The NTS-DBL2X region of VAR2CSA induces cross-reactive antibodies that inhibit adhesion of several Plasmodium falciparum isolates to chondroitin sulfate A
Abstract
BACKGROUND: Binding to chondroitin sulfate A by VAR2CSA, a parasite protein expressed on infected erythrocytes, allows placental sequestration of Plasmodium falciparum-infected erythrocytes. This leads to severe consequences such as maternal anemia, stillbirths, and intrauterine growth retardation. The latter has been clearly associated to increased morbidity and mortality of the infants. Acquired anti-VAR2CSA antibodies have been associated with improved pregnancy outcomes, suggesting a vaccine could prevent the syndrome. However, identifying functionally important regions in the large VAR2CSA protein is difficult. METHODS: Using genetic immunization, we raised polyclonal antisera against overlapping segments of VAR2CSA in mice and rabbits. The adhesion-inhibition capacities of induced antisera and of specific antibodies purified from plasma of malaria-exposed pregnant women were assessed on laboratory-adapted parasite lines and field isolates expressing VAR2CSA. Competition enzyme-linked immunosorbent assay (ELISA) was employed to analyze functional resemblance between antibodies induced in animals and those naturally acquired by immune multigravidae. RESULTS: Antibodies targeting the N-terminal sequence (NTS) up to DBL2X (NTS-DBL2X) efficiently blocked parasite adhesion to chondroitin sulfate A in a manner similar to that of antibodies raised against the entire VAR2CSA extracellular domain. Interestingly, naturally acquired antibodies and those induced by vaccination against NTS-DBL2X target overlapping strain-transcendent anti-adhesion epitopes. CONCLUSIONS: This study highlights an important step achieved toward development of a protective vaccine against placental malaria.
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Antibodies induced in animals to the NTS-DBL1-ID1-DBL2-ID2a multi-domain have heterologous functional activity, and the serum activity induced by this recombinant form has been broader than that induced by the smaller ID1-DBL2 fragment.
“However, antibodies induced in animals to the NTS–DBL1–ID1–DBL2–ID2a multi-domain have heterologous functional activity, and the serum activity induced by this recombinant form has been broader than that induced by the smaller ID1–DBL2 fragment [52,56].”
From Designing a VAR2CSA-based vaccine to prevent placental malaria (2015) · cites this paper as [52]
The section ‘Antibodies Induced Against VAR2CSA Abrogate Binding of Infected Erythrocytes to Chondroitin Sulphate Proteoglycan’ reports that antibodies induced by the paper’s NTS-DBL2X construct inhibited adhesion of both FCR3 and the heterologous HB3 parasite line. Our copy does not report a comparison showing broader serum activity than the smaller ID1-DBL2 fragment. No page number is supplied for this section. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDNA vaccination with NTS-DBL1-ID1-DBL2 elicited antibodies that blocked the binding of the majority of the isolates to CSA by >50% (FCR3 allele: 12/15; 3D7 allele: 13/18; FCR3 allele: 11/18).
“DNA vaccination with NTS–DBL1–ID1–DBL2 elicited antibodies that blocked the binding of the majority of the isolates to CSA by >50% (FCR3 allele: 12/15; 3D7 allele: 13/18; FCR3 allele: 11/18) [52,56].”
From Designing a VAR2CSA-based vaccine to prevent placental malaria (2015) · cites this paper as [52]
The section “Antibodies Induced Against NTS-DBL2X Specifically Recognized Isolates From Pregnant Women” reports that anti-NTS-DBL2X sera strongly inhibited CSA binding in 12 of 15 isolates; Table 2 (p. 1127) shows inhibition above 50% for those 12. The paper describes DNA immunization with an FCR3-derived NTS-DBL2X construct, but our copy does not report the claimed 3D7 13/18 or second FCR3 11/18 results. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe N-terminal region of VAR2CSA, NTS-DBL1-ID1-DBL2, elicited antibodies that almost completely inhibited the binding of homologous FCR3 and heterologous HB3 IE.
“The N-terminal region of VAR2CSA, NTS–DBL1–ID1–DBL2, elicited antibodies that almost completely inhibited the binding of homologous FCR3 and heterologous HB3 IE [52]”
From Designing a VAR2CSA-based vaccine to prevent placental malaria (2015) · cites this paper as [52]
VAR2CSA antibodies can block adhesion of infected erythrocytes to chondroitin sulfate A in vitro.
“These antibodies can block adhesion of IEs to CSA in vitro (4,5) and are associated with protection from placental malaria and other adverse delivery outcomes (6,7).”
From Clinical outcomes of submicroscopic infections and correlates of protection of VAR2CSA antibodies in a longitudinal study of pregnant women in Colombia (2018) · cites this paper as [5]
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“The N-terminal region of VAR2CSA, NTS–DBL1–ID1–DBL2, elicited antibodies that almost completely inhibited the binding of homologous FCR3 and heterologous HB3 IE [52], consistent with an earlier study reporting anti-adhesion activity by antibodies raised against multidomain immunogens including NTS–DBL1–ID1–DBL2 [47].”
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- Authors
- Bigey, P., Gnidehou, S., Doritchamou, J., Quiviger, M., Viwami, F., Couturier, A., Salanti, A., Nielsen, M. A., Scherman, D., Deloron, P., & Tuikue Ndam, N.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Santé Internationale de la mère et de l'enfant (FR)
- Université d'Abomey-Calavi (BJ)
- University of Copenhagen (DK)
- ORCID
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-10-01
- Volume
- 204
- Issue
- 7
- Pages
- 1125-1133
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- OpenAlex
- W2162915418
- Cited by
- 63
- References
- 33
- Citations by year
- 2023: 1 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 9 · 2016: 3 · 2015: 7 · 2014: 8 · 2013: 8 · 2012: 5
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Bill and Melinda Gates Foundation (47029)
- European Commission (200889, 201222)
- Agence Nationale de la Recherche (009-01, ANR-05)
- 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, Plasmodium falciparum, placental malaria, chondroitin sulfate A, erythrocyte adhesion, cross-reactive antibodies, placental sequestration, pregnancy outcomes, malaria vaccine, naturally acquired antibodies, genetic immunization, epitope mapping
- MeSH terms
- Animals, Antibodies, Protozoan, Antigens, Protozoan, Cell Adhesion, Chondroitin Sulfates, Enzyme-Linked Immunosorbent Assay, Erythrocytes, Female, Humans, Immunoglobulin G, Immunity, Active, Plasmids, Plasmodium falciparum, Pregnancy, Protein Binding, Rabbits, Vaccination, Gene Expression, Malaria, Falciparum, Mice
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