ROCKVILLE, Md., May 18, 2017 /PRNewswire/ — In research published online today in Cell, a team of scientists describe an antibody called CA45, elicited by immunization of nonhuman primates (NHP) that binds to a region of the Ebola virus surface protein that is shared among all pathogenic ebolaviruses. CA45 blocks cells from by Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) viruses, the only ebolaviruses known to cause lethal disease in humans. The team of scientists led by Dr. M. Javad Aman from Integrated Biotherapeutics, and Dr. Yuxing Li from the Institute for Bioscience and Biotechnology Research (IBBR) and Department of Microbiology and Immunology, University of Maryland School of Medicine, also included researchers from Albert Einstein College of Medicine, U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), National Institute of Allergy and Infectious Disease (NIAID), Garvan Institute of Medical Research, The Scripps Research Institute, Integral Molecular, the University of Manitoba, and the Public Health Agency of Canada.
Members of the Filovirus family are among the deadliest viruses with no approved treatments or vaccines available for human use. Several vaccines are currently in development but these vaccines primarily elicit responses against single species called Zaire Ebola virus, which caused the 2014 Ebola virus disease outbreak in West Africa. However, over the past four decades multiple outbreaks of SUDV and BDBV with high mortality rates have been recorded. Given the unknown nature of future ebolavirus outbreaks development of vaccines and therapeutics that can broadly protect people against infection with any of these viruses is critically important.
The team of investigators immunized a macaque with a special cocktail of engineered proteins mimicking the various surface glycoproteins of ebolaviruses to induce broadly protective responses. The scientists then used a strategy to specifically isolate those monoclonal antibodies that react to multiple ebolaviruses from the immune cells of the vaccinated animal. Upon searching through millions of B lymphocytes, a cross-reactive antibody (CA45) was isolated that was able to neutralize cellular infection by all pathogenic ebolaviruses.
CA45, when given to the already infected rodents at the peak of their disease, was able to protect the animals from the otherwise lethal infection. The scientists then combined CA45 with another antibody they previously discovered and demonstrated that the combination shows superior activity, protecting mice, guinea pigs and ferrets from infections with Ebola, Sudan, and Bundibugyo viruses with almost no sign of disease. This is the first time a therapeutic agent has been able to fully protect animals against all three pathogenic ebolaviruses.
A key site of vulnerability revealed:
The glycoprotein (GP) on the surface of the ebolavirus is responsible for entry into the cells. The process of entry involves interaction with the cell surface followed by entry into specialized cellular compartments called endosomes where GP interacts with its cellular receptor. Finally, the GP mediates the last step in the entry known as fusion of the viral and endosomal membrane that allows the virus to release its content into the cells. Using a variety of methods, the team identified the specific region of ebolavirus GP that is attacked by CA45. This region is within the so-called fusion loop that mediates fusion of the viral and endosomal membrane. The site attacked by CA45 has a remarkably similar structure in the GP of various ebolaviruses, explaining its ability to cross protect against multiple viruses. Recently, similar broadly neutralizing antibodies targeting the fusion domain of HIV and influenza have been discovered indicating that this region is a key site of vulnerability for these viruses.
Prospect of a Pan-ebolavirus vaccine
The fact that such a broadly protective antibody was elicited by immunization with an engineered vaccine suggests that development of a vaccine protective against multiple ebolaviruses may be feasible. "With every new antibody we learn a little more about this virus and how it can be attacked," says Dr. M. Javad Aman of Integrated BioTherapeutics and a senior author on the paper. He went on to say "We are carefully analyzing this information to devise strategies to make a single vaccine effective against all ebolaviruses– such a vaccine may be entirely within reach now."
"We are on our way to designing novel vaccines and immunotherapeutics for broader protection against all pathogenic ebolaviruses, with the insights we have been gaining," says Dr. Yuxing Li, Associate Professor of IBBR and the co-correspondence author of the paper.
The paper is titled "Immunization-elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability." In addition to Drs. Li and Aman and the co-first authors Drs. Xuelian Zhao and Katie A. Howell, contributors include Shihua He, Jennifer M. Brannan, Anna Z. Wec, Edgar Davidson, Hannah L. Turner, Chi-I Chiang, Lin Lei, J. Maximilian Fels, Hong Vu, Sergey Shulenin, Ashley N. Turonis, Ana I. Kuehne, Guodong Liu, Mi Ta, Yimeng Wang, Christopher Sundling, Yongli Xiao, Jennifer S. Spence, Benjamin J. Doranz, Frederick W. Holtsberg, Andrew B. Ward, Kartik Chandran, John M. Dye, and Xiangguo Qiu.
This work was supported by a contract (HDTRA1-13-C-0015) from US Defense Threat Reduction Agency (DTRA) and NIAID/NIH grants R43AI124765, R01AI126587, U19AI109762, Intramural Research Award from IBBR, University of Maryland, NIAID contract HHSN272201400058C, JSTO-DTRA project CB4077, and also partially supported by Public Health Agency of Canada (PHAC).
About Integrated Biotherapeutics (IBT)
IBT is a biotechnology company focused on the discovery of novel vaccines and therapies for emerging infectious diseases with a pipeline that includes promising product candidates for bacterial and viral infections including unique pan-filovirus immunotherapeutics and vaccines, vaccines for Staphylococcal infections, and a variety of other product candidates for emerging viruses. Located in Rockville, MD, IBT has a close working relationship with United States Government agencies including the National Institute of Allergy and Infectious Diseases (NIAID/NIH). National Cancer Research Institute (NCI), Department of Defense (DOD), United States Army Medical Research Institute of Infection Diseases (USAMRIID) as well as many biotechnology and pharmaceutical companies and academic laboratories. For more information, visit www.integratedbiotherapeutics.com.
About the Institute for Bioscience and Biotechnology Research (IBBR)
IBBR is a University System of Maryland joint research enterprise among the University of Maryland College Park, the University of Maryland Baltimore, and the National Institute of Standards and Technology. With a long-standing scientific focus on structure-function relationships of biomolecules, genetic systems, and applications, e.g., vaccines, therapeutics, drug delivery technologies, and biomanufacturing, IBBR’s mission is to leverage its unique capabilities and infrastructure to marshal innovative technologies and expertise across its partnering institutions, to foster integrated, cross-disciplinary team approaches to scientific research and education, and to pursue translational programs and projects aimed at advancing innovations to commercialization in real world applications. The Institute also serves to expand the economic base of science and technology in the state of Maryland and at the national level. For more information, visit https://www.ibbr.umd.edu/.
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