Abstract
In pregnant women, Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen bind to chondroitin sulfate A in the placenta causing placental malaria. The binding site of VAR2CSA is present in the ID1-ID2a region. This study sought to determine if pregnant Cameroonian women naturally acquire antibodies to ID1-ID2a and if antibodies to ID1-ID2a correlate with absence of placental malaria at delivery. Antibody levels to full-length VAR2CSA and ID1-ID2a were measured in plasma samples from 745 pregnant Cameroonian women, 144 Cameroonian men, and 66 US subjects. IgM levels and IgG avidity to ID1-ID2a were also determined. As expected, antibodies to ID1-ID2a were absent in US controls. Although pregnant Cameroonian women developed increasing levels of antibodies to full-length VAR2CSA during pregnancy, no increase in either IgM or IgG to ID1-ID2a was observed. Surprisingly, no differences in antibody levels to ID1-ID2a were detected between Cameroonian men and pregnant women. For example, in rural settings only 8–9% of males had antibodies to full-length VAR2CSA, but 90–96% had antibodies to ID1-ID2a. In addition, no significant difference in the avidity of IgG to ID1-ID2a was found between pregnant women and Cameroonian men, and no correlation between antibody levels at delivery and absence of placental malaria was found. Thus, the response to ID1-ID2a was not pregnancy specific, but predominantly against cross-reactivity epitopes, which may have been induced by other PfEMP1 antigens, malarial antigens, or microbes. Currently, ID1-ID2a is a leading vaccine candidate, since it binds to the CSA with the same affinity as the full-length molecule and elicits binding-inhibitory antibodies in animals. Further studies are needed to determine if the presence of naturally acquired cross-reactive antibodies in women living in malaria endemic countries will alter the response to ID1-ID2a following vaccination with ID1-ID2a.
Highlights
P. falciparum-infected erythrocytes (IE) express the adhesion ligand VAR2CSA that binds to chondroitin sulfate A (CSA) on syncytiotrophoblasts lining the intervillous space (IVS) of the placenta [1,2,3,4]
IgG to full length VAR2CSA (FV2) increased during the course of pregnancy in Ngali II, as women became repeatedly infected with malaria and boosting occurred
Data were stratified by placental malaria (PM) status and no significant differences were found in Ab levels to either the 3D7 or FCR3 strain of ID1-ID2a between PM+ and PM- women at delivery, both in the city of Yaounde
Summary
P. falciparum-infected erythrocytes (IE) express the adhesion ligand VAR2CSA that binds to chondroitin sulfate A (CSA) on syncytiotrophoblasts lining the intervillous space (IVS) of the placenta [1,2,3,4]. Pathology resulting from PM increases the risk of maternal anemia and poor pregnancy outcomes, including low birth weight babies due to prematurity and intrauterine growth restriction [5,6]. Pregnant women produce antibodies (Ab) to VAR2CSA that inhibit the binding of IE to CSA in vitro [7,8], reduce maternal anemia [9], lower placental parasitemia at delivery [10,11], increase the length of gestation [12], and improve infant birth weight [12]. Data support the feasibility of a VAR2CSA-based vaccine for protecting pregnant women. The large size of the molecule makes it difficult to produce a vaccine using the entire molecule; extensive efforts are being made to identify the region(s) within the molecule that binds CSA
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