Modeling Favipiravir Antiviral Efficacy Against Emerging Viruses: from Animal Studies to Clinical Trials
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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, -
COVID-19) Pandemic on National Antimicrobial Consumption in Jordan
antibiotics Article An Assessment of the Impact of Coronavirus Disease (COVID-19) Pandemic on National Antimicrobial Consumption in Jordan Sayer Al-Azzam 1, Nizar Mahmoud Mhaidat 1, Hayaa A. Banat 2, Mohammad Alfaour 2, Dana Samih Ahmad 2, Arno Muller 3, Adi Al-Nuseirat 4 , Elizabeth A. Lattyak 5, Barbara R. Conway 6,7 and Mamoon A. Aldeyab 6,* 1 Clinical Pharmacy Department, Jordan University of Science and Technology, Irbid 22110, Jordan; [email protected] (S.A.-A.); [email protected] (N.M.M.) 2 Jordan Food and Drug Administration (JFDA), Amman 11181, Jordan; [email protected] (H.A.B.); [email protected] (M.A.); [email protected] (D.S.A.) 3 Antimicrobial Resistance Division, World Health Organization, Avenue Appia 20, 1211 Geneva, Switzerland; [email protected] 4 World Health Organization Regional Office for the Eastern Mediterranean, Cairo 11371, Egypt; [email protected] 5 Scientific Computing Associates Corp., River Forest, IL 60305, USA; [email protected] 6 Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK; [email protected] 7 Institute of Skin Integrity and Infection Prevention, University of Huddersfield, Huddersfield HD1 3DH, UK * Correspondence: [email protected] Citation: Al-Azzam, S.; Mhaidat, N.M.; Banat, H.A.; Alfaour, M.; Abstract: Coronavirus disease 2019 (COVID-19) has overlapping clinical characteristics with bacterial Ahmad, D.S.; Muller, A.; Al-Nuseirat, respiratory tract infection, leading to the prescription of potentially unnecessary antibiotics. This A.; Lattyak, E.A.; Conway, B.R.; study aimed at measuring changes and patterns of national antimicrobial use for one year preceding Aldeyab, M.A. -
Signature Redacted Signature of Author
Developing VHH-based tools to study Ebolavirus Infection By Jason V. M. H. Nguyen B.S., Biochemistry and Molecular Biology University of California, Santa Cruz, 2012 Submitted to the Microbiology Graduate Program in partial fulfillment of the requirements for the degree of Doctor of Philosophy At the Massachusetts Institute of Technology June 2019 2019 Massachusetts Institute of Technology. All rights reserved. Signature redacted Signature of Author...... .................................................................... V Y' Jason V. M. H. Nguyen Microbiology Graduate Program May 13, 2019 Signature redacted Certified by.............. ................................................................... Hidde L. Ploegh Senior Investigator Boston Children's Hospital It Signature redacted Accepted by....... ......................................................................... Jacquin C. Niles Associate Professor of Biological Engineering Chair of Microbiology Program MASSACHUSETTS INSTITUTE OF TECHNOLOGY JUN 2 12019 1 LIBRARIES ARCHIVES 2 Developing VHH-based tools to study Ebolavirus Infection By Jason V. M. H. Nguyen Submitted to the Microbiology Graduate Program on May 13th, 2019 in partial fulfillment of the requirements for the degree of Doctor of Philosophy ABSTRACT Variable domains of camelid-derived heavy chain-only antibodies, or VHHs, have emerged as a unique antigen binding moiety that holds promise in its versatility and utilization as a tool to study biological questions. This thesis focuses on two aspects on developing tools to study infectious disease, specifically Ebolavirus entry. In Chapter 1, I provide an overview about antibodies and how antibodies have transformed the biomedical field and how single domain antibody fragments, or VHHs, have entered this arena. I will also touch upon how VHHs have been used in various fields and certain aspects that remain underexplored. Chapter 2 focuses on the utilization of VHHs to study Ebolavirus entry using VHHs that were isolated from alpacas. -
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. -
Remdesivir Targets a Structurally Analogous Region of the Ebola Virus and SARS-Cov-2 Polymerases
Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases Michael K. Loa,1, César G. Albariñoa, Jason K. Perryb, Silvia Changb, Egor P. Tchesnokovc,d, Lisa Guerreroa, Ayan Chakrabartia, Punya Shrivastava-Ranjana, Payel Chatterjeea, Laura K. McMullana, Ross Martinb, Robert Jordanb,2, Matthias Göttec,d, Joel M. Montgomerya, Stuart T. Nichola, Mike Flinta, Danielle Porterb, and Christina F. Spiropouloua,1 aViral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329; bGilead Sciences Inc., Foster City, CA 94404; cDepartment of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada; and dLi Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved September 7, 2020 (received for review June 14, 2020) Remdesivir is a broad-spectrum antiviral nucleotide prodrug that remdesivir-selected EBOV lineages; this mutation resulted in a has been clinically evaluated in Ebola virus patients and recently nonconservative amino acid substitution at residue 548 (F548S) in received emergency use authorization (EUA) for treatment of the fingers subdomain of the EBOV L RdRp. We examined this COVID-19. With approvals from the Federal Select Agent Program mutation in several contexts: a cell-based minigenome, a cell-free and the Centers for Disease Control and Prevention’s Institutional biochemical polymerase assay, as well as in a full-length infectious Biosecurity Board, we characterized the resistance profile of recombinant EBOV. In the context of the infectious virus, the F548S remdesivir by serially passaging Ebola virus under remdesivir se- substitution recapitulated the reduced susceptibility phenotype to lection; we generated lineages with low-level reduced susceptibil- remdesivir, and potentially showed a marginal decrease in viral fit- ity to remdesivir after 35 passages. -
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. -
Potential Drug Candidates Underway Several Registered Clinical Trials for Battling COVID-19
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 20 April 2020 doi:10.20944/preprints202004.0367.v1 Potential Drug Candidates Underway Several Registered Clinical Trials for Battling COVID-19 Fahmida Begum Minaa, Md. Siddikur Rahman¥a, Sabuj Das¥a, Sumon Karmakarb, Mutasim Billahc* aDepartment of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi-6205, Bangladesh bMolecular Biology and Protein Science Laboratory, University of Rajshahi, Rajshahi-6205, Bangladesh cProfessor Joarder DNA & Chromosome Research Laboratory, University of Rajshahi, Rajshahi-6205, Bangladesh *Corresponding Author: Mutasim Billah, Professor Joarder DNA & Chromosome Research Laboratory, University of Rajshahi, Rajshahi, Bangladesh Corresponding Author Mail: [email protected] ¥Co-second author Abstract The emergence of new type of viral pneumonia cases in China, on December 31, 2019; identified as the cause of human coronavirus, labeled as "COVID-19," took a heavy toll of death and reported cases of infected people all over the world, with the potential to spread widely and rapidly, achieved worldwide prominence but arose without the procurement guidance. There is an immediate need for active intervention and fast drug discovery against the 2019-nCoV outbreak. Herein, the study provides numerous candidates of drugs (either alone or integrated with another drugs) which could prove to be effective against 2019- nCoV, are under different stages of clinical trials. This review will offer rapid identification of a number of repurposable drugs and potential drug combinations targeting 2019-nCoV and preferentially allow the international research community to evaluate the findings, to validate the efficacy of the proposed drugs in prospective trials and to lead potential clinical practices. Keywords: COVID-19; Drugs; 2019-nCoV; Clinical trials; SARS-CoV-2 Introduction A new type of viral pneumonia cases occurred in Wuhan, Hubei Province in China, on December 31, 2019; named "COVID-19" on January 12, 2020 by the World Health Organization (WHO) [1]. -
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. -
Determining Ribavirin's Mechanism of Action Against Lassa Virus Infection
www.nature.com/scientificreports OPEN Determining Ribavirin’s mechanism of action against Lassa virus infection Received: 28 March 2017 Paola Carrillo-Bustamante1, Thi Huyen Tram Nguyen2,3, Lisa Oestereich4,5, Stephan Accepted: 4 August 2017 Günther4,5, Jeremie Guedj 2,3 & Frederik Graw1 Published: xx xx xxxx Ribavirin is a broad spectrum antiviral which inhibits Lassa virus (LASV) replication in vitro but exhibits a minor effect on viremiain vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin’s mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin’s main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response. Lassa fever (LF) is a severe and often fatal hemorrhagic disease caused by Lassa virus (LASV), a member of the Arenaviridae virus family. -
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. -
Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir
RESEARCH ARTICLE Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir Ana I. de AÂ vila1, Isabel Gallego1,2, Maria Eugenia Soria3, Josep Gregori2,3,4, Josep Quer2,3,5, Juan Ignacio Esteban2,3,5, Charles M. Rice6, Esteban Domingo1,2*, Celia Perales1,2,3* 1 Centro de BiologõÂa Molecular ªSevero Ochoaº (CSIC-UAM), Consejo Superior de Investigaciones CientõÂficas (CSIC), Campus de Cantoblanco, 28049, Madrid, Spain, 2 Centro de InvestigacioÂn BiomeÂdica en Red de Enfermedades HepaÂticas y Digestivas (CIBERehd), Barcelona, Spain, 3 Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d a11111 ÂHebron, (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain, 4 Roche Diagnostics, S.L., Sant Cugat del ValleÂs, Spain, 5 Universitat AutoÂnoma de Barcelona, Barcelona, Spain, 6 Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America * [email protected] (ED); [email protected] (CP) OPEN ACCESS Abstract Citation: de AÂvila AI, Gallego I, Soria ME, Gregori J, Quer J, Esteban JI, et al. (2016) Lethal Lethal mutagenesis is an antiviral approach that consists in extinguishing a virus by an Mutagenesis of Hepatitis C Virus Induced by excess of mutations acquired during replication in the presence of a mutagen. Here we Favipiravir. PLoS ONE 11(10): e0164691. show that favipiravir (T-705) is a potent mutagenic agent for hepatitis C virus (HCV) during doi:10.1371/journal.pone.0164691 its replication in human hepatoma cells. T-705 leads to an excess of G ! A and C ! U tran- Editor: Ming-Lung Yu, Kaohsiung Medical sitions in the mutant spectrum of preextinction HCV populations. -
2019 Icar Program & Abstracts Book
Hosted by the International Society for Antiviral Research (ISAR) ND International Conference 32on Antiviral Research (ICAR) Baltimore MARYLAND PROGRAM and USA Hyatt Regency BALTIMORE ABSTRACTS May 12-15 2019 ND TABLE OF International Conference CONTENTS 32on Antiviral Research (ICAR) Daily Schedule . .3 Organization . 4 Contributors . 5 Keynotes & Networking . 6 Schedule at a Glance . 7 ISAR Awardees . 10 The 2019 Chu Family Foundation Scholarship Awardees . 15 Speaker Biographies . 17 Program Schedule . .25 Posters . 37 Abstracts . 53 Author Index . 130 PROGRAM and ABSTRACTS of the 32nd International Conference on Antiviral Research (ICAR) 2 ND DAILY International Conference SCHEDULE 32on Antiviral Research (ICAR) SUNDAY, MAY 12, 2019 › Women in Science Roundtable › Welcome and Keynote Lectures › Antonín Holý Memorial Award Lecture › Influenza Symposium › Opening Reception MONDAY, MAY 13, 2019 › Women in Science Award Lecture › Emerging Virus Symposium › Short Presentations 1 › Poster Session 1 › Retrovirus Symposium › ISAR Award of Excellence Presentation › PechaKucha Event with Introduction of First Time Attendees TUESDAY, MAY 14, 2019 › What’s New in Antiviral Research 1 › Short Presentations 2 & 3 › ISAR Award for Outstanding Contributions to the Society Presentation › Career Development Panel › William Prusoff Young Investigator Award Lecture › Medicinal Chemistry Symposium › Poster Session 2 › Networking Reception WEDNESDAY, MAY 15, 2019 › Gertrude Elion Memorial Award Lecture › What’s New in Antiviral Research 2 › Shotgun Oral