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Nat Med. 2018 May;24(4):408-416. doi: 10.1038/nm.4512. Epub 2018 Mar 19.

A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite.

Author information

1
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
2
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
3
Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
4
Seattle Biomedical Research Institute, Seattle, Washington, USA.
5
Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.
6
Division of Health Sciences and Technology, Institute for Medical Engineering and Science, and The Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
7
Duke Human Vaccine Institute, Durham, North Carolina, USA.
8
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
9
Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
10
Department of Surgery, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
11
Sanaria Inc., Rockville, Maryland, USA.

Abstract

Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.

PMID:
29554083
PMCID:
PMC5893371
DOI:
10.1038/nm.4512
[Indexed for MEDLINE]
Free PMC Article

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