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Reviews of "Broadly Inhibitory Antibodies against Severe Malaria Virulence Proteins"

Reviewers: B Wilder (Oregon Health & Science University) | 📘📘📘📘📘 • T Tsuobi (Ehime University) | 📘📘📘📘📘

Published onJun 13, 2024
Reviews of "Broadly Inhibitory Antibodies against Severe Malaria Virulence Proteins"
key-enterThis Pub is a Review of
Broadly inhibitory antibodies against severe malaria virulence proteins
Broadly inhibitory antibodies against severe malaria virulence proteins

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.

To read the original manuscript, click the link above.

Summary of Reviews: 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. They commended the comprehensive experimental approach, combining advanced techniques like monoclonal antibody isolation, functional assays, structural biology, and in vitro modeling of cytoadhesion under physiological conditions. The conclusions about the common binding mechanism targeting conserved epitopes on the PfEMP1 CIDRα1 domain were well supported by the structural data. However, one reviewer suggested tempering the claim that the identified antibodies represent a "uniform mode of binding," as the analysis was limited to only two antibodies. Additionally, providing further context on the potential implications for antibody-based therapies or vaccine design against severe malaria could strengthen the discussion.

Reviewer 1 (Brandon W…) | 📘📘📘📘📘

Reviewer 2 (Takafumi T…) | 📘📘📘📘📘

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

To read the reviews, click the links below. 

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