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

Autor: Kisalu NK; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Idris AH; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Weidle C; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Flores-Garcia Y; Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA., Flynn BJ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Sack BK; Seattle Biomedical Research Institute, Seattle, Washington, USA., Murphy S; Seattle Biomedical Research Institute, Seattle, Washington, USA., Schön A; Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA., Freire E; Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA., Francica JR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Miller AB; Division of Health Sciences and Technology, Institute for Medical Engineering and Science, and The Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Gregory J; Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA., March S; Division of Health Sciences and Technology, Institute for Medical Engineering and Science, and The Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Liao HX; Duke Human Vaccine Institute, Durham, North Carolina, USA., Haynes BF; Duke Human Vaccine Institute, Durham, North Carolina, USA.; Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.; Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA., Wiehe K; Duke Human Vaccine Institute, Durham, North Carolina, USA.; Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA., Trama AM; Duke Human Vaccine Institute, Durham, North Carolina, USA., Saunders KO; Duke Human Vaccine Institute, Durham, North Carolina, USA.; Department of Surgery, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA., Gladden MA; Duke Human Vaccine Institute, Durham, North Carolina, USA., Monroe A; Duke Human Vaccine Institute, Durham, North Carolina, USA., Bonsignori M; Duke Human Vaccine Institute, Durham, North Carolina, USA.; Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA., Kanekiyo M; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Wheatley AK; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., McDermott AB; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Farney SK; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Chuang GY; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Zhang B; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Kc N; Sanaria Inc., Rockville, Maryland, USA., Chakravarty S; Sanaria Inc., Rockville, Maryland, USA., Kwong PD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Sinnis P; Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA., Bhatia SN; Division of Health Sciences and Technology, Institute for Medical Engineering and Science, and The Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Kappe SHI; Seattle Biomedical Research Institute, Seattle, Washington, USA., Sim BKL; Sanaria Inc., Rockville, Maryland, USA., Hoffman SL; Sanaria Inc., Rockville, Maryland, USA., Zavala F; Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA., Pancera M; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Seder RA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2018 May; Vol. 24 (4), pp. 408-416. Date of Electronic Publication: 2018 Mar 19.
DOI: 10.1038/nm.4512
Abstrakt: 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.
Databáze: MEDLINE
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