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Andrew I Flyak, Natalia Kuzmina, Charles D Murin, Christopher Bryan, Edgar Davidson, Pavlo Gilchuk, Christopher P Gulka, Philipp A Ilinykh, Xiaoli Shen, Kai Huang, Palaniappan Ramanathan, Hannah Turner, Marnie L Fusco, Rebecca Lampley, Nurgun Kose, Hannah King, Gopal Sapparapu, Benjamin J Doranz, Thomas G Ksiazek, David W Wright, Erica Ollmann Saphire, Andrew B Ward, Alexander Bukreyev, James E Crowe
Ebola virus (EBOV) in humans causes a severe illness with high mortality rates. Several strategies have been developed in the past to treat EBOV infection, including the antibody cocktail ZMapp, which has been shown to be effective in nonhuman primate models of infection 1 and has been used under compassionate-treatment protocols in humans 2 . ZMapp is a mixture of three chimerized murine monoclonal antibodies (mAbs)3-6 that target EBOV-specific epitopes on the surface glycoprotein7,8 . However, ZMapp mAbs do not neutralize other species from the genus Ebolavirus, such as Bundibugyo virus (BDBV), Reston virus (RESTV) or Sudan virus (SUDV)...
May 7, 2018: Nature Microbiology
Jin Won Lee, Woon Heo, Jinu Lee, Narae Jin, Sei Mee Yoon, Ki Youl Park, Eun Yu Kim, Woo Taek Kim, Joo Young Kim
Plants have attracted attention as bio-drug production platforms because of their economical and safety benefits. The preliminary efficacy of ZMapp, a cocktail of antibodies produced in N. benthamiana (Nicotiana benthamiana L.), suggested plants may serve as a platform for antibody production. However, because the amino acid sequences of the Fab fragment are diverse and differences in post-transcriptional processes between animals and plants remain to be elucidated, it is necessary to confirm functional equivalence of plant-produced antibodies to the original antibody...
2018: PloS One
Séverine Caluwaerts
During the 2014-2016 Ebola epidemic, Médecins Sans Frontières (MSF) treated Ebola-positive pregnant women in its Ebola Treatment Centers (ETCs). For pregnant women with confirmed Ebola virus disease, inclusion in clinical vaccine/drug/therapeutic trials was complicated. Despite their extremely high Ebola-related mortality in previous epidemics (89-93%) and a neonatal mortality of 100%, theoretical concerns about safety of vaccines and therapeutics in pregnancy were invoked, limiting pregnant women's access to an experimental live attenuated vaccine and brincidofovir, an experimental antiviral...
December 14, 2017: Reproductive Health
Marc-André Robert, Nasha Nassoury, Parminder S Chahal, Marie-Hélène Venne, Trina Racine, Xiangguo Qiu, Gary Kobinger, Amine Kamen, Rénald Gilbert, Bruno Gaillet
Vectored delivery of the ZMapp antibody cocktail (c2G4, c4G7, and c13C6) by using recombinant adeno-associated viruses (rAAVs) could be useful for preventive immunization against Ebola virus infections because rAAVs can generate long-term antibody expression. Three rAAVs (serotype 9) encoding chimeric ZMapp antibodies were produced by triple-plasmid transfection up to 10 L-scale in WAVE bioreactors using HEK293 cells grown in suspension/serum-free conditions. Efficacy of AAV-c2G4 via intravenous (i.v.), intramuscular (i...
March 1, 2018: Human Gene Therapy
Denis Malvy, Daouda Sissoko, Alseny-Modet Camara
During the 2013-2016 west African Ebola outbreak that affected West Africa, accelerated clinical trials, testing unproven but promising and potentially lifesaving experimental interventions emerged as a key component of the global outbreak. In 2017, no Ebola medical countermeasures had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried a list of potential drug candidates developed or repurposed with demonstrated antiviral efficacy in vitro or in animal models...
October 2017: Médecine Sciences: M/S
Sandra L Bixler, Allen J Duplantier, Sina Bavari
PURPOSE OF REVIEW: Ebola virus, a member of the Filoviridae family, is a causative agent of severe viral hemorrhagic fever in humans. Over the past 40 years, the virus has been linked to several high mortality outbreaks in Africa with the recent West African outbreak resulting in over 11,000 deaths. This review provides a summary of the status of the drug discovery and development process for therapeutics for Ebola virus disease, with a focus on the strategies being used and the challenges facing each stage of the process...
2017: Current Treatment Options in Infectious Diseases
Lilya Kopertekh, Joachim Schiemann
During the last two decades the production of pharmaceutical proteins in plants evolved from proof of concept to established technology adopted by several biotechnological companies. This progress is particularly based on intensive research starting stable genetic transformation and moving to transient expression. Due to its advantages in yield and speed of protein production transient expression platforms became leading plant-based manufacturing technology. Current transient expression methods rely on Agrobacterium-mediated delivery of expression vectors into plant cells...
July 18, 2017: Current Medicinal Chemistry
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
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