Immunization-elicited Antibody Shows Universal Protection against Multiple Ebolaviruses

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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/.

Contact: Robert Blackwell, 240-778-6513, rblackwell@integratedbiotherapeutics.com

Publications

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability.  Zhao X, Howell KA, He S, Brannan JM, Wec AZ, Davidson E, Turner HL, Chiang CI, Lei L, Fels JM, Vu H, Shulenin S, Turonis AN, Kuehne AI, Liu G, Ta M, Wang Y, Sundling C, Xiao Y, Spence JS, Doranz BJ, Holtsberg FW, Ward AB, Chandran K, Dye JM, Qiu X, Li Y, Aman MJ.  Cell. 2017 May 18;169(5):891-904.e15. doi: 10.1016/j.cell.2017.04.038.

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Cooperativity Enables Non-neutralizing Antibodies to Neutralize Ebolavirus.  Howell KA, Brannan JM, Bryan C, McNeal A, Davidson E, Turner HL, Vu H, Shulenin S, He S, Kuehne A, Herbert AS, Qiu X, Doranz BJ, Holtsberg FW, Ward AB, Dye JM, Aman MJ.  Cell Rep. 2017 Apr 11;19(2):413-424. doi: 10.1016/j.celrep.2017.03.049.

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Protective efficacy of a novel alpha hemolysin subunit vaccine (AT62) against Staphylococcus aureus skin and soft tissue infections.  Adhikari RP, Thompson CD, Aman MJ, Lee JC.  Vaccine. 2016 Dec 7;34(50):6402-6407. doi:10.1016/j.vaccine.2016.09.061. Epub 2016 Nov 12.
 

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Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax. Chen WH, Pasetti MF, Adhikari RP, Baughman H, Douglas R, El-Khorazaty J, Greenberg N, Holtsberg FW, Liao GC, Reymann MK, Wang X, Warfield KL, Aman MJ. Clin Vaccine Immunol. 2016 Dec 5;23(12):918-925. Print 2016 Dec.
 

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A "Trojan Horse" Bispecific Antibody Strategy for Broad Protection against Ebolaviruses. Wec, A.Z. Nyakatura, E.K. Herbert, A.S. Howell, K.A. Holtsberg, F.W. Bakken, R.R. Mittler, E. Christin, J.R. Shulenin, S. Jangra, R.K. Bharrhan, S. Kuehne, A.I. Bornholdt, Z.A. Flyak, A.I. Saphire, E. Crowe Jr., J.E. Aman, M.J. Dye, J.M. Lai, J.R. Chandran, K. (2016) Science 8(2016). doi: 10.1126/science.aag3267

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Feverish Quest for Ebola Immunotherapy: Straight or Cocktail?  Aman, M.J. Saphire, EO. (2016) Trends Microbiol 10(1016). pii: SD966-842X(16)30049-X

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Zika Virus: A New Animal Model for an Arbovirus.  Aman, M.J. Kashanchi, F. (2016) PLoS Negl Trop Dis 10(5): e0004702. doi:10.1371/journal.pntd.0004702

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Virus-Like Particle Vaccination Protects Nonhuman Primates from Lethal Aerosol Exposure with Marburgvirus (VLP Vaccination Protects Macaques against Aerosol Challenges).  Dye JM, Warfield KL, Wells JB, Unfer RC, Shulenin S, Vu H, Nichols DK, Aman MJ, Bavari S. Viruses. 2016 Apr 8;8(4). pii: E94. doi: 10.3390/v8040094

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Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site.  Howell KA, Qiu X, Brannan JM, Bryan C, Davidson E, Holtsberg FW, Wec AZ, Shulenin S, Biggins JE, Douglas R, Enterlein SG, Turner HL, Pallesen J, Murin CD, He S, Kroeker K, Vu H, Herbert AS, Fusco ML, Nyakatura EK, Lai JR, Keck ZY, Foung SKH, Saphire EO, Zeitlin L, Ward AB, Chandran K, Doranz BJ, Kobinger GP, Dye JM, Aman MJ. (2016) Cell Reports 15, 1–13.

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Monoclonal antibody therapy for Junin virus infection.  Zeitlin L, Geisbert JB, Deer DJ, Fenton KA, Bohorov O, Bohorova N, Goodman C, Kim D, Hiatt A, Pauly MH, Velasco J, Whaley KJ, Altmann F, Gruber C, Steinkellner H, Honko AN, Kuehne AI, Aman MJ, Sahandi S, Enterlein S, Zhan X, Enria D, Geisbert TW. Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4458-63.

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Aman MJ, Chasing Ebola through the Endosomal Labyrinth:, MBio, 2016, 7(2):e00346-16

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Holtsberg et al., Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses, J Virol, 2014

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Keck et al., Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein, J Virol, 2014

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Adhikari et al., Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs, PLoS One, 2015

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Fusco et al., Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs, PLoS Pathog, 2015

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Warfield et al., Homologous and heterologous protection of nonhuman primates by Ebola and Sudan virus-like particles, PLoS One, 2015

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Sully et al., A tripartite cocktail of chimeric monoclonal antibodies passively protects mice against ricin, staphylococcal enterotoxin B and Clostridium perfringens epsilon toxin, Toxicon, 2014

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Warfield et al., Vaccinating captive chimpanzees to save wild chimpanzees, Proc Natl Acad Sci USA, 2014

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Aman and Adhikari, Staphylococcal bicomponent pore-forming toxins: targets for prophylaxis and immunotherapy, Toxins, 2014

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Karauzum et al., Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model, PLoS One, 2013

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Adhikari et al., Lower antibody levels to Staphylococcus aureus exotoxins are associated with sepsis in hospitalized adults with invasive S. aureus infections, J Infect Dis, 2012

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Adhikari et al., Novel structurally designed vaccine for S. aureus α-hemolysin: protection against bacteremia and pneumonia, PLoS One, 2012.

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