Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein
Abstract
Filoviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members of Filoviridae such as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2016
- Source ID
- 10.1128/jvi.02172-15
Entities
People
- Andrew S Herbert
- Ariel S Wirchnianski
- Calli M. Lear-rooney
- Frederick W Holtsberg
- Hong Vu
- Jeffrey W. Froude
- John M Dye
- Julia Biggins
- Katie A. Howell
- Kelly L. Warfield
- M. Javad Aman
- Nazli Araghi
- Pamela J Glass
- Patrick Lau
- Robin Douglas
- Sergey Shulenin
- Steven K. H. Foung
- Sven G. Enterlein
- Yong Wang
- Zhen-yong Keck
Organizations
- Defense Threat Reduction Agency
- National Institute of Allergy and Infectious Diseases
- Stanford University
- United States Army Medical Research Institute of Infectious Diseases