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Protective Antibodies against Placental Malaria and Poor Outcomes during Pregnancy, Benin - Volume 21, Number 5—May 2015 - Emerging Infectious Disease journal - CDC

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Protective Antibodies against Placental Malaria and Poor Outcomes during Pregnancy, Benin - Volume 21, Number 5—May 2015 - Emerging Infectious Disease journal - CDC





Volume 21, Number 5—May 2015

Research

Protective Antibodies against Placental Malaria and Poor Outcomes during Pregnancy, Benin

Nicaise Tuikue NdamComments to Author , Lise Denoeud-Ndam, Justin Doritchamou, Firmine Viwami, Ali Salanti, Morten A. Nielsen, Nadine Fievet, Achille Massougbodji, Adrian J.F. Luty, and Philippe Deloron
Author affiliations: Institut de Recherche pour le Développement, Paris, France (N. Tuikue Ndam, L. Denoeud-Ndam, J. Doritchamou, N. Fievet, A.J.F. Luty, P. Deloron)Pôle de Recherche et d’Enseignement Supérieur Sorbonne Paris Cité, Paris (N.Tuikue Ndam, N. Fievet, A.J.F. Luty, P. Deloron),Université d’Abomey-Calavi, Cotonou, Benin (F. Viwami, A. Massougbodji, A.J.F. Luty)University of Copenhagen, Copenhagen, Denmark (A. Salanti, M.A. Nielsen)

Abstract

Placental malaria is caused by Plasmodium falciparum–infected erythrocytes that bind to placental tissue. Binding is mediated by VAR2CSA, a parasite antigen coded by the var gene, which interacts with chondroitin sulfate A (CSA). Consequences include maternal anemia and fetal growth retardation. Antibody-mediated immunity to placental malaria is acquired during successive pregnancies, but the target of VAR2CSA-specific protective antibodies is unclear. We assessed VAR2CSA-specific antibodies in pregnant women and analyzed their relationships with protection against placental infection, preterm birth, and low birthweight. Antibody responses to the N-terminal region of VAR2CSA during early pregnancy were associated with reduced risks for infections and low birthweight. Among women infected during pregnancy, an increase in CSA binding inhibition was associated with reduced risks for placental infection, preterm birth, and low birthweight. These data suggest that antibodies against VAR2CSA N-terminal region mediate immunity to placental malaria and associated outcomes. Our results validate current vaccine development efforts with VAR2CSA N-terminal constructs.
Tissue sequestration of Plasmodium falciparum–infected erythrocytes drives malaria-related pathologic changes (1). Tissue sequestration is primarily mediated by members of the parasite variant antigen family of P. falciparumerythrocyte membrane protein 1, which is expressed on the membrane of infected erythrocytes. These proteins display extensive antigenic variation, concurrently changing receptor recognition, and tissue tropism of infected erythrocytes (2). Accumulation of infected erythrocytes in placental intervillous spaces characterizes malaria during pregnancy (3). This sequestration of infected erythrocytes results in maternal anemia and low birthweight (LBW) (46), as well as consequences for child health (710).
Sequestration of infected erythrocytes in the placenta is mediated by VAR2CSA, the P. falciparum erythrocyte membrane protein 1 variant that binds to chondroitin sulfate A (CSA) on the syncytiotrophoblast (11,12). VAR2CSA is a multidomain protein (≈350 kDa). Acquisition of antibodies against VAR2CSA occurs during pregnancy after exposure to infected erythrocytes sequestering in the placenta. Concentrations of these antibodies and those of antibodies that inhibit binding of infected erythrocytes to CSA (13,14) increase with parity. Furthermore, women with VAR2CSA-specific antibodies give birth to babies with higher birthweights (15). VAR2CSA-expressing parasites are the primary cause of placental malaria (16,17), which suggests that parasites can escape preexisting immunity (i.e., that naturally acquired immunity against preerythrocytic or erythrocytic stages of malaria does not protect against this syndrome).
The demonstration that parasites that have the var2csa knockout gene irreversibly lose the ability to adhere to CSA (18), as well as the ability of VAR2CSA to induce antibodies that inhibit adherence of placental infective erythrocytes to CSA in vitro, strongly argue for use of VAR2CSA as a vaccine against placental malaria. However, VAR2CSA-based vaccine research is challenged by the size and polymorphism of this protein and requires identification of smaller functional domains that combine an ability to induce strain-transcending antibody responses with a facility of production in a recombinant protein form. Therefore, identifying the region of VAR2CSA that induces antibodies associated with protection in multigravid women in malaria-endemic regions is a priority. The VAR2CSA critical CSA binding site is located in its N-terminal region (1921), but the characteristics of naturally acquired antibodies against this region remain to be defined.




The Strategies to Prevent Pregnancy-associated Malaria Project, a cohort study of pregnant women enrolled early in pregnancy and followed up until delivery, was conducted during 2008–2011 in Comé in southern Benin. In this substudy, we assessed the effect of antibody response to placental infected erythrocytes, measured early in pregnancy and at delivery, on major pregnancy outcomes.

Dr. Tuikue Ndam is a senior research officer the Mother and Child Health in the Tropics Laboratory Branch of the Institut de Recherche pour le Développement, Paris, France. His research interests focus on using molecular and cell biology approaches to identify critical biological factors that control pathogenesis of P. falciparum infections.

Acknowledgments


We thank the women for participating in the study; the medical staffs of Akodeha, Come Central, and Ouedeme Pedah Health Centers for making valuable contributions; Thomas Clausen for producing FV2 recombinant protein; and Valérie Briand for providing ultrasound data.
This study was supported by the European 7th Framework Program (contract no. 200889 for the Small & Medium Scale Collaborative Project Strategies To Prevent Pregnancy-Associated Malaria). J. D. was supported by a PhD studentship from Agence Inter-établissements de Recherche pour le Dévelopement.
N.T.N., P.D., and A.J.F.L. conceived and designed the study; J.D., F.V., and N.T.N. conducted laboratory experiments; L.D.-N. and N.T.N. analyzed data; N.F., M.A.N., A.S., and A.M. provided reagents, materials, and analysis tools; J.D., L.D., A.J.F.L., P.D., and N.T.N drafted and finalized the manuscript.

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Figures

Tables

Suggested citation for this article: Tuikue Ndam N, 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 May [date cited]. http://dx.doi.org/10.3201/eid2105.141626
DOI: 10.3201/eid2105.141626

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