[Source: Science, full page: (LINK). Abstract, edited.]
Structural and molecular basis for Ebola virus neutralization by protective human antibodies
John Misasi 1,5,8*, Morgan S. A. Gilman 2,*, Masaru Kanekiyo 1,*, Miao Gui 4*, Alberto Cagigi 1, Sabue Mulangu 1, Davide Corti 6, Julie E. Ledgerwood 1, Antonio Lanzavecchia 6,9, James Cunningham 5, Jean Jacques Muyembe-Tamfun 7, Ulrich Baxa 3,Barney S. Graham 1, Ye Xiang 4, Nancy J. Sullivan 1, Jason S. McLellan 2
Author Affiliations: 1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. 2Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.3Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. 4Centre for Infectious Diseases Research, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084 China. 5Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. 6Institute for Research in Biomedicine, Università della Svizzera Italiana, CH-6500 Bellinzona, Switzerland. 7National Institute for Biomedical Research, National Laboratory of Public Health, Kinshasa B.P. 1197, Democratic Republic of the Congo. 8Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA 02215, USA. 9Institute of Microbiology, ETH Zurich, CH-8093 Zurich, Switzerland.
‡Corresponding author. E-mail: (N.J.S.); (Y.X.)
* These authors contributed equally to this work.
† These authors contributed equally to this work.
Science 18 Mar 2016: Vol. 351, Issue 6279, pp. 1343-1346 / DOI: 10.1126/science.aad6117
Antibodies block Ebola virus entry
The recent Ebola virus outbreak in West Africa illustrates the need for both an effective vaccine and therapies to treat infected individuals. Corti et al. isolated two monoclonal antibodies from a survivor of the 1995 Kikwit outbreak and demonstrated their therapeutic efficacy in Ebola virus–infected macaques. In fact, one antibody protected macaques when it was given up to 5 days after infection. Misasi et al. solved the crystal structures of fragments of the two antibodies bound to the Ebola virus glycoprotein (GP), which mediates viral cell entry. The two antibodies targeted different regions of GP, but in both cases blocked steps required for viral entry.
Ebola virus causes hemorrhagic fever with a high case fatality rate for which there is no approved therapy. Two human monoclonal antibodies, mAb100 and mAb114, in combination, protect nonhuman primates against all signs of Ebola virus disease, including viremia. Here, we demonstrate that mAb100 recognizes the base of the Ebola virus glycoprotein (GP) trimer, occludes access to the cathepsin-cleavage loop, and prevents the proteolytic cleavage of GP that is required for virus entry. We show that mAb114 interacts with the glycan cap and inner chalice of GP, remains associated after proteolytic removal of the glycan cap, and inhibits binding of cleaved GP to its receptor. These results define the basis of neutralization for two protective antibodies and may facilitate development of therapies and vaccines.
Keywords: Research; Abstracts; Ebola; Monoclonal Antibodes.