Broadly inhibitory antibodies to severe malaria virulence proteins
Open accessPublished version of a preprint
Abstract
Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels 1. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis 2. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.
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- Authors
- Reyes, R. A., Raghavan, S. S. R., Hurlburt, N. K., Introini, V., Bol, S., Kana, I. H., Jensen, R. W., Martinez-Scholze, E., Gestal-Mato, M., López-Gutiérrez, B., Sanz, S., Bancells, C., Fernández-Quintero, M. L., Loeffler, J. R., Ferguson, J. A., Lee, W.-H., Martin, G. M., Theander, T. G., Lusingu, J. P. A., Minja, D. T. R., Ssewanyana, I., Feeney, M. E., Greenhouse, B., Ward, A. B., Bernabeu, M., Pancera, M., Turner, L., Bunnik, E. M., & Lavstsen, T.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Scripps Research Institute (US)
- Fred Hutch Cancer Center (US)
- European Molecular Biology Laboratory (ES)
- University of Copenhagen (DK)
- National Institute for Medical Research (TZ)
- Infectious Diseases Research Collaboration (UG)
- University of California, San Francisco (US)
- Corresponding author
- Turner, Louise
- Bunnik, Evelien M.
- Lavstsen, Thomas
- ORCID
- Reyes, Raphael A.
- Raghavan, Sai Sundar Rajan
- Hurlburt, Nicholas K.
- Introini, Viola
- Bol, Sebastiaan
- Kana, Ikhlaq Hussain
- Jensen, Rasmus W.
- Gestal-Mato, María
- López-Gutiérrez, Borja
- Sanz, Silvia
- Bancells, Cristina
- Fernández-Quintero, Monica Lisa
- Loeffler, Johannes R.
- Ferguson, James Alexander
- Lee, Wen-Hsin
- Theander, Thor G.
- Lusingu, John P. A.
- Minja, Daniel T. R.
- Ssewanyana, Isaac
- Feeney, Margaret E.
- Greenhouse, Bryan
- Ward, Andrew B.
- Bernabeu, Maria
- Pancera, Marie
- Turner, Louise
- Bunnik, Evelien M.
- Lavstsen, Thomas
- Venue
- Nature
- Published
- 2024-11-20
- Volume
- 636
- Issue
- 8041
- Pages
- 182-189
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC12338075
- OpenAlex
- W4404566626
- Cited by
- 35
- References
- 4
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 5
- FWCI
- 14.50
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, cc-by-nc)
- RePEc: Research Papers in Economics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, DE-AC02-)
- Cancer Prevention and Research Institute of Texas (RP210126, CA054174)
- Wellcome Trust
- European Molecular Biology Laboratory
- Lundbeckfonden (R344-2020-934)
- Novo Nordisk
- Novo Nordisk Fonden (NNF23OC0086433)
- H. Lundbeck A/S
- National Institutes of Health (1s10od030432-01a1, DE-AC02–05CH11231, TL1TR002647, 1s10od028581-01, AI089674, CA054174)
- Office of Science (DEAC02–05CH11231, AC02-05CH11231, DE-AC02)
- University of Texas Health Science Center at San Antonio (TL1TR002647, P30 CA054174, TR002647)
- National Cancer Institute (CA-054174, P30CA054174, DE-AC02-05CH11231)
- National Institute of Allergy and Infectious Diseases (U01AI150741, K23AI076614, AI089674, F31AI169993, R01AI153425, R01AI093615, U19AI089674, K24AI144048)
- National Center for Advancing Translational Sciences
- Basic Energy Sciences (DE-AC02, DE-AC02-05CH11231., AC02–05CH11231)
- H2020 Marie Skłodowska-Curie Actions
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Hematology › Blood groups and transfusion
- Keywords
- severe malaria, Plasmodium falciparum, PfEMP1, monoclonal antibodies, endothelial protein C receptor, erythrocyte sequestration, cerebral microvasculature, adaptive immunity, antibody structure, vaccine design, malaria treatment
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