Trends in Molecular Medicine
Volume 23, Issue 9, September 2017, Pages 820-830
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Review
Clinical Evaluation of Ebola Virus Disease Therapeutics

https://doi.org/10.1016/j.molmed.2017.07.002Get rights and content

Trends

EVD causes severe hemorrhagic fever in humans, with high fatality rates, with no approved drugs for treatment. Several candidate therapeutics were clinically assessed during the recent 2013–2016 outbreak in West Africa.

Two small molecule inhibitors of viral replication and transcription, a nucleotide analog (favipiravir), and siRNA, did not yield a survival benefit in clinical trials, although administration of favipiravir appeared to be more beneficial for patients with lower viral loads (i.e., in the earlier stages of EVD).

The survival benefit was inconclusive in clinical trials with immune-product-based therapies, including interferon, convalescent plasma, and an mAb cocktail. The data show that the mAb cocktail, ZMapp, may have the best potential for a substantial therapeutic benefit.

Further clinical investigations that could be rapidly initiated early during an outbreak will help conclusively evaluate the true effectiveness of available candidate therapeutics.

Ebola virus disease (EVD) was first described over 40 years ago, but no treatment has been approved for humans. The 2013–2016 EVD outbreak in West Africa has expedited the clinical evaluation of several candidate therapeutics that act through different mechanisms, but with mixed results. Nevertheless, these studies are important because the accumulation of clinical data and valuable experience in conducting efficacy trials under emergency circumstances will lead to better implementation of similar studies in the future. Here, we summarize the results of EVD clinical trials, focus on the discussion of factors that may have potentially impeded the effectiveness of existing candidate therapeutics, and highlight considerations that may help meet the challenges ahead in the quest to develop clinically approved drugs.

Section snippets

EVD Therapeutics Are Urgently Needed

The outbreak of Ebola virus (EBOV) in West Africa from December 2013 to March 2016 was the largest ever reported to date, with 28 616 cases and 11 310 deaths (http://apps.who.int/iris/bitstream/10665/208883/1/ebolasitrep_10Jun2016_eng.pdf?ua=1). EBOV belongs to the genus Ebolavirus, which causes EVD – clinically manifested by a spectrum of symptoms including fever, fatigue, muscle pain, vomiting, diarrhea, anorexia, rash, bleeding, and multiorgan failure 1, 2. Disease fatality rate can be up to

Small Molecule Inhibitors: Direct Intracellular Inhibition of EBOV

A popular approach in the search for effective therapeutics is the identification and characterization of small molecules that might inhibit EBOV; presumably through different mechanisms, including suppression of viral transcription and replication. Many small molecules, such as brincidofovir, BCX4430, favipiravir, GS-5734, and AVI-6002, have been shown to be protective in cultured cells, or in animal models such as mice and NHPs 15, 16, but remain to be assessed against EVD in humans.

IFN-β, a Proof-of-Concept Immunomodulation Trial

IFNs are important components of innate immunity against viral infection and have been used as broad-spectrum antiviral therapies. Protective effects of IFN-α, -β, or -γ against EBOV have been tested in different animal models including mice 49, 50, guinea pigs [51], and NHPs 52, 53. In one EVD patient, IFNs prepared from Sendai-virus-stimulated peripheral lymphocytes were administered intramuscularly in combination with convalescent serum, and this patient survived [54]. However, IFN

Concluding Remarks

Despite challenges of testing candidate therapeutics in the midst of EVD outbreaks, valuable experience has been gained in the design and conduct of expedited clinical trials. A common problem with the trials discussed here has been the relatively low enrollment of patients because trials may have been initiated late during an outbreak, rendering it difficult to conclude whether a specific treatment protocol presented any statistically significant benefits to patients. Nonrandomized single-arm

Acknowledgments

This study was supported by the Public Health Agency of Canada, and partially supported by a NIH grant (U19 AI109762-1) to Gary Kobinger and Xiangguo Qiu, and the National Science and Technology Major Project (2016ZX10004222) to George F. Gao, Yuhai Bi and Gary Wong. The authors have no conflicts of interest to declare. Gary Wong, Gary Kobinger, and Xiangguo Qiu were involved in the development and characterization of ZMapp discussed in this review. Yuhai Bi is supported by the Youth Innovation

Glossary

Convalescent serum/plasma
collected from convalescent patients who presumably carry specific antibodies against the pathogen causing the disease. Convalescent plasma, serum, or whole blood can be used as therapies for infectious diseases, particularly under circumstances of limited medical resources.
Cycle threshold (Ct)
in real-time quantitative PCR reaction, Ct refers to the cycle at which fluorescent signals from PCR amplification exceed background signals. It is a measurement of the amount of

References (83)

  • T. Wolf

    Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care

    Lancet

    (2015)
  • A.I. Flyak

    Cross-reactive and potent neutralizing antibody responses in human survivors of natural Ebolavirus infection

    Cell

    (2016)
  • X. Qiu

    Characterization of Zaire ebolavirus glycoprotein-specific monoclonal antibodies

    Clin. Immunol.

    (2011)
  • E.J. Mendoza

    Progression of Ebola therapeutics during the 2014-2015 outbreak

    Trends Mol. Med.

    (2016)
  • K.A. Howell

    Antibody treatment of Ebola and Sudan virus infection via a uniquely exposed epitope within the glycoprotein receptor-binding site

    Cell Rep.

    (2016)
  • L. Baseler

    The pathogenesis of Ebola virus disease

    Ann. Rev. Pathol

    (2017)
  • T.E. West et al.

    Clinical presentation and management of severe Ebola virus disease

    Ann. Am. Thorac. Soc.

    (2014)
  • G.F. Deen

    Ebola RNA persistence in semen of Ebola virus disease survivors – preliminary report

    N. Engl. J. Med.

    (2015)
  • A. Thorson

    Systematic review of the literature on viral persistence and sexual transmission from recovered Ebola survivors: evidence and recommendations

    BMJ Open

    (2016)
  • I. Messaoudi

    Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus

    Nat. Rev. Microbiol.

    (2015)
  • C.F. Basler

    Molecular pathogenesis of viral hemorrhagic fever

    Semin. Immunopathol.

    (2017)
  • L. Falasca

    Molecular mechanisms of Ebola virus pathogenesis: focus on cell death

    Cell Death Differ.

    (2015)
  • C.M. Bosio

    Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation

    J. Infect. Dis.

    (2003)
  • S. Mahanty

    Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses

    J. Immunol.

    (2003)
  • N. Wauquier

    Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis

    PLoS Negl. Trop. Dis.

    (2010)
  • S.B. Bradfute

    Functional CD8+ T cell responses in lethal Ebola virus infection

    J. Immunol.

    (2008)
  • A.K. McElroy

    Human Ebola virus infection results in substantial immune activation

    Proc Natl. Acad. Sci. U. S. A.

    (2015)
  • A.P. Cardile

    Will there be a cure for Ebola?

    Ann. Rev. Pharmacol. Toxicol.

    (2017)
  • J.G. Julander

    Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106

    Antimicrob. Agents Chemother.

    (2009)
  • Y. Furuta

    In vitro and in vivo activities of anti-influenza virus compound T-705

    Antimicrob. Agents Chemother.

    (2002)
  • Y. Furuta

    Mechanism of action of T-705 against influenza virus

    Antimicrob. Agents Chemother.

    (2005)
  • M. Kiso

    T-705 (favipiravir) activity against lethal H5N1 influenza A viruses

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • K. Sleeman

    In vitro antiviral activity of favipiravir (T-705) against drug-resistant influenza and 2009 A(H1N1) viruses

    Antimicrob. Agents Chemother.

    (2010)
  • A.L. Caroline

    Broad spectrum antiviral activity of favipiravir (T-705): protection from highly lethal inhalational Rift Valley Fever

    PLoS Negl. Trop. Dis

    (2014)
  • L. Oestereich

    Evaluation of antiviral efficacy of ribavirin, arbidol, and T-705 (favipiravir) in a mouse model for Crimean-Congo hemorrhagic fever

    PLoS Negl. Trop. Dis

    (2014)
  • D. Sissoko

    Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea

    PLoS Med.

    (2016)
  • C.Q. Bai

    Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705) – Sierra Leone, 2014

    Clin. Infect. Dis.

    (2016)
  • J.S. Schieffelin

    Clinical illness and outcomes in patients with Ebola in Sierra Leone

    N. Engl. J. Med.

    (2014)
  • E.I. Bah

    Clinical presentation of patients with Ebola virus disease in Conakry, Guinea

    N. Engl. J. Med.

    (2015)
  • M.A. de La Vega

    Ebola viral load at diagnosis associates with patient outcome and outbreak evolution

    J. Clin. Invest.

    (2015)
  • M.G. Kortepeter

    Basic clinical and laboratory features of filoviral hemorrhagic fever

    J. Infect. Dis.

    (2011)
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