A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
- National Institute of Allergy and Infectious Diseases, United States
Abstract
Placental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum-infected erythrocytes (IE) that express the surface antigen VAR2CSA and bind to chondroitin sulfate A (CSA) in the placenta. Women become PM-resistant over successive pregnancies as they develop anti-adhesion and anti-VAR2CSA antibodies, supporting VAR2CSA as the leading PM-vaccine candidate. However, the first VAR2CSA subunit vaccines failed to induce broadly neutralizing antibody and it is known that naturally acquired antibodies target both variant-specific and conserved epitopes. It is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA variants. Here, IgG from multigravidae was sequentially purified on five full-length VAR2CSA ectodomain variants, thereby depleting IgG reactivity to each. The five VAR2CSA variants purified ~0.7% of total IgG and yielded both strain-transcending and strain-specific reactivity to VAR2CSA and IE-surface antigen. In two independent antibody purification/depletion experiments with permutated order of VAR2CSA variants, IgG purified on the first VAR2CSA antigen displayed broad cross-reactivity to both recombinant and native VAR2CSA variants, and inhibited binding of all isolates to CSA. IgG remaining after depletion on all variants showed significantly reduced binding-inhibition activity compared to initial total IgG. These findings demonstrate that a single VAR2CSA ectodomain variant displays conserved epitopes that are targeted by neutralizing (or binding-inhibitory) antibodies shared by multiple parasite strains, including maternal isolates. This suggests that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures.
Article and author information
Author details
Funding
Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Justin YA Doritchamou
- Jonathan P Renn
- Bethany Jenkins
- Michal Fried
- Patrick E Duffy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: For this study, a plasma pool was prepared using samples from multigravid women participating in the previously described Immuno-epidemiology (IMEP) study (Fried et al., 2018). Briefly, pregnant women aged 15-45 years without clinical evidence of chronic or debilitating illness were enrolled from 2010-2013 into a longitudinal cohort study of mother-infant pairs conducted in Ouélessébougou, Mali. All participants provided signed informed consent after receiving a study explanation form and oral explanation from a study clinician in their native language. The study protocol and study procedures were approved by the institutional review board of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health (ClinicalTrials.gov ID NCT01168271), and the Ethics Committee of the Faculty of Medicine, Pharmacy and Dentistry at the University of Bamako, Mali.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
eLife 11:e76264.
https://doi.org/10.7554/eLife.76264
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