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A Multicenter, Multi-Outbreak, Randomized, Controlled Safety And
2018 Ebola MCM RCT Protocol Page 1 of 92 IND#: 125530 CONFIDENTIAL 4 October 2019, version 7.0 A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and Efficacy Study of Investigational Therapeutics for the Treatment of Patients with Ebola Virus Disease Short Title: 2018 Ebola MCM RCT Protocol Sponsored by: Office of Clinical Research Policy and Regulatory Operations (OCRPRO) National Institute of Allergy and Infectious Diseases 5601 Fishers Lane Bethesda, MD 20892 NIH Protocol Number: 19-I-0003 Protocol IND #: 125530 ClinicalTrials.gov Number: NCT03719586 Date: 4 October 2019 Version: 7.0 CONFIDENTIAL This document is confidential. No part of it may be transmitted, reproduced, published, or used by other persons without prior written authorization from the study sponsor and principal investigator. 2018 Ebola MCM RCT Protocol Page 2 of 92 IND#: 125530 CONFIDENTIAL 4 October 2019, version 7.0 KEY ROLES DRC Principal Investigator: Jean-Jacques Muyembe-Tamfum, MD, PhD Director-General, DRC National Institute for Biomedical Research Professor of Microbiology, Kinshasa University Medical School Kinshasa Gombe Democratic Republic of the Congo Phone: +243 898949289 Email: [email protected] Other International Investigators: see Appendix E Statistical Lead: Lori Dodd, PhD Biostatistics Research Branch, DCR, NIAID 5601 Fishers Lane, Room 4C31 Rockville, MD 20852 Phone: 240-669-5247 Email: [email protected] U.S. Principal Investigator: Richard T. Davey, Jr., MD Clinical Research Section, LIR, NIAID, NIH Building 10, Room 4-1479, Bethesda, -
Plotting the Course of Ebola Vaccines
March 2016 Ebola Vaccine Team B Plotting the Course of Ebola Vaccines CHALLENGES AND UNANSWERED QUESTIONS Plotting the Course of Ebola Vaccines CHALLENGES AND UNANSWERED QUESTIONS March 2016 Plotting the Course of Ebola Vaccines: Challenges and Unanswered Questions was made possible through a joint project of Wellcome Trust and the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota. Wellcome Trust is a global charitable foundation dedicated to improving health by supporting bright minds in science, the humanities and social sciences, and public engagement. Wellcome Trust is independent of both political and commercial interests. For more information, visit www.wellcome.ac.uk/index.htm. The Center for Infectious Disease Research and Policy (CIDRAP), founded in 2001, is a global leader in addressing public health preparedness and emerging infectious disease response. Part of the Academic Health Center at the University of Minnesota, CIDRAP works to prevent illness and death from targeted infectious disease threats through research and the translation of scientific information into real-world, practical applications, policies, and solutions. For more information, visit www.cidrap.umn.edu. Permissions: CIDRAP authorizes the making and distribution of copies or excerpts (in a manner that does not distort the meaning of the original) of this information for non-commercial, educational purposes within organizations. The following credit line must appear: “Reprinted with permission of the Center for Infectious Disease Research and Policy. Copyright Regents of the University of Minnesota.” This publication is designed to provide accurate and authoritative information with regard to the subject matter covered. It is published with the understanding that the publisher is not engaged in rendering legal, medical, or other professional services. -
Brincidofovir Is Highly Efficacious in Controlling Adenoviremia In
Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant Prashant Hiwarkar,1 Persis Amrolia,2 Ponni Sivaprakasam,3 Su Han Lum,4 Hemalatha Doss,5 Ciara O’Rafferty,1 Toni Petterson,6 Katharine Patrick,7 Juliana Silva,2 Mary Slatter,5 Sarah Lawson,1 Kanchan Rao,2 Colin Steward,3 Adam Gassas,3 Paul Veys,2 Robert Wynn4 On behalf of the UK Paediatric BMT Group 1Department of Haematology and Bone Marrow Transplantation, Birmingham Children’s Hospital, Birmingham, UK; 2Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children, London; 3Department of Bone Marrow Transplantation, Royal Hospital for Children, Bristol, UK; 4Department of Bone Marrow Transplantation, Royal Manchester Children's Hospital, Manchester, UK; 5Department of Bone Marrow Transplantation, Great North Children's Hospital, Newcastle upon Tyne, UK; 6Department of Bone Marrow Transplantation, Royal Marsden Hospital, Sutton, UK; 7Department of Bone Marrow Transplantation, Sheffield Children's Hospital, Sheffield, UK Address for Correspondence: [email protected] Department of Haematology and Bone Marrow transplantation Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK B4 6NH Tel. +44 (0)121 333 9999 Key points Brincidofovir has superior anti-adenoviral activity and safety profile compared to Cidofovir. Brincidofovir is highly efficacious in controlling adenoviraemia during lymphopenic phase of HCT. Summary Cidofovir is pre-emptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid conjugated prodrug of Cidofovir, Brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. -
Ebola Hemorrhagic Fever: Properties of the Pathogen and Development of Vaccines and Chemotherapeutic Agents O
ISSN 00268933, Molecular Biology, 2015, Vol. 49, No. 4, pp. 480–493. © Pleiades Publishing, Inc., 2015. Original Russian Text © O.I. Kiselev, A.V. Vasin, M.P. Shevyryova, E.G. Deeva, K.V. Sivak, V.V. Egorov, V.B. Tsvetkov, A.Yu. Egorov, E.A. RomanovskayaRomanko, L.A. Stepanova, A.B. Komissarov, L.M. Tsybalova, G.M. Ignatjev, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 4, pp. 541–554. REVIEWS UDC 578.2,578.76 Ebola Hemorrhagic Fever: Properties of the Pathogen and Development of Vaccines and Chemotherapeutic Agents O. I. Kiseleva, A. V. Vasina, b, M. P. Shevyryovac, E. G. Deevaa, K. V. Sivaka, V. V. Egorova, V. B. Tsvetkova, d, A. Yu. Egorova, E. A. RomanovskayaRomankoa, L. A. Stepanovaa, A. B. Komissarova, L. M. Tsybalovaa, and G. M. Ignatjeva a Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, 197376 Russia; email: [email protected] b St. Petersburg State Polytechnic University, St. Petersburg, 195251 Russia c Ministry of Health of the Russian Federation, Moscow, 127994 Russia d Topchiev Institute of Petrochemical Synthesis, Moscow, 119991 Russia Received December 29, 2014; in final form, January 16, 2015 Abstract—Ebola hemorrhagic fever (EHF) epidemic currently ongoing in West Africa is not the first among numerous epidemics in the continent. Yet it seems to be the worst EHF epidemic outbreak caused by Ebola virus Zaire since 1976 as regards its extremely large scale and rapid spread in the population. Experiments to study the agent have continued for more than 20 years. The EHF virus has a relatively simple genome with seven genes and additional reading frame resulting from RNA editing. -
Kinase Inhibitors and Nucleoside Analogues As Novel Therapies to Inhibit HIV-1 Or ZEBOV Replication
Kinase Inhibitors and Nucleoside Analogues as Novel Therapies to Inhibit HIV-1 or ZEBOV Replication by Stephen D. S. McCarthy A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Laboratory Medicine and Pathobiology University of Toronto © Copyright by Stephen D. S. McCarthy (2017) Kinase Inhibitors and Nucleoside Analogues as Novel Therapies to Inhibit HIV-1 or ZEBOV Replication Stephen D.S. McCarthy Doctor of Philosophy Graduate Department of Laboratory Medicine and Pathobiology University of Toronto 2017 Abstract Without a vaccine for Human Immunodeficiency Virus type 1 (HIV-1), or approved therapy for treating Zaire Ebolavirus (ZEBOV) infection, new means to treat either virus during acute infection are under intense investigation. Repurposing tyrosine kinase inhibitors of known specificity may not only inhibit HIV-1 replication, but also treat associated inflammation or neurocognitive disorders caused by chronic HIV-1 infection. Moreover, tyrosine kinase inhibitors may effectively treat other infections, including ZEBOV. In addition, established nucleoside/nucleotide analogues that effectively inhibit HIV-1 infection, could also be repurposed to inhibit ZEBOV replication. In this work the role of two host cell kinases, cellular protoncogene SRC (c-SRC) and Protein Tyrosine Kinase 2 Beta (PTK2B), were found to have key roles during early HIV-1 replication in primary activated CD4+ T-cells ex vivo. siRNA knockdown of either kinase increased intracellular reverse transcripts and decreased nuclear proviral integration, suggesting they act at the level of pre-integration complex (PIC) formation or PIC nuclear translocation. c-SRC siRNA knockdown consistently reduced p24 levels of IIIB(X4) and Ba-L(R5) infection, or luciferase ii activity of HXB2(X4) or JR-FL(R5) recombinant viruses, prompting further drug inhibition studies of this kinase. -
Leafbio Announces Conclusion of Zmapp™ Clinical Trial Therapy to Treat Ebola Shows Promise
FOR IMMEDIATE RELEASE Contact: Kerri Lyon [email protected] February 23, 2016 917-348-2191 LeafBio Announces Conclusion of ZMapp™ Clinical Trial Therapy to Treat Ebola Shows Promise February 23, 2016 – SAN DIEGO – LeafBio, Inc., the commercial arm of Mapp Biopharmaceutical, Inc., announced today results from the Prevail II clinical trial of its ZMapp™ therapy for treatment of Ebola Virus Disease. The trial, conducted in Liberia, Sierra Leone, Guinea and the United States over the course of nearly a year, was initiated to evaluate the efficacy of ZMapp™ in treating Ebola Virus Disease and concluded on January 29, 2016. While the trial did not ultimately enroll enough patients to produce definitive results, researchers said the drug was well-tolerated and showed promise. As a result, the U.S. Food and Drug Administration has encouraged Mapp Biopharmaceutical to continue to make ZMapp™ available to patients under an expanded access treatment protocol during the product’s ongoing development. “We are encouraged by these results,” said Dr. Larry Zeitlin, president of Mapp Bio. “The outcome of this truncated study is supportive of ZMapp’s™ antiviral activity in humans. While this trial is not definitive, its results are consistent with the favorable results observed in animal efficacy testing in nonhuman primates.” The study closed short of its enrollment goals due to the waning of the Ebola epidemic in West Africa. Liberia, Sierra Leone and Guinea, the three countries hardest hit by the epidemic, had been declared Ebola-free by the World Health Organization at various points through the end of 2015, and there are presently no confirmed cases in the region. -
Situación Actual Del Tratamiento Farmacológico Frente a La Enfermedad Causada Por El Virus Ébola
Revisión Jordi Reina Situación actual del tratamiento farmacológico frente a la enfermedad causada por el virus Ébola Unidad de Virología. Servicio de Microbiología. Hospital Universitario Son Espases. Palma de Mallorca RESUMEN Current status of drug treatment against the disease caused by the Ebola virus La reciente epidemia de enfermedad causada por el virus Ébola ha puesto en evidencia la necesidad de desarrollar y dis- ABSTRACT poner de fármacos específicos para hacer frente a esta entidad. De acuerdo con los datos virológicos se han diseñado algunos The recent epidemic of disease caused by the Ebola virus fármacos nuevos y se ha comprobado que otros podrían tener has highlighted the need to develop specific drugs and have to eficacia frente a este virus. deal with this entity. According to virological analysis they have Las principales líneas terapéuticas se basan en la inmu- been designed to give you some new drugs and are proven to noterapia (suero de pacientes convalescientes y anticuerpos others might be effective against this virus. monoclonales específicos), en fármacos antivirales (favipiora- The main lines of therapy are based on immunotherapy vir, BCX4430, Brincidofovir), RNAs de interferencia (TKM-Ébola) (convalescent serum of patients and specific monoclonal an- y oligonucleótidos sin sentido (morfolino fosforodiamidato) y tibodies), antiviral drugs (favipiravir, BCX4430, brincidofovir), otros fármacos no antivirales (clomifeno, NSC62914, FGI-103, interfering RNAs (TKM-Ebola) and antisense oligonucleotides amilorida y la ouabaina). (morpholino phosphorodiamidate) and other drugs no antiviral Los estudios existentes son escasos y principalmente en (clomiphene NSC62914, FGI-103, amiloride and ouabain). modelos animales y los ensayos clínicos han quedado la ma- Existing studies are scarce and mainly in animal models yoría inconclusos por la disminución drástica del número de and clinical trials have been inconclusive most by the drastic nuevos casos. -
The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak
viruses Perspective The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak Scott A. Foster 1,*, Scott Parker 2 ID and Randall Lanier 1 1 Chimerix, Durham, NC 27713, USA; [email protected] 2 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-919-597-7741 Received: 29 September 2017; Accepted: 26 October 2017; Published: 30 October 2017 Abstract: Smallpox (variola) virus is considered a Category A bioterrorism agent due to its ability to spread rapidly and the high morbidity and mortality rates associated with infection. Current recommendations recognize the importance of oral antivirals and call for having at least two smallpox antivirals with different mechanisms of action available in the event of a smallpox outbreak. Multiple antivirals are recommended due in large part to the propensity of viruses to become resistant to antiviral therapy, especially monotherapy. Advances in synthetic biology heighten concerns that a bioterror attack with variola would utilize engineered resistance to antivirals and potentially vaccines. Brincidofovir, an oral antiviral in late stage development, has proven effective against orthopoxviruses in vitro and in vivo, has a different mechanism of action from tecovirimat (the only oral smallpox antiviral currently in the US Strategic National Stockpile), and has a resistance profile that reduces concerns in the scenario of a bioterror attack using genetically engineered smallpox. Given the devastating potential of smallpox as a bioweapon, preparation of a multi-pronged defense that accounts for the most obvious bioengineering possibilities is strategically imperative. Keywords: smallpox; variola virus; bioterrorism; bioweapon; brincidofovir; CMX001; antiviral 1. -
Integrated Computational Approach for Virtual Hit Identification Against
International Journal of Molecular Sciences Article Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40 Muhammad Usman Mirza 1,2,*,† and Nazia Ikram 2 1 Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Defense Road, Lahore 54000, Pakistan 2 Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +92-333-839-6037 † Current address: Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, University of Leuven, Leuven B-3000, Belgium. Academic Editors: Christo Z. Christov and Tatyana Karabencheva-Christova Received: 28 July 2016; Accepted: 22 September 2016; Published: 26 October 2016 Abstract: The Ebola virus (EBOV) has been recognised for nearly 40 years, with the most recent EBOV outbreak being in West Africa, where it created a humanitarian crisis. Mortalities reported up to 30 March 2016 totalled 11,307. However, up until now, EBOV drugs have been far from achieving regulatory (FDA) approval. It is therefore essential to identify parent compounds that have the potential to be developed into effective drugs. Studies on Ebola viral proteins have shown that some can elicit an immunological response in mice, and these are now considered essential components of a vaccine designed to protect against Ebola haemorrhagic fever. The current study focuses on chemoinformatic approaches to identify virtual hits against Ebola viral proteins (VP35 and VP40), including protein binding site prediction, drug-likeness, pharmacokinetic and pharmacodynamic properties, metabolic site prediction, and molecular docking. Retrospective validation was performed using a database of non-active compounds, and early enrichment of EBOV actives at different false positive rates was calculated. -
A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19
bioRxiv preprint doi: https://doi.org/10.1101/2020.04.23.058776; this version posted April 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19 Steffen Jockusch1,2,#, Chuanjuan Tao1,3,#, Xiaoxu Li1,3,#, Thomas K. Anderson5,6, Minchen Chien1,3, Shiv Kumar1,3, James J. Russo1,3, Robert N. Kirchdoerfer5,6,*, Jingyue Ju1,3,4,* 1Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027; Departments of 2 Chemistry, 3Chemical Engineering, and 4Pharmacology, Columbia University, New York, NY 10027; 5Departments of Biochemistry and 6Institute of Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706 #SJ, CT and XL contributed equally to this work. *To whom correspondence should be addressed: [email protected] (JJ); [email protected] (RNK) Abstract SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA- dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of additional nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2’ or 3’ modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base. -
To Ebola Reston
WHO/HSE/EPR/2009.2 WHO experts consultation on Ebola Reston pathogenicity in humans Geneva, Switzerland 1 April 2009 EPIDEMIC AND PANDEMIC ALERT AND RESPONSE WHO experts consultation on Ebola Reston pathogenicity in humans Geneva, Switzerland 1 April 2009 © World Health Organization 2009 All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distin- guished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either express or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the policies of the World Health Organization. -
How Severe and Prevalent Are Ebola and Marburg Viruses?
Nyakarahuka et al. BMC Infectious Diseases (2016) 16:708 DOI 10.1186/s12879-016-2045-6 RESEARCHARTICLE Open Access How severe and prevalent are Ebola and Marburg viruses? A systematic review and meta-analysis of the case fatality rates and seroprevalence Luke Nyakarahuka1,2,5* , Clovice Kankya2, Randi Krontveit3, Benjamin Mayer4, Frank N. Mwiine2, Julius Lutwama5 and Eystein Skjerve1 Abstract Background: Ebola and Marburg virus diseases are said to occur at a low prevalence, but are very severe diseases with high lethalities. The fatality rates reported in different outbreaks ranged from 24–100%. In addition, sero-surveys conducted have shown different seropositivity for both Ebola and Marburg viruses. We aimed to use a meta-analysis approach to estimate the case fatality and seroprevalence rates of these filoviruses, providing vital information for epidemic response and preparedness in countries affected by these diseases. Methods: Published literature was retrieved through a search of databases. Articles were included if they reported number of deaths, cases, and seropositivity. We further cross-referenced with ministries of health, WHO and CDC databases. The effect size was proportion represented by case fatality rate (CFR) and seroprevalence. Analysis was done using the metaprop command in STATA. Results: The weighted average CFR of Ebola virus disease was estimated to be 65.0% [95% CI (54.0–76.0%), I2 = 97.98%] whereas that of Marburg virus disease was 53.8% (26.5–80.0%, I2 = 88.6%). The overall seroprevalence of Ebola virus was 8.0% (5.0%–11.0%, I2 = 98.7%), whereas that for Marburg virus was 1.2% (0.5–2.0%, I2 = 94.8%).