Skip to main content
Top
Published in: Malaria Journal 1/2018

Open Access 01-12-2018 | Research

Antibody levels to recombinant VAR2CSA domains vary with Plasmodium falciparum parasitaemia, gestational age, and gravidity, but do not predict pregnancy outcomes

Authors: Michal Fried, Jonathan D. Kurtis, Bruce Swihart, Robert Morrison, Sunthorn Pond-Tor, Amadou Barry, Youssoufa Sidibe, Sekouba Keita, Almahamoudou Mahamar, Naissem Andemel, Oumar Attaher, Adama B. Dembele, Kadidia B. Cisse, Bacary S. Diarra, Moussa B. Kanoute, David L. Narum, Alassane Dicko, Patrick E. Duffy

Published in: Malaria Journal | Issue 1/2018

Login to get access

Abstract

Background

Maternal malaria is a tropical scourge associated with poor pregnancy outcomes. Women become resistant to Plasmodium falciparum pregnancy malaria as they acquire antibodies to the variant surface antigen VAR2CSA, a leading vaccine candidate. Because malaria infection may increase VAR2CSA antibody levels and thereby confound analyses of immune protection, gravidity-dependent changes in antibody levels during and after infection, and the effect of VAR2CSA antibodies on pregnancy outcomes were evaluated.

Methods

Pregnant women enrolled in a longitudinal cohort study of mother-infant pairs in Ouelessebougou, Mali provided plasma samples at enrollment, gestational week 30–32, and delivery. Antibody levels to VAR2CSA domains were measured using a multiplex bead-based assay.

Results

Antibody levels to VAR2CSA were higher in multigravidae than primigravidae. Malaria infection was associated with increased antibody levels to VAR2CSA domains. In primigravidae but not in secundigravidae or multigravidae, antibodies levels sharply declined after an infection. A relationship between any VAR2CSA antibody specificity and protection from adverse pregnancy outcomes was not detected.

Conclusions

During malaria infection, primigravidae acquire short-lived antibodies. The lack of an association between VAR2CSA domain antibody reactivity and improved pregnancy outcomes suggests that the recombinant proteins may not present native epitopes targeted by protective antibodies.
Appendix
Available only for authorised users
Literature
1.
go back to reference Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007;7:93–104.CrossRefPubMed Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007;7:93–104.CrossRefPubMed
2.
go back to reference Fried M, Duffy PE. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science. 1996;272:1502–4.CrossRefPubMed Fried M, Duffy PE. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science. 1996;272:1502–4.CrossRefPubMed
3.
go back to reference Salanti A, Dahlback M, Turner L, Nielsen MA, Barfod L, Magistrado P, et al. Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J Exp Med. 2004;200:1197–203.CrossRefPubMedPubMedCentral Salanti A, Dahlback M, Turner L, Nielsen MA, Barfod L, Magistrado P, et al. Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J Exp Med. 2004;200:1197–203.CrossRefPubMedPubMedCentral
4.
go back to reference Tuikue Ndam NG, Salanti A, Bertin G, Dahlback M, Fievet N, Turner L, et al. High level of var2csa transcription by Plasmodium falciparum isolated from the placenta. J Infect Dis. 2005;192:331–5.CrossRefPubMed Tuikue Ndam NG, Salanti A, Bertin G, Dahlback M, Fievet N, Turner L, et al. High level of var2csa transcription by Plasmodium falciparum isolated from the placenta. J Infect Dis. 2005;192:331–5.CrossRefPubMed
5.
go back to reference Barfod L, Dobrilovic T, Magistrado P, Khunrae P, Viwami F, Bruun J, et al. Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants. J Immunol. 2010;185:7553–61.CrossRefPubMedPubMedCentral Barfod L, Dobrilovic T, Magistrado P, Khunrae P, Viwami F, Bruun J, et al. Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants. J Immunol. 2010;185:7553–61.CrossRefPubMedPubMedCentral
7.
go back to reference Fried M, Nosten F, Brockman A, Brabin BJ, Duffy PE. Maternal antibodies block malaria. Nature. 1998;395:851–2.CrossRefPubMed Fried M, Nosten F, Brockman A, Brabin BJ, Duffy PE. Maternal antibodies block malaria. Nature. 1998;395:851–2.CrossRefPubMed
9.
go back to reference Oleinikov AV, Rossnagle E, Francis S, Mutabingwa TK, Fried M, Duffy PE. Effects of sex, parity, and sequence variation on seroreactivity to candidate pregnancy malaria vaccine antigens. J Infect Dis. 2007;196:155–64.CrossRefPubMed Oleinikov AV, Rossnagle E, Francis S, Mutabingwa TK, Fried M, Duffy PE. Effects of sex, parity, and sequence variation on seroreactivity to candidate pregnancy malaria vaccine antigens. J Infect Dis. 2007;196:155–64.CrossRefPubMed
10.
go back to reference Brolin KJ, Persson KE, Wahlgren M, Rogerson SJ, Chen Q. Differential recognition of P. falciparum VAR2CSA domains by naturally acquired antibodies in pregnant women from a malaria endemic area. PLoS ONE. 2010;5:e9230.CrossRefPubMedPubMedCentral Brolin KJ, Persson KE, Wahlgren M, Rogerson SJ, Chen Q. Differential recognition of P. falciparum VAR2CSA domains by naturally acquired antibodies in pregnant women from a malaria endemic area. PLoS ONE. 2010;5:e9230.CrossRefPubMedPubMedCentral
11.
go back to reference Mayor A, Kumar U, Bardaji A, Gupta P, Jimenez A, Hamad A, et al. Improved pregnancy outcomes in women exposed to malaria with high antibody levels against Plasmodium falciparum. J Infect Dis. 2013;207:1664–74.CrossRefPubMed Mayor A, Kumar U, Bardaji A, Gupta P, Jimenez A, Hamad A, et al. Improved pregnancy outcomes in women exposed to malaria with high antibody levels against Plasmodium falciparum. J Infect Dis. 2013;207:1664–74.CrossRefPubMed
12.
go back to reference Ndam NT, Denoeud-Ndam L, Doritchamou J, Viwami F, Salanti A, Nielsen MA, et al. Protective antibodies against placental malaria and poor outcomes during pregnancy, Benin. Emerg Infect Dis. 2015;21:813–23.CrossRefPubMedPubMedCentral Ndam NT, Denoeud-Ndam L, Doritchamou J, Viwami F, Salanti A, Nielsen MA, et al. Protective antibodies against placental malaria and poor outcomes during pregnancy, Benin. Emerg Infect Dis. 2015;21:813–23.CrossRefPubMedPubMedCentral
13.
go back to reference Dechavanne S, Srivastava A, Gangnard S, Nunes-Silva S, Dechavanne C, Fievet N, et al. Parity-dependent recognition of DBL1X-3X suggests an important role of the VAR2CSA high-affinity CSA-binding region in the development of the humoral response against placental malaria. Infect Immun. 2015;83:2466–74.CrossRefPubMedPubMedCentral Dechavanne S, Srivastava A, Gangnard S, Nunes-Silva S, Dechavanne C, Fievet N, et al. Parity-dependent recognition of DBL1X-3X suggests an important role of the VAR2CSA high-affinity CSA-binding region in the development of the humoral response against placental malaria. Infect Immun. 2015;83:2466–74.CrossRefPubMedPubMedCentral
14.
go back to reference Tutterrow YL, Avril M, Singh K, Long CA, Leke RJ, Sama G, et al. High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission. Infect Immun. 2012;80:1479–90.CrossRefPubMedPubMedCentral Tutterrow YL, Avril M, Singh K, Long CA, Leke RJ, Sama G, et al. High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission. Infect Immun. 2012;80:1479–90.CrossRefPubMedPubMedCentral
15.
go back to reference Tutterrow YL, Salanti A, Avril M, Smith JD, Pagano IS, Ako S, et al. High avidity antibodies to full-length VAR2CSA correlate with absence of placental malaria. PLoS ONE. 2012;7:e40049.CrossRefPubMedPubMedCentral Tutterrow YL, Salanti A, Avril M, Smith JD, Pagano IS, Ako S, et al. High avidity antibodies to full-length VAR2CSA correlate with absence of placental malaria. PLoS ONE. 2012;7:e40049.CrossRefPubMedPubMedCentral
16.
go back to reference Babakhanyan A, Fang R, Wey A, Salanti A, Sama G, Efundem C, et al. Comparison of the specificity of antibodies to VAR2CSA in Cameroonian multigravidae with and without placental malaria: a retrospective case-control study. Malar J. 2015;14:480.CrossRefPubMedPubMedCentral Babakhanyan A, Fang R, Wey A, Salanti A, Sama G, Efundem C, et al. Comparison of the specificity of antibodies to VAR2CSA in Cameroonian multigravidae with and without placental malaria: a retrospective case-control study. Malar J. 2015;14:480.CrossRefPubMedPubMedCentral
17.
go back to reference Ofori MF, Dodoo D, Staalsoe T, Kurtzhals JA, Koram K, Theander TG, et al. Malaria-induced acquisition of antibodies to Plasmodium falciparum variant surface antigens. Infect Immun. 2002;70:2982–8.CrossRefPubMedPubMedCentral Ofori MF, Dodoo D, Staalsoe T, Kurtzhals JA, Koram K, Theander TG, et al. Malaria-induced acquisition of antibodies to Plasmodium falciparum variant surface antigens. Infect Immun. 2002;70:2982–8.CrossRefPubMedPubMedCentral
18.
go back to reference Snounou G, Viriyakosol S, Zhu XP, Jarra W, Pinheiro L, do Rosario VET, et al. High sensitivity of detection of human malaria parasites by the use of nested polymerase chain reaction. Mol Biochem Parasitol. 1993;61:315–20.CrossRefPubMed Snounou G, Viriyakosol S, Zhu XP, Jarra W, Pinheiro L, do Rosario VET, et al. High sensitivity of detection of human malaria parasites by the use of nested polymerase chain reaction. Mol Biochem Parasitol. 1993;61:315–20.CrossRefPubMed
19.
go back to reference Schmiegelow C, Scheike T, Oesterholt M, Minja D, Pehrson C, Magistrado P, et al. Development of a fetal weight chart using serial trans-abdominal ultrasound in an East African population: a longitudinal observational study. PLoS ONE. 2012;7:e44773.CrossRefPubMedPubMedCentral Schmiegelow C, Scheike T, Oesterholt M, Minja D, Pehrson C, Magistrado P, et al. Development of a fetal weight chart using serial trans-abdominal ultrasound in an East African population: a longitudinal observational study. PLoS ONE. 2012;7:e44773.CrossRefPubMedPubMedCentral
20.
go back to reference Obiakor H, Avril M, Macdonald NJ, Srinivasan P, Reiter K, Anderson C, et al. Identification of VAR2CSA domain-specific inhibitory antibodies of the Plasmodium falciparum erythrocyte membrane protein 1 using a novel flow cytometry assay. Clin Vaccine Immunol. 2013;20:433–42.CrossRefPubMedPubMedCentral Obiakor H, Avril M, Macdonald NJ, Srinivasan P, Reiter K, Anderson C, et al. Identification of VAR2CSA domain-specific inhibitory antibodies of the Plasmodium falciparum erythrocyte membrane protein 1 using a novel flow cytometry assay. Clin Vaccine Immunol. 2013;20:433–42.CrossRefPubMedPubMedCentral
21.
go back to reference Salanti A, Resende M, Ditlev SB, Pinto VV, Dahlback M, Andersen G, et al. Several domains from VAR2CSA can induce Plasmodium falciparum adhesion-blocking antibodies. Malar J. 2010;9:11.CrossRefPubMedPubMedCentral Salanti A, Resende M, Ditlev SB, Pinto VV, Dahlback M, Andersen G, et al. Several domains from VAR2CSA can induce Plasmodium falciparum adhesion-blocking antibodies. Malar J. 2010;9:11.CrossRefPubMedPubMedCentral
22.
go back to reference Doritchamou JY, Herrera R, Aebig JA, Morrison R, Nguyen V, Reiter K, et al. VAR2CSA domain-specific analysis of naturally acquired functional antibodies to Plasmodium falciparum placental malaria. J Infect Dis. 2016;214:577–86.CrossRefPubMedPubMedCentral Doritchamou JY, Herrera R, Aebig JA, Morrison R, Nguyen V, Reiter K, et al. VAR2CSA domain-specific analysis of naturally acquired functional antibodies to Plasmodium falciparum placental malaria. J Infect Dis. 2016;214:577–86.CrossRefPubMedPubMedCentral
23.
go back to reference Cham GK, Turner L, Lusingu J, Vestergaard L, Mmbando BP, Kurtis JD, et al. Sequential, ordered acquisition of antibodies to Plasmodium falciparum erythrocyte membrane protein 1 domains. J Immunol. 2009;183:3356–63.CrossRefPubMed Cham GK, Turner L, Lusingu J, Vestergaard L, Mmbando BP, Kurtis JD, et al. Sequential, ordered acquisition of antibodies to Plasmodium falciparum erythrocyte membrane protein 1 domains. J Immunol. 2009;183:3356–63.CrossRefPubMed
24.
25.
go back to reference Staalsoe T, Megnekou R, Fievet N, Ricke CH, Zornig HD, Leke R, et al. Acquisition and decay of antibodies to pregnancy-associated variant antigens on the surface of Plasmodium falciparum-infected erythrocytes that protect against placental parasitemia. J Infect Dis. 2001;84:618–26.CrossRef Staalsoe T, Megnekou R, Fievet N, Ricke CH, Zornig HD, Leke R, et al. Acquisition and decay of antibodies to pregnancy-associated variant antigens on the surface of Plasmodium falciparum-infected erythrocytes that protect against placental parasitemia. J Infect Dis. 2001;84:618–26.CrossRef
26.
go back to reference Ampomah P, Stevenson L, Ofori MF, Barfod L, Hviid L. Kinetics of B cell responses to Plasmodium falciparum erythrocyte membrane protein 1 in Ghanaian women naturally exposed to malaria parasites. J Immunol. 2014;192:5236–44.CrossRefPubMedPubMedCentral Ampomah P, Stevenson L, Ofori MF, Barfod L, Hviid L. Kinetics of B cell responses to Plasmodium falciparum erythrocyte membrane protein 1 in Ghanaian women naturally exposed to malaria parasites. J Immunol. 2014;192:5236–44.CrossRefPubMedPubMedCentral
28.
go back to reference Duffy PE, Fried M. Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are associated with increased birth weight and the gestational age of newborns. Infect Immun. 2003;71:6620–3.CrossRefPubMedPubMedCentral Duffy PE, Fried M. Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are associated with increased birth weight and the gestational age of newborns. Infect Immun. 2003;71:6620–3.CrossRefPubMedPubMedCentral
29.
go back to reference Elliott SR, Kuns RD, Good MF. Heterologous immunity in the absence of variant-specific antibodies after exposure to subpatent infection with blood-stage malaria. Infect Immun. 2005;73:2478–85.CrossRefPubMedPubMedCentral Elliott SR, Kuns RD, Good MF. Heterologous immunity in the absence of variant-specific antibodies after exposure to subpatent infection with blood-stage malaria. Infect Immun. 2005;73:2478–85.CrossRefPubMedPubMedCentral
30.
go back to reference Fowkes FJ, McGready R, Cross NJ, Hommel M, Simpson JA, Elliott SR, et al. New insights into acquisition, boosting, and longevity of immunity to malaria in pregnant women. J Infect Dis. 2012;206:1612–21.CrossRefPubMedPubMedCentral Fowkes FJ, McGready R, Cross NJ, Hommel M, Simpson JA, Elliott SR, et al. New insights into acquisition, boosting, and longevity of immunity to malaria in pregnant women. J Infect Dis. 2012;206:1612–21.CrossRefPubMedPubMedCentral
31.
go back to reference Ampomah P, Stevenson L, Ofori MF, Barfod L, Hviid L. B-cell responses to pregnancy-restricted and -unrestricted Plasmodium falciparum erythrocyte membrane protein 1 antigens in Ghanaian women naturally exposed to malaria parasites. Infect Immun. 2014;82:1860–71.CrossRefPubMedPubMedCentral Ampomah P, Stevenson L, Ofori MF, Barfod L, Hviid L. B-cell responses to pregnancy-restricted and -unrestricted Plasmodium falciparum erythrocyte membrane protein 1 antigens in Ghanaian women naturally exposed to malaria parasites. Infect Immun. 2014;82:1860–71.CrossRefPubMedPubMedCentral
32.
go back to reference Chene A, Houard S, Nielsen MA, Hundt S, D’Alessio F, Sirima SB, et al. Clinical development of placental malaria vaccines and immunoassays harmonization: a workshop report. Malar J. 2016;15:476.CrossRefPubMedPubMedCentral Chene A, Houard S, Nielsen MA, Hundt S, D’Alessio F, Sirima SB, et al. Clinical development of placental malaria vaccines and immunoassays harmonization: a workshop report. Malar J. 2016;15:476.CrossRefPubMedPubMedCentral
33.
go back to reference Srivastava A, Gangnard S, Dechavanne S, Amirat F, Lewit Bentley A, Bentley GA, et al. Var2CSA minimal CSA binding region is located within the N-terminal region. PLoS ONE. 2011;6:e20270.CrossRefPubMedPubMedCentral Srivastava A, Gangnard S, Dechavanne S, Amirat F, Lewit Bentley A, Bentley GA, et al. Var2CSA minimal CSA binding region is located within the N-terminal region. PLoS ONE. 2011;6:e20270.CrossRefPubMedPubMedCentral
34.
go back to reference Clausen TM, Christoffersen S, Dahlback M, Langkilde AE, Jensen KE, Resende M, et al. Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate A in placental malaria. J Biol Chem. 2012;287:23332–45.CrossRefPubMedPubMedCentral Clausen TM, Christoffersen S, Dahlback M, Langkilde AE, Jensen KE, Resende M, et al. Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate A in placental malaria. J Biol Chem. 2012;287:23332–45.CrossRefPubMedPubMedCentral
35.
go back to reference Bigey P, Gnidehou S, Doritchamou J, Quiviger M, Viwami F, Couturier A, et al. The NTS-DBL2X region of VAR2CSA induces cross-reactive antibodies that inhibit adhesion of several Plasmodium falciparum isolates to chondroitin sulfate A. J Infect Dis. 2011;204:1125–33.CrossRefPubMed Bigey P, Gnidehou S, Doritchamou J, Quiviger M, Viwami F, Couturier A, et al. The NTS-DBL2X region of VAR2CSA induces cross-reactive antibodies that inhibit adhesion of several Plasmodium falciparum isolates to chondroitin sulfate A. J Infect Dis. 2011;204:1125–33.CrossRefPubMed
36.
go back to reference Nielsen MA, Resende M, de Jongh WA, Ditlev SB, Mordmuller B, Houard S, et al. 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. PLoS ONE. 2015;10:e0135406.CrossRefPubMedPubMedCentral Nielsen MA, Resende M, de Jongh WA, Ditlev SB, Mordmuller B, Houard S, et al. 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. PLoS ONE. 2015;10:e0135406.CrossRefPubMedPubMedCentral
37.
go back to reference Babakhanyan A, Leke RG, Salanti A, Bobbili N, Gwanmesia P, Leke RJ, et al. The antibody response of pregnant Cameroonian women to VAR2CSA ID1-ID2a, a small recombinant protein containing the CSA-binding site. PLoS ONE. 2014;9:e88173.CrossRefPubMedPubMedCentral Babakhanyan A, Leke RG, Salanti A, Bobbili N, Gwanmesia P, Leke RJ, et al. The antibody response of pregnant Cameroonian women to VAR2CSA ID1-ID2a, a small recombinant protein containing the CSA-binding site. PLoS ONE. 2014;9:e88173.CrossRefPubMedPubMedCentral
Metadata
Title
Antibody levels to recombinant VAR2CSA domains vary with Plasmodium falciparum parasitaemia, gestational age, and gravidity, but do not predict pregnancy outcomes
Authors
Michal Fried
Jonathan D. Kurtis
Bruce Swihart
Robert Morrison
Sunthorn Pond-Tor
Amadou Barry
Youssoufa Sidibe
Sekouba Keita
Almahamoudou Mahamar
Naissem Andemel
Oumar Attaher
Adama B. Dembele
Kadidia B. Cisse
Bacary S. Diarra
Moussa B. Kanoute
David L. Narum
Alassane Dicko
Patrick E. Duffy
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2018
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-018-2258-9

Other articles of this Issue 1/2018

Malaria Journal 1/2018 Go to the issue