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      Remdesivir is efficacious in rhesus monkeys exposed to aerosolized Ebola virus

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          Abstract

          Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.

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          Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.

          Timothy Sheahan, Amy Sims, Rachel Graham … (2017)
          Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. We show that a nucleotide prodrug, GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar IC50 values. GS-5734 was also effective against bat CoVs, prepandemic bat CoVs, and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory function. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future.
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            A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics

            Sabue Mulangu, Lori Dodd, Richard Davey … (2019)
            Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial.
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              Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

              Emmie de Wit, Friederike Feldmann, Jacqueline Cronin … (2020)
              Significance Middle East Respiratory Syndrome, caused by the MERS coronavirus (MERS-CoV), continues to cause severe respiratory disease with a high case fatality rate. To date, potential antiviral treatments for MERS-CoV have shown limited efficacy in animal studies. Here, we tested the efficacy of the broad-acting antiviral remdesivir in the rhesus macaque model of MERS-CoV infection. Remdesivir reduced the severity of disease, virus replication, and damage to the lungs when administered either before or after animals were infected with MERS-CoV. Our data show that remdesivir is a promising antiviral treatment against MERS that could be considered for implementation in clinical trials. It may also have utility for related coronaviruses such as the novel coronavirus 2019-nCoV emerging from Wuhan, China.
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                Author and article information

                Contributors
                Xiankun Zeng: xiankun.zeng.civ@mail.mil
                Patrick L. Iversen: piversen@genevausa.org
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 30 September 2021
                Publication date PMC-release: 30 September 2021
                Publication date Collection: 2021
                Volume: 11
                Electronic Location Identifier: 19458
                Affiliations
                [1 ]GRID grid.416900.a, ISNI 0000 0001 0666 4455, United States Army Medical Research Institute of Infectious Diseases, ; Fort Detrick, Frederick, MD 21702 USA
                [2 ]GRID grid.417469.9, ISNI 0000 0004 0646 0972, The Geneva Foundation, ; Tacoma, WA 98402 USA
                [3 ]GRID grid.418227.a, ISNI 0000 0004 0402 1634, Gilead Sciences, ; Foster City, CA 94404 USA
                [4 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Present Address: Laulima Government Solutions, , Integrated Research Facility NIAID/NIH, ; Fort Detrick, Frederick, MD 21702 USA
                [5 ]GRID grid.48336.3a, ISNI 0000 0004 1936 8075, Present Address: National Cancer Institute, ; Frederick, MD 21702 USA
                [6 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Present Address: SARS-CoV-2 Virology Core, LVD/NIAID/NIH, ; Bethesda, MD 20892 USA
                [7 ]Present Address: Thomas Scientific, Swedesboro, NJ 08085 USA
                [8 ]Present Address: Helios, Frederick, MD 21702 USA
                Article
                Publisher ID: 98971
                DOI: 10.1038/s41598-021-98971-0
                PMC ID: 8484580
                PubMed ID: 34593911
                SO-VID: ff1181af-92ed-47ae-b95f-b46c42dd66b9
                Copyright © © The Author(s) 2021
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 6 May 2021
                Date accepted : 2 September 2021
                Funding
                Funded by: US Army Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense Joint Project Manager for Chemical, Biological, Radiological, and Nuclear Defense Medical under
                Award ID: W911QY-16-9-0001
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                ScienceOpen disciplines: Uncategorized
                Keywords: microbiology,virology,ebola virus,infectious diseases
                Data availability:
                ScienceOpen disciplines: Uncategorized
                Keywords: microbiology, virology, ebola virus, infectious diseases

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