Broadly inhibitory antibodies to severe malaria virulence proteins

Raphael A. Reyes, Sai Sundar Rajan Raghavan, Nicholas K. Hurlburt, Viola Introini, Sebastiaan Bol, Ikhlaq Hussain Kana, Rasmus W. Jensen, Elizabeth Martinez-Scholze, María Gestal-Mato, Borja López-Gutiérrez, Silvia Sanz, Cristina Bancells, Monica Lisa Fernández-Quintero, Johannes R. Loeffler, James Alexander Ferguson, Wen-Hsin Lee, Greg Michael Martin, Thor G. Theander, John P. A. Lusingu, Daniel T. R. Minja, Isaac Ssewanyana, Margaret E. Feeney, Bryan Greenhouse, Andrew B. Ward, Maria Bernabeu, Marie Pancera, Louise Turner (), Evelien M. Bunnik () and Thomas Lavstsen ()
Additional contact information
Raphael A. Reyes: The University of Texas Health Science Center at San Antonio
Sai Sundar Rajan Raghavan: Righospitalet
Nicholas K. Hurlburt: Fred Hutchinson Cancer Center
Viola Introini: EMBL Barcelona
Sebastiaan Bol: The University of Texas Health Science Center at San Antonio
Ikhlaq Hussain Kana: Righospitalet
Rasmus W. Jensen: Righospitalet
Elizabeth Martinez-Scholze: The University of Texas Health Science Center at San Antonio
María Gestal-Mato: EMBL Barcelona
Borja López-Gutiérrez: EMBL Barcelona
Silvia Sanz: EMBL Barcelona
Cristina Bancells: EMBL Barcelona
Monica Lisa Fernández-Quintero: The Scripps Research Institute
Johannes R. Loeffler: The Scripps Research Institute
James Alexander Ferguson: The Scripps Research Institute
Wen-Hsin Lee: The Scripps Research Institute
Greg Michael Martin: The Scripps Research Institute
Thor G. Theander: Righospitalet
John P. A. Lusingu: Tanga Research Centre
Daniel T. R. Minja: Tanga Research Centre
Isaac Ssewanyana: Infectious Disease Research Collaboration
Margaret E. Feeney: University of California San Francisco
Bryan Greenhouse: University of California San Francisco
Andrew B. Ward: The Scripps Research Institute
Maria Bernabeu: EMBL Barcelona
Marie Pancera: Fred Hutchinson Cancer Center
Louise Turner: Righospitalet
Evelien M. Bunnik: The University of Texas Health Science Center at San Antonio
Thomas Lavstsen: Righospitalet

Nature, 2024, vol. 636, issue 8041, 182-189

Abstract: Abstract Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels1. 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 pathogenesis2. 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.

Date: 2024
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DOI: 10.1038/s41586-024-08220-3

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