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Review 1: "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 1: "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

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.


Review: Through the use of monoclonal antibodies, advanced in vitro functional testing and structural biology the authors demonstrate a key mechanism by which antibodies can elicit broadly neutralizing antibodies to PfEMP1. The authors also provide strong evidence for two basic serotypes of PfEMP1 and the CIDR domain. These findings will contribute to our understanding of P. falciparum antibody evasion and the development of novel interventions for severe malaria.

In general, the work is conducted using the best available methods and the conclusions largely supported by the data presented. The work is important in understanding how broad broadly neutralizing antibodies to PfEMP1 may be and will greatly inform monoclonal and vaccine development. The only major shortcoming is summarized in the Discssion sentence: “The functional and molecular characterization of mAbs C7 and C74 presented in this study not only provides conclusive evidence for the presence of broadly inhibitory antibodies against EPCR-binding PfEMP1, but also unveils that such antibodies likely share a uniform mode of binding.” The first portion of the statement is correct while the second clause overstates the case and should be changed from “likely” to “can” (or similar). This is because the authors analyzed in depth only two antibodies out of thousands from three individuals. In order to make broader claims from their monoclonals to the interplay between CIDR/PfEMP1 variants, connections to polyclonal reactivity of individuals to variant CIDR serotypes would need to be made, and likely done in a large number of samples.