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Emelissa J Mendoza, Trina Racine, Gary P Kobinger
The 2014-2016 Ebola virus outbreak in West Africa was the deadliest in history, prompting the evaluation of various drug candidates, including antibody-based therapeutics for the treatment of Ebola hemorrhagic fever (EHF). Prior to 2014, only convalescent blood products from EHF survivors had been administered to newly infected individuals as a form of treatment. However, during the recent outbreak, monoclonal antibody cocktails such as ZMapp, ZMAb and MB-003 were either tested in a human clinical safety and efficacy trial or provided to some based on compassionate grounds...
March 2017: Immunotherapy
Richard T Davey, Jacquie Nordwall, Michael A Proschan
No abstract text is available yet for this article.
February 16, 2017: New England Journal of Medicine
Jenny Dörnemann, Chiara Burzio, Axelle Ronsse, Armand Sprecher, Hilde De Clerck, Michel Van Herp, Marie-Claire Kolié, Vesselina Yosifiva, Severine Caluwaerts, Anita K McElroy, Annick Antierens
A neonate born to an Ebola virus-positive woman was diagnosed with Ebola virus infection on her first day of life. The patient was treated with monoclonal antibodies (ZMapp), a buffy coat transfusion from an Ebola survivor, and the broad-spectrum antiviral GS-5734. On day 20, a venous blood specimen tested negative for Ebola virus by quantitative reverse-transcription polymerase chain reaction. The patient was discharged in good health on day 33 of life. Further follow-up consultations showed age-appropriate weight gain and neurodevelopment at the age of 12 months...
January 15, 2017: Journal of Infectious Diseases
Anthony P Cardile, Travis K Warren, Karen A Martins, Ronald B Reisler, Sina Bavari
Despite the unprecedented Ebola virus outbreak response in West Africa, no Ebola medical countermeasures have been approved by the US Food and Drug Administration. However, multiple valuable lessons have been learned about the conduct of clinical research in a resource-poor, high risk-pathogen setting. Numerous therapeutics were explored or developed during the outbreak, including repurposed drugs, nucleoside and nucleotide analogues (BCX4430, brincidofovir, favipiravir, and GS-5734), nucleic acid-based drugs (TKM-Ebola and AVI-7537), and immunotherapeutics (convalescent plasma and ZMapp)...
January 6, 2017: Annual Review of Pharmacology and Toxicology
Richard T Davey, Lori Dodd, Michael A Proschan, James Neaton, Jacquie Neuhaus Nordwall, Joseph S Koopmeiners, John Beigel, John Tierney, H Clifford Lane, Anthony S Fauci, Moses B F Massaquoi, Foday Sahr, Denis Malvy
BACKGROUND: Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS: Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day)...
October 13, 2016: New England Journal of Medicine
Maria P Limberis, Anna Tretiakova, Kalyani Nambiar, Gary Wong, Trina Racine, Marco Crosariol, Qiu Xiangguo, Gary Kobinger, James M Wilson
Adeno-associated viral vectors can be used as a platform for delivering biological countermeasures against pandemic and biological threats. We show that vector delivery of two antibody components of the ZMapp product is effective in mice against systemic and airway challenge with a mouse-adapted strain of Ebola virus. This platform provides a generic manufacturing solution and overcomes some of the delivery challenges associated with repeated administration of the protective protein.
December 15, 2016: Journal of Infectious Diseases
A L Moekotte, M A M Huson, A J van der Ende, S T Agnandji, E Huizenga, A Goorhuis, M P Grobusch
To date, the management of patients with suspected or confirmed Ebolavirus disease (EVD) depends on quarantine, symptomatic management and supportive care, as there are no approved vaccines or treatments available for human use. However, accelerated by the recent large outbreak in West Africa, significant progress has been made towards vaccine development but also towards specific treatment with convalescent plasma and monoclonal antibodies. Areas covered: We describe recent developments in monoclonal antibody treatment for EVD, encompassing mAb114 and the MB-003, ZMAb, ZMapp™ and MIL-77E cocktails...
November 2016: Expert Opinion on Investigational Drugs
Marissa Balmith, Mbuso Faya, Mahmoud E S Soliman
The Ebola virus, formally known as the Ebola hemorrhagic fever, is an acute viral syndrome causing sporadic outbreaks that have ravaged West Africa. Due to its extreme virulence and highly transmissible nature, Ebola has been classified as a category A bioweapon organism. Only recently have vaccine or drug regimens for the Ebola virus been developed, including Zmapp and peptides. In addition, existing drugs which have been repurposed toward anti-Ebola virus activity have been re-examined and are seen to be promising candidates toward combating Ebola...
March 2017: Chemical Biology & Drug Design
Shannon L M Whitmer, César Albariño, Samuel S Shepard, Gytis Dudas, Mili Sheth, Shelley C Brown, Deborah Cannon, Bobbie R Erickson, Aridth Gibbons, Amy Schuh, Tara Sealy, Elizabeth Ervin, Mike Frace, Timothy M Uyeki, Stuart T Nichol, Ute Ströher
BACKGROUND:  Several patients with Ebola virus disease (EVD) managed in the United States have received ZMapp monoclonal antibodies, TKM-Ebola small interfering RNA, brincidofovir, and/or convalescent plasma as investigational therapeutics. METHODS:  To investigate whether treatment selected for Ebola virus (EBOV) mutations conferring resistance, viral sequencing was performed on RNA extracted from clinical blood specimens from patients with EVD following treatment, and putative viral targets were analyzed...
October 15, 2016: Journal of Infectious Diseases
Andrew Hiatt, Michael Pauly, Kevin Whaley, Xiangguo Qiu, Gary Kobinger, Larry Zeitlin
This review describes the history of Ebola monoclonal antibody (mAb) development leading up to the recent severe Ebola outbreak in West Africa. The Ebola virus has presented numerous perplexing challenges in the long effort to develop therapeutic antibody strategies. Since the first report of a neutralizing human anti-Ebola mAb in 1999, the straightforward progression from in vitro neutralization resulting in in vivo protection and therapy has not occurred. A number of mAbs, including the first reported, failed to protect non-human primates (NHPs) in spite of protection in rodents...
December 23, 2015: Human Antibodies
Stuart D Dowall, Andrew Bosworth, Emma Rayner, Irene Taylor, John Landon, Ian Cameron, Ruth Coxon, Ibrahim Al Abdulla, Victoria A Graham, Graham Hall, Gary Kobinger, Roger Hewson, Miles W Carroll
Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. An ovine polyclonal antibody therapy has been developed against EBOV, named EBOTAb. When tested in the stringent guinea pig model of EBOV disease, EBOTAb has been shown to confer protection at levels of 83.3%, 50% and 33.3% when treatment was first started on days 3, 4 and 5 post-challenge, respectively. These timepoints of when EBOTAb treatment was initiated correspond to when levels of EBOV are detectable in the circulation and thus mimic when treatment would likely be initiated in human infection...
2016: Scientific Reports
Erin E H Tran, Elizabeth A Nelson, Pranay Bonagiri, James A Simmons, Charles J Shoemaker, Connie S Schmaljohn, Gary P Kobinger, Larry Zeitlin, Sriram Subramaniam, Judith M White
UNLABELLED: ZMapp, a cocktail of three monoclonal antibodies (MAbs; c2G4, c4G7, and c13C6) against the ebolavirus (EBOV) glycoprotein (GP), shows promise for combatting outbreaks of EBOV, as occurred in West Africa in 2014. Prior studies showed that Fabs from these MAbs bind a soluble EBOV GP ectodomain and that MAbs c2G4 and c4G7, but not c13C6, neutralize infections in cell cultures. Using cryo-electron tomography, we extended these findings by characterizing the structures of c2G4, c4G7, and c13C6 IgGs bound to native, full-length GP from the West African 2014 isolate embedded in filamentous viruslike particles (VLPs)...
September 1, 2016: Journal of Virology
Qiang Chen, Keith R Davis
The growing promise of plant-made biologics is highlighted by the success story of ZMapp™ as a potentially life-saving drug during the Ebola outbreak of 2014-2016. Current plant expression platforms offer features beyond the traditional advantages of low cost, high scalability, increased safety, and eukaryotic protein modification. Novel transient expression vectors have been developed that allow the production of vaccines and therapeutics at unprecedented speed to control potential pandemics or bioterrorism attacks...
2016: F1000Research
Katie A Howell, Xiangguo Qiu, Jennifer M Brannan, Christopher Bryan, Edgar Davidson, Frederick W Holtsberg, Anna Z Wec, Sergey Shulenin, Julia E Biggins, Robin Douglas, Sven G Enterlein, Hannah L Turner, Jesper Pallesen, Charles D Murin, Shihua He, Andrea Kroeker, Hong Vu, Andrew S Herbert, Marnie L Fusco, Elisabeth K Nyakatura, Jonathan R Lai, Zhen-Yong Keck, Steven K H Foung, Erica Ollmann Saphire, Larry Zeitlin, Andrew B Ward, Kartik Chandran, Benjamin J Doranz, Gary P Kobinger, John M Dye, M Javad Aman
Previous efforts to identify cross-neutralizing antibodies to the receptor-binding site (RBS) of ebolavirus glycoproteins have been unsuccessful, largely because the RBS is occluded on the viral surface. We report a monoclonal antibody (FVM04) that targets a uniquely exposed epitope within the RBS; cross-neutralizes Ebola (EBOV), Sudan (SUDV), and, to a lesser extent, Bundibugyo viruses; and shows protection against EBOV and SUDV in mice and guinea pigs. The antibody cocktail ZMapp™ is remarkably effective against EBOV (Zaire) but does not cross-neutralize other ebolaviruses...
May 17, 2016: Cell Reports
Xuexing Zheng, Gary Wong, Yongkun Zhao, Hualei Wang, Shihua He, Yuhai Bi, Weijin Chen, Hongli Jin, Weiwei Gai, Di Chu, Zengguo Cao, Chong Wang, Quanshui Fan, Hang Chi, Yuwei Gao, Tiecheng Wang, Na Feng, Feihu Yan, Geng Huang, Ying Zheng, Nan Li, Yuetao Li, Jun Qian, Yong Zou, Gary Kobinger, George Fu Gao, Xiangguo Qiu, Songtao Yang, Xianzhu Xia
Recent successes with monoclonal antibody cocktails ZMapp(TM) and MIL77 against Ebola virus (EBOV) infections have reignited interest in antibody-based therapeutics. Since the production process for monoclonal antibodies can be prolonged and costly, alternative treatments should be investigated. We produced purified equine antisera from horses hyperimmunized with EBOV virus-like particles, and tested the post-exposure efficacy of the antisera in a mouse model of infection. BALB/c mice were given up to 2 mg of purified equine antisera per animal, at 30 minutes, 1 or 2 days post-infection (dpi), in which all animals survived...
April 12, 2016: Scientific Reports
M Javad Aman
During virus entry, the surface glycoprotein of Ebola virus (EBOV) undergoes a complex set of transformations within the endosomal network. Tools to study EBOV entry have been limited to static immunofluorescence or biochemical and functional analysis. In a recent article inmBio, Spence et al. reported a novel, live-cell-imaging method that tracks this transformational journey of EBOV in real time [J. S. Spence, T. B. Krause, E. Mittler, R. K. Jangra, and K. Chandran, mBio 7(1):e01857-15, 2016, http://dx.doi...
2016: MBio
Xiangguo Qiu, Jonathan Audet, Ming Lv, Shihua He, Gary Wong, Haiyan Wei, Longlong Luo, Lisa Fernando, Andrea Kroeker, Hugues Fausther Bovendo, Alexander Bello, Feng Li, Pei Ye, Michael Jacobs, Giuseppe Ippolito, Erica Ollmann Saphire, Shengli Bi, Beifen Shen, George F Gao, Larry Zeitlin, Jiannan Feng, Boyan Zhang, Gary P Kobinger
The 2014-2015 Ebola virus (EBOV) outbreak in West Africa highlighted the urgent need for specific therapeutic interventions for infected patients. The human-mouse chimeric monoclonal antibody (mAb) cocktail ZMapp, previously shown to be efficacious in EBOV (variant Kikwit) lethally infected nonhuman primates (NHPs) when administration was initiated up to 5 days, was used in some patients during the outbreak. We show that a two-antibody cocktail, MIL77E, is fully protective in NHPs when administered at 50 mg/kg 3 days after challenge with a lethal dose of EBOV variant Makona, the virus responsible for the ongoing 2014-2015 outbreak, whereas a similar formulation of ZMapp protected two of three NHPs...
March 9, 2016: Science Translational Medicine
Wakako Furuyama, Andrea Marzi, Asuka Nanbo, Elaine Haddock, Junki Maruyama, Hiroko Miyamoto, Manabu Igarashi, Reiko Yoshida, Osamu Noyori, Heinz Feldmann, Ayato Takada
During the latest outbreak of Ebola virus disease in West Africa, monoclonal antibody therapy (e.g., ZMapp) was utilized to treat patients. However, due to the antigenic differences among the five ebolavirus species, the current therapeutic monoclonal antibodies are only effective against viruses of the species Zaire ebolavirus. Although this particular species has indeed caused the majority of human infections in Central and, recently, West Africa, other ebolavirus species (e.g., Sudan ebolavirus and Bundibugyo ebolavirus) have also repeatedly caused outbreaks in Central Africa and thus should not be neglected in the development of countermeasures against ebolaviruses...
February 10, 2016: Scientific Reports
Vincent Madelain, Thi Huyen Tram Nguyen, Anaelle Olivo, Xavier de Lamballerie, Jérémie Guedj, Anne-Marie Taburet, France Mentré
The 2014-2015 outbreak of Ebola virus disease is the largest epidemic to date in terms of the number of cases, deaths, and affected areas. In October 2015, no antiviral agents had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried and has since regularly updated a list of potential drug candidates with demonstrated antiviral efficacy in in vitro or animal models. This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2)...
August 2016: Clinical Pharmacokinetics
Dean K Pettit, Richard S Rogers, Kelly Arthur, Yan Brodsky, Rutilio H Clark, Chris Crowell, Jane Ennis, Alison Gillespie, Ron Gillespie, Brittney Livingston, Edith Nalbandian, Danielle Pace, Pauline Smidt, Michael Pauly, Ken Timmons, Michael Trentalange, Kevin J Whaley, Larry Zeitlin, James N Thomas
From March 2014 through February 2015, the Ebola virus spread rapidly in West Africa, resulting in almost 30,000 infections and approximately 10,000 deaths. With no approved therapeutic options available, an experimental antibody cocktail known as ZMapp™ was administered to patients on a limited compassionate-use basis. The supply of ZMapp™ was highly constrained at the time because it was in preclinical development and a novel production system (tobacco plants) was being used for manufacturing. To increase the production of ZMapp™ for an uncertain future demand, a consortium was formed in the fall of 2014 to quickly manufacture these anti-Ebola antibodies in Chinese hamster ovary (CHO) cells using bioreactors for production at a scale appropriate for thousands of doses...
2016: MAbs
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