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Review 2: "Broadly Inhibitory Antibodies against Severe Malaria Virulence Proteins"

The reviewers found the study compelling, providing strong evidence for the existence of broadly inhibitory human antibodies that can recognize and neutralize the diverse range of PfEMP1 variants from Plasmodium falciparum involved in severe malaria pathogenesis.

Published onJun 13, 2024
Review 2: "Broadly Inhibitory Antibodies against Severe Malaria Virulence Proteins"
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Broadly inhibitory antibodies against severe malaria virulence proteins
Broadly inhibitory antibodies against severe malaria virulence proteins
Description

Abstract Plasmodium falciparum pathology is driven by the accumulation of parasite-infected erythrocytes in microvessels. This process is mediated by the parasite’s polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. A subset of PfEMP1 variants that bind human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here, we describe two broadly reactive and binding-inhibitory human monoclonal antibodies against CIDRα1. The antibodies isolated from two different individuals exhibited a similar and consistent EPCR-binding inhibition of 34 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 brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with two 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 likely 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.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: The study reports the discovery of two human monoclonal antibodies that react to the CIDRα1 domain of PfEMP1 from P. falciparum-infected cases. The researchers also solved the structure of mAb in complex with CIDR1 domains. The structural analyses revealed that the binding mechanisms are common and rely on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1.

One of the major causes of severe falciparum malaria is the accumulation of parasite-infected red blood cells (iRBCs) in the capillaries. This is due to the binding of a critical parasite ligand called PfEMP1, located on the surface of iRBCs, to endothelial protein C receptor (EPCR) through their CIDRα1 domains. However, it is still uncertain whether individual antibodies can recognize the diverse range of circulating PfEMP1 variants. 

To address this question, Reyes et al. conducted a study where they isolated two human monoclonal antibodies (C7 and C74) that are broadly reactive and binding inhibitory against CIDRα1. Both antibodies consistently inhibited the EPCR binding of 34 CIDRα1 domains. The team also found that both antibodies inhibited EPCR binding of both recombinant and native PfEMP1 proteins, as well as parasite sequestration in 3D brain microvessels under flow conditions. 

Structural analyses revealed that the binding mechanisms of the two antibodies are similar and rely on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These findings suggest that these broadly reactive antibodies likely represent a common mechanism of acquired immunity to severe malaria.

All of the findings in this study were well-supported by carefully designed high-quality experiments.

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