority of polymorphic VAR2CSA variants, which supports the feasibility of VAR2CSA-based vaccines against placental malaria.

Original language	English
Journal	Journal of Immunology
Volume	185
Issue number	12
Pages (from-to)	7553-61
Number of pages	9
ISSN	0022-1767
DOIs	https://doi.org/10.4049/jimmunol.1002390
Publication status	Published - 15 Dec 2010

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Barfod, L., Dobrilovic, T., Magistrado, P., Khunrae, P., Viwami, F., Bruun, J., Dahlbäck, M., Bernasconi, N. L., Fried, M., John, D., Duffy, P. E., Salanti, A., Lanzavecchia, A., Lim, C. T., Ndam, N. T., Higgins, M. K., & Hviid, L. (2010). Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants. Journal of Immunology, 185(12), 7553-61. https://doi.org/10.4049/jimmunol.1002390

Barfod, L, Dobrilovic, T, Magistrado, P, Khunrae, P, Viwami, F, Bruun, J, Dahlbäck, M, Bernasconi, NL, Fried, M, John, D, Duffy, PE, Salanti, A, Lanzavecchia, A, Lim, CT, Ndam, NT, Higgins, MK & Hviid, L 2010, 'Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants', Journal of Immunology, vol. 185, no. 12, pp. 7553-61. https://doi.org/10.4049/jimmunol.1002390

@article{f8ebb0a7aead4fe2a58d5d0b1b7522e8,

title = "Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants",

abstract = "Acquired protection from Plasmodium falciparum placental malaria, a major cause of maternal, fetal, and infant morbidity, is mediated by IgG specific for the P. falciparum erythrocyte membrane protein 1 variant VAR2CSA. This protein enables adhesion of P. falciparum-infected erythrocytes to chondroitin sulfate A in the intervillous space. Although interclonal variation of the var2csa gene is lower than that among var genes in general, VAR2CSA-specific Abs appear to target mainly polymorphic epitopes. This has raised doubts about the feasibility of VAR2CSA-based vaccines. We used eight human monoclonal IgG Abs from affinity-matured memory B cells of P. falciparum-exposed women to study interclonal variation and functional importance of Ab epitopes among placental and peripheral parasites from East and West Africa. Most placental P. falciparum isolates were labeled by several mAbs, whereas peripheral isolates from children were essentially nonreactive. The mAb reactivity of peripheral isolates from pregnant women indicated that some were placental, whereas others had alternative sequestration foci. Most of the mAbs were comparable in their reactivity with bound infected erythrocytes (IEs) and recombinant VAR2CSA and interfered with IE and/or VAR2CSA binding to chondroitin sulfate A. Pair-wise mAb combinations were more inhibitory than single mAbs, and all of the mAbs together was the most efficient combination. Each mAb could opsonize IEs for phagocytosis, and a combination of the eight mAbs caused phagocytosis similar to that of plasma IgG-opsonized IEs. We conclude that functionally important Ab epitopes are shared by the majority of polymorphic VAR2CSA variants, which supports the feasibility of VAR2CSA-based vaccines against placental malaria.",

author = "Lea Barfod and Tina Dobrilovic and Pamela Magistrado and Pongsak Khunrae and Firmine Viwami and Jonas Bruun and Madeleine Dahlb{\"a}ck and Bernasconi, {Nadia L} and Michal Fried and Davis John and Duffy, {Patrick E} and Ali Salanti and Antonio Lanzavecchia and Lim, {Chwee Teck} and Ndam, {Nicaise Tuikue} and Higgins, {Matthew K} and Lars Hviid",

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doi = "10.4049/jimmunol.1002390",

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T1 - Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants

AU - Barfod, Lea

AU - Dobrilovic, Tina

AU - Magistrado, Pamela

AU - Khunrae, Pongsak

AU - Viwami, Firmine

AU - Bruun, Jonas

AU - Dahlbäck, Madeleine

AU - Bernasconi, Nadia L

AU - Fried, Michal

AU - John, Davis

AU - Duffy, Patrick E

AU - Salanti, Ali

AU - Lanzavecchia, Antonio

AU - Lim, Chwee Teck

AU - Ndam, Nicaise Tuikue

AU - Higgins, Matthew K

AU - Hviid, Lars

PY - 2010/12/15

Y1 - 2010/12/15

N2 - Acquired protection from Plasmodium falciparum placental malaria, a major cause of maternal, fetal, and infant morbidity, is mediated by IgG specific for the P. falciparum erythrocyte membrane protein 1 variant VAR2CSA. This protein enables adhesion of P. falciparum-infected erythrocytes to chondroitin sulfate A in the intervillous space. Although interclonal variation of the var2csa gene is lower than that among var genes in general, VAR2CSA-specific Abs appear to target mainly polymorphic epitopes. This has raised doubts about the feasibility of VAR2CSA-based vaccines. We used eight human monoclonal IgG Abs from affinity-matured memory B cells of P. falciparum-exposed women to study interclonal variation and functional importance of Ab epitopes among placental and peripheral parasites from East and West Africa. Most placental P. falciparum isolates were labeled by several mAbs, whereas peripheral isolates from children were essentially nonreactive. The mAb reactivity of peripheral isolates from pregnant women indicated that some were placental, whereas others had alternative sequestration foci. Most of the mAbs were comparable in their reactivity with bound infected erythrocytes (IEs) and recombinant VAR2CSA and interfered with IE and/or VAR2CSA binding to chondroitin sulfate A. Pair-wise mAb combinations were more inhibitory than single mAbs, and all of the mAbs together was the most efficient combination. Each mAb could opsonize IEs for phagocytosis, and a combination of the eight mAbs caused phagocytosis similar to that of plasma IgG-opsonized IEs. We conclude that functionally important Ab epitopes are shared by the majority of polymorphic VAR2CSA variants, which supports the feasibility of VAR2CSA-based vaccines against placental malaria.

AB - Acquired protection from Plasmodium falciparum placental malaria, a major cause of maternal, fetal, and infant morbidity, is mediated by IgG specific for the P. falciparum erythrocyte membrane protein 1 variant VAR2CSA. This protein enables adhesion of P. falciparum-infected erythrocytes to chondroitin sulfate A in the intervillous space. Although interclonal variation of the var2csa gene is lower than that among var genes in general, VAR2CSA-specific Abs appear to target mainly polymorphic epitopes. This has raised doubts about the feasibility of VAR2CSA-based vaccines. We used eight human monoclonal IgG Abs from affinity-matured memory B cells of P. falciparum-exposed women to study interclonal variation and functional importance of Ab epitopes among placental and peripheral parasites from East and West Africa. Most placental P. falciparum isolates were labeled by several mAbs, whereas peripheral isolates from children were essentially nonreactive. The mAb reactivity of peripheral isolates from pregnant women indicated that some were placental, whereas others had alternative sequestration foci. Most of the mAbs were comparable in their reactivity with bound infected erythrocytes (IEs) and recombinant VAR2CSA and interfered with IE and/or VAR2CSA binding to chondroitin sulfate A. Pair-wise mAb combinations were more inhibitory than single mAbs, and all of the mAbs together was the most efficient combination. Each mAb could opsonize IEs for phagocytosis, and a combination of the eight mAbs caused phagocytosis similar to that of plasma IgG-opsonized IEs. We conclude that functionally important Ab epitopes are shared by the majority of polymorphic VAR2CSA variants, which supports the feasibility of VAR2CSA-based vaccines against placental malaria.

U2 - 10.4049/jimmunol.1002390

DO - 10.4049/jimmunol.1002390

M3 - Journal article

C2 - 21078904

SN - 0022-1767

VL - 185

SP - 7553

EP - 7561

JO - Journal of Immunology

JF - Journal of Immunology

IS - 12

ER -

Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants

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