A conserved epitope in VAR2CSA is targeted by a cross-reactive antibody originating from Plasmodium vivax Duffy binding protein
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During Plasmodium falciparum infection in pregnancy, VAR2CSA is expressed on the surface of infected erythrocytes (IEs) and mediates their sequestration in the placenta. As a result, antibodies to VAR2CSA are largely restricted to women who were infected during pregnancy. However, we discovered that VAR2CSA antibodies can also be elicited by P. vivax Duffy binding protein (PvDBP). We proposed that infection with P. vivax in non-pregnant individuals can generate antibodies that cross-react with VAR2CSA. To better understand the specificity of these antibodies, we took advantage of a mouse monoclonal antibody (3D10) raised against PvDBP that cross-reacts with VAR2CSA and identified the epitopes targeted by this antibody. We screened two peptide arrays that span the ectodomain of VAR2CSA from the FCR3 and NF54 alleles. Based on the top epitope recognized by 3D10, we designed a 34-amino acid synthetic peptide, which we call CRP1, that maps to a highly conserved region in DBL3X. Specific lysine residues are critical for 3D10 recognition, and these same amino acids are within a previously defined chondroitin sulfate A (CSA) binding site in DBL3X. We showed by isothermal titration calorimetry that the CRP1 peptide can bind directly to CSA, and antibodies to CRP1 raised in rats significantly blocked the binding of IEs to CSA in vitro. In our Colombian cohorts of pregnant and non-pregnant individuals, at least 45% were seroreactive to CRP1. Antibody reactivities to CRP1 and the 3D10 natural epitope in PvDBP region II, subdomain 1 (SD1), were strongly correlated in both cohorts. These findings suggest that antibodies arising from PvDBP may cross-react with VAR2CSA through the epitope in CRP1 and that CRP1 could be a potential vaccine candidate to target a distinct CSA binding site in VAR2CSA.
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Iyamu et al. (2023) demonstrated that the VAR2CSA protein is expressed on the surface of erythrocytes infected with P.vivax and facilitates their sequestration within the placenta.
“In contrast, Iyamu et al. (2023) demonstrated that the VAR2CSA protein is expressed on the surface of erythrocytes infected with P.vivax and facilitates their sequestration within the placenta.”
From Current update on malaria in pregnancy: a systematic review (2025) · cites this paper as Iyamu et al. (2023)
The Introduction attributes placental sequestration through VAR2CSA to P. falciparum-infected erythrocytes, not P. vivax-infected erythrocytes. The paper discusses P. vivax Duffy binding protein as a source of antibodies that cross-react with VAR2CSA; it does not say P. vivax expresses VAR2CSA on infected erythrocytes. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredAntibodies targeting VAR2CSA have been primarily associated with infections during pregnancy, and antibodies directed against the P.vivax Duffy Binding Protein (PvDBP) were found to cross-react with VAR2CSA due to the presence of an epitope in the CRP1 domain, suggesting that CRP1 is a potential vaccine candidate that could target a specific CSA binding site within VAR2CSA.
“Antibodies targeting VAR2CSA have been primarily associated with infections during pregnancy, and antibodies directed against the P.vivax Duffy Binding Protein (PvDBP) were found to cross-react with VAR2CSA due to the presence of an epitope in the CRP1 domain, suggesting that CRP1 is a potential vaccine candidate that could target a specific CSA binding site within VAR2CSA [113].”
From Current update on malaria in pregnancy: a systematic review (2025) · cites this paper as [113]
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- Authors
- Iyamu, U., Vinals, D. F., Tornyigah, B., Arango, E., Bhat, R., Adra, T. R., Grewal, S., Martin, K., Maestre, A., Overduin, M., Hazes, B., & Yanow, S. K.
- Affiliations
- University of Alberta (CA)
- Fundación Universitaria San Martín (CO)
- Universidad de Antioquia (CO)
- Corresponding author
- Yanow, Stephanie K.
- Venue
- Frontiers in Cellular and Infection Microbiology
- Publisher
- Frontiers Media SA
- Published
- 2023-06-16
- Volume
- 13
- Pages
- 1202276-1202276
- ISSN
- 2235-2988 (ISSN-L)
- PMC
- PMC10312377
- OpenAlex
- W4380992446
- Cited by
- 7
- References
- 59
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3
- FWCI
- 1.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular and Infection Microbiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Greater South Information System
- Funders
- National Institute of Allergy and Infectious Diseases
- Li Ka Shing Institute of Virology, University of Alberta
- Canadian Institutes of Health Research
- Canada Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Health Sciences › Medicine › Hematology › Blood groups and transfusion
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- VAR2CSA, cross-reactive antibodies, conserved epitopes, placental sequestration, malaria in pregnancy, Plasmodium falciparum, vaccine candidate, epitope mapping
- MeSH terms
- Animals, Antibodies, Protozoan, Epitopes, Antigens, Protozoan, Chondroitin Sulfates, Erythrocytes, Female, Placenta, Plasmodium falciparum, Plasmodium vivax, Pregnancy, Protein Binding, Malaria, Falciparum, Malaria, Vivax, Mice, Rats
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