High efficacy of anti DBL4ɛ-VAR2CSA antibodies in inhibition of CSA-binding Plasmodium falciparum-infected erythrocytes from pregnant women

Magistrado, Pamela; Minja, Daniel T. R.; Doritchamou, Justin; Ndam, Nicaise Tuikue; John, Davis; Schmiegelow, Christentze; Massougbodji, Achille; Dahlbäck, Madeleine; Ditlev, Sisse B.; Pinto, Vera V.; Resende, Mafalda; Lusingu, John; Theander, Thor G.; Salanti, Ali; Nielsen, Morten A.

doi:10.1016/j.vaccine.2010.10.080

Cited by 48 publications

(50 citation statements)

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“…Nielsen et al, for example, expressed strain FCR3 DBL4ε in baculovirus cells and observed that rat antibodies against this domain were highly inhibitory of FCR3 IE binding to CSA but variably inhibited heterologous lab isolates (20). Magistrado et al tested FCR3 DBL4ε-based antisera against field isolates from Benin and Tanzania and observed inhibition between 45% and 60%, depending on the DBL4ε-based construct used for immunization (29). These data are similar in range to what we observed here.…”

Section: Discussionsupporting

confidence: 88%

“…DBL4ε domains from multiple strains have been implicated in the generation of antiadhesive antibodies (20,29), despite reports that strain FCR3 and 7G8-based DBL4ε domains do not bind to CSA (12,(36)(37)(38). These data indicate that the CSA-binding ability of a domain does not necessarily correlate with the induction of protective antibodies.…”

Section: Discussionmentioning

confidence: 88%

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Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue

et al. 2013

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c Placental malaria (PM) is characterized by infected erythrocytes (IEs) that selectively bind to chondroitin sulfate A (CSA) and sequester in placental tissue. Variant surface antigen 2-CSA (VAR2CSA), a Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) protein family member, is expressed on the surface of placental IEs and mediates adherence to CSA on the surface of syncytiotrophoblasts. This transmembrane protein contains 6 Duffy binding-like (DBL) domains which might contribute to the specific adhesive properties of IEs. Here, we use laboratory isolate 3D7 VAR2CSA DBL domains expressed in Escherichia coli to generate antibodies specific for this protein. Flow cytometry results showed that antibodies generated against DBL4, DBL5, DBL6, and tandem double domains of DBL4-DBL5 and DBL5-DBL6 all bind to placental parasite isolates and to lab strains selected for CSA binding but do not bind to children's parasites. Antisera to DBL4 and to DBL5 inhibit maternal IE binding to placental tissue in a manner comparable to that for plasma collected from multigravid women. These antibodies also inhibit binding to CSA of several field isolates derived from pregnant women, while antibodies to double domains do not enhance the functional immune response. These data support DBL4 and DBL5 as vaccine candidates for pregnancy malaria and demonstrate that E. coli is a feasible tool for the large-scale manufacture of a vaccine based on these VAR2CSA domains.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 88%

Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue

et al. 2013

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“…Recent studies reported that antibodies raised against other VAR2CSA domains also show a high degree of activity against maternal isolates. Rat IgG to DBL4-FCR3 inhibited 10 out of 13 parasite isolates collected from pregnant women at a level of 58 to 97% (38). Similarly, sera from mice immunized with the amino-terminal portion of VAR2CSA (NTS-DBL2X) inhibited the majority of maternal isolates under study to various degrees (39).…”

Section: Discussionmentioning

confidence: 94%

Multilaboratory Approach to Preclinical Evaluation of Vaccine Immunogens for Placental Malaria

et al. 2013

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f Pregnancy malaria is caused by Plasmodium falciparum-infected erythrocytes that adhere to the placental receptor chondroitin sulfate A (CSA) and sequester in the placenta; women become resistant to pregnancy malaria as they acquire antiadhesion antibodies that target surface proteins of placental parasites. VAR2CSA, a member of the P. falciparum EMP1 variant surface antigen family, is the leading candidate for a pregnancy malaria vaccine. Because VAR2CSA is a high-molecular-weight protein, a vaccine based on the full-length protein may not be feasible. An alternative approach has been to develop a vaccine targeting individual Duffy binding-like (DBL) domains. In this study, a consortium of laboratories under the Pregnancy Malaria Initiative compared the functional activity of antiadhesion antibodies elicited by different VAR2CSA domains and variants produced in prokaryotic and eukaryotic expression systems. Antisera were initially tested against laboratory lines of maternal parasites, and the most promising reagents were evaluated in the field against fresh placental parasite samples. Recombinant proteins expressed in Escherichia coli elicited antibody levels similar to those expressed in eukaryotic systems, as did the two allelic forms of the DBL4 and DBL5 domains. The procedures developed for this head-to-head comparison will be useful for future evaluation and down-selection of malaria vaccine immunogens.

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“…Importantly, high levels of antibodies against VAR2CSA are associated with protection from delivering LBW infants (21). Furthermore, naturally acquired antibodies to VAR2CSA can efficiently block IE adhesion to CSA (22,23). These antibodies are occasionally detected in nonpregnant patients (24,25); however, the prevalence and levels of anti-VAR2CSA antibodies are much lower than in pregnant women from the same region (24).…”

mentioning

confidence: 99%

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

et al. 2014

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iIn pregnancy, parity-dependent immunity is observed in response to placental infection with Plasmodium falciparum. Antibodies recognize the surface antigen, VAR2CSA, expressed on infected red blood cells and inhibit cytoadherence to the placental tissue. In most settings of malaria endemicity, antibodies against VAR2CSA are predominantly observed in multigravid women and infrequently in men, children, and nulligravid women. However, in Colombia, we detected antibodies against multiple constructs of VAR2CSA among men and children with acute P. falciparum and Plasmodium vivax infection. The majority of men and children (>60%) had high levels of IgGs against three recombinant domains of VAR2CSA: DBL5, DBL3X, and ID1-ID2. Surprisingly, these antibodies were observed only in pregnant women, men, and children exposed either to P. falciparum or to P. vivax. Moreover, the anti-VAR2CSA antibodies are of high avidity and efficiently inhibit adherence of infected red blood cells to chondroitin sulfate A in vitro, suggesting that they are specific and functional. These unexpected results suggest that there may be genotypic or phenotypic differences in the parasites of this region or in the host response to either P. falciparum or P. vivax infection outside pregnancy. These findings may hold significant clinical relevance to the pathophysiology and outcome of malaria infections in this region.

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High efficacy of anti DBL4ɛ-VAR2CSA antibodies in inhibition of CSA-binding Plasmodium falciparum-infected erythrocytes from pregnant women

Cited by 48 publications

References 47 publications

Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue

Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue

Multilaboratory Approach to Preclinical Evaluation of Vaccine Immunogens for Placental Malaria

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

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