#Ribavirin and #Interferon #Therapy for Critically Ill Patients With #MERS: A Multicenter Observational Study (Clin Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Clin Infect Dis. 2019 Jun 25. pii: ciz544. doi: 10.1093/cid/ciz544. [Epub ahead of print]

Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study.

Arabi YM1, Shalhoub S2,3, Mandourah Y4, Al-Hameed F5, Al-Omari A6, Al Qasim E1, Jose J1, Alraddadi B7,8, Almotairi A9, Al Khatib K10, Abdulmomen A11, Qushmaq I7, Sindi AA12, Mady A13,14, Solaiman O15, Al-Raddadi R16, Maghrabi K15, Ragab A17, Al Mekhlafi GA18, Balkhy HH19, Al Harthy A13, Kharaba A20, Gramish JA21, Al-Aithan AM22, Al-Dawood A1, Merson L23, Hayden FG23,24, Fowler R25.

Author information: 1 Intensive Care Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia. 2 Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada. 3 King Fahad Armed Forces Hospital, Jeddah. 4 Military Medical Services, Ministry of Defense, Prince Sultan Military Medical City, Riyadh. 5 Department of Intensive Care, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Jeddah. 6 Department of Intensive Care, College of Medicine, Alfaisal University, Dr Sulaiman Al-Habib Group Hospitals, Riyadh. 7 Department of Medicine, King Faisal Specialist Hospital and Research Center, Jeddah. 8 Department of Medicine, University of Jeddah. 9 Department of Critical Care Medicine, King Fahad Medical City, Riyadh. 10 Intensive Care Department, Al-Noor Specialist Hospital, Makkah. 11 Department of Critical Care Medicine, King Saud University, Riyadh. 12 Department of Anesthesia and Critical Care, Faculty of Medicine, King Abdulaziz University, Jeddah. 13 Intensive Care Department, King Saud Medical City, Riyadh, Saudi Arabia. 14 Tanta University Hospitals, Egypt. 15 Intensive Care Department, King Faisal Specialist Hospital and Research Center, Riyadh. 16 Department of Community Medicine, Faculty of Medicine, King Abdulaziz University. 17 Intensive Care Department, King Fahd Hospital, Jeddah. 18 Department of Intensive Care Services, Prince Sultan Military Medical City. 19 Department of Infection Prevention and Control, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh. 20 Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah. 21 Pharmaceutical Care Department, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh. 22 Department of Medicine, Critical Care Division, King Abdulaziz Hospital, Al Ahsa, Saudi Arabia. 23 International Severe Acute Respiratory and Emerging Infection Consortium, Infectious Diseases Data Observatory, Oxford University, United Kingdom. 24 Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville. 25 Institute of Health Policy Management and Evaluation, University of Toronto, Department of Critical Care Medicine and Department of Medicine, Sunnybrook Hospital, Ontario, Canada.

 

Abstract

BACKGROUND:

The objective of this study was to evaluate the effect of ribavirin and recombinant interferon (RBV/rIFN) therapy on the outcomes of critically ill patients with Middle East respiratory syndrome (MERS), accounting for time-varying confounders.

METHODS:

This is a retrospective cohort study of critically ill patients with laboratory-confirmed MERS from 14 hospitals in Saudi Arabia diagnosed between September 2012 and January 2018. We evaluated the association of RBV/rIFN with 90-day mortality and MERS coronavirus (MERS-CoV) RNA clearance using marginal structural modeling to account for baseline and time-varying confounders.

RESULTS:

Of 349 MERS patients, 144 (41.3%) patients received RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a; none received rIFN-β1b). RBV/rIFN was initiated at a median of 2 days (Q1, Q3: 1, 3 days) from intensive care unit admission. Crude 90-day mortality was higher in patients with RBV/rIFN compared to no RBV/rIFN (106/144 [73.6%] vs 126/205 [61.5%]; P = .02]. After adjusting for baseline and time-varying confounders using a marginal structural model, RBV/rIFN was not associated with changes in 90-day mortality (adjusted odds ratio, 1.03 [95% confidence interval {CI}, .73-1.44]; P = .87) or with more rapid MERS-CoV RNA clearance (adjusted hazard ratio, 0.65 [95% CI, .30-1.44]; P = .29).

CONCLUSIONS:

In this observational study, RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a) therapy was commonly used in critically ill MERS patients but was not associated with reduction in 90-day mortality or in faster MERS-CoV RNA clearance.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

KEYWORDS: Middle East respiratory syndrome; coronavirus; interferon; pneumonia; ribavirin

PMID: 31925415 DOI: 10.1093/cid/ciz544

Keywords: Antivirals; Ribavirin; Interferons; MERS-CoV.

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Comparative #therapeutic efficacy of #remdesivir and combination #lopinavir#, ritonavir, and #interferon beta against #MERS-CoV (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Timothy P. Sheahan, Amy C. Sims, Sarah R. Leist, Alexandra Schäfer, John Won, Ariane J. Brown, Stephanie A. Montgomery, Alison Hogg, Darius Babusis, Michael O. Clarke, Jamie E. Spahn, Laura Bauer, Scott Sellers, Danielle Porter, Joy Y. Feng, Tomas Cihlar, Robert Jordan, Mark R. Denison & Ralph S. Baric

Nature Communications, volume 11, Article number: 222 (2020)

 

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.

Keywords: Antivirals; Remdesivir; Lopinavir; Ritonavir; Interferons; MERS-CoV; Animal models.

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#MERS #Coronavirus #Transmission (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 26, Number 2—February 2020 / Perspective

Middle East Respiratory Syndrome Coronavirus Transmission

Marie E. Killerby  , Holly M. Biggs, Claire M. Midgley, Susan I. Gerber, and John T. Watson

Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA

 

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) infection causes a spectrum of respiratory illness, from asymptomatic to mild to fatal. MERS-CoV is transmitted sporadically from dromedary camels to humans and occasionally through human-to-human contact. Current epidemiologic evidence supports a major role in transmission for direct contact with live camels or humans with symptomatic MERS, but only limited evidence supports the possibility of transmission from camel products or asymptomatic MERS cases. Because a proportion of case-patients do not report direct contact with camels or with persons who have symptomatic MERS, further research is needed to conclusively determine additional mechanisms of transmission, to inform public health practice, and to refine current precautionary recommendations.

Keywords: MERS-CoV; Human; Camels.

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#Treatment of #MERS with a #combination of #lopinavir / #ritonavir and #interferon-β1b (#MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential #RCT (Trials, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Trials. 2020 Jan 3;21(1):8. doi: 10.1186/s13063-019-3846-x.

Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial.

Arabi YM1,2, Asiri AY3, Assiri AM4, Aziz Jokhdar HA5, Alothman A6,7, Balkhy HH6,8, AlJohani S6,9, Al Harbi S10,11, Kojan S6,7, Al Jeraisy M10,11, Deeb AM12,13, Memish ZA14,15, Ghazal S3, Al Faraj S3, Al-Hameed F16,17, AlSaedi A16,18, Mandourah Y19, Al Mekhlafi GA20, Sherbeeni NM21, Elzein FE21, Almotairi A22, Al Bshabshe A23, Kharaba A24, Jose J25, Al Harthy A26, Al Sulaiman M27, Mady A28,29, Fowler RA30,31, Hayden FG32, Al-Dawood A6,33, Abdelzaher M34,35, Bajhmom W36, Hussein MA13,25; and the Saudi Critical Care Trials group.

Author information: 1 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. arabi@ngha.med.sa. 2 Intensive Care Department, Ministry of the National Guard – Health Affairs, ICU 1425, P.O. Box 22490, Riyadh, 11426, Saudi Arabia. arabi@ngha.med.sa. 3 Prince Mohammed bin Abdulaziz Hospital, Riyadh, Saudi Arabia. 4 Infection Prevention and Control, Assistant Deputy Minister, Preventive Health, Ministry of Health, Riyadh, Saudi Arabia. 5 Deputy Minister for Public Health, Ministry of Health, Riyadh, Saudi Arabia. 6 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. 7 Department of Medicine, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 8 Department of Infection Prevention and Control, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 9 Department of Pathology and Laboratory Medicine, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 10 College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. 11 Pharmaceutical Care Department, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 12 King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Research Office, Riyadh, Saudi Arabia. 13 Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 14 Prince Mohammed bin Abdulaziz Hospital, Ministry of Health & College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 15 Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA. 16 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia. 17 Intensive Care Department, Ministry of the National Guard – Health Affairs, Jeddah, Saudi Arabia. 18 Department of Infection Prevention and Control, Ministry of the National Guard – Health Affairs, Jeddah, Saudi Arabia. 19 Military Medical Services, Ministry of Defense, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 20 Department of Intensive Care Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 21 Infectious Diseases Division, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 22 Department of Critical Care Medicine, King Fahad Medical City, Riyadh, Saudi Arabia. 23 Department of Critical Care Medicine, King Khalid University, Aseer Central Hospital, Abha, Saudi Arabia. 24 Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, Saudi Arabia. 25 Department Biostatistics and Bioinformatics, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. 26 Intensive Care Unit, King Saud Medical City, Riyadh, Saudi Arabia. 27 Infectious Disease, King Saud Medical City, Riyadh, Saudi Arabia. 28 Intensive Care Department, King Saud Medical City, Riyadh, Saudi Arabia. 29 Department of Anesthesiology and Intensive Care, Tanta University Hospitals, Tanta, Egypt. 30 Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Canada. 31 Department of Critical Care Medicine and Department of Medicine, Sunnybrook Hospital, Bayview Avenue, Room D478, Toronto, 2075, Canada. 32 International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA. 33 Intensive Care Department, Ministry of the National Guard – Health Affairs, ICU 1425, P.O. Box 22490, Riyadh, 11426, Saudi Arabia. 34 Critical Care Medicine Department, King Abdullah Medical Complex, Jeddah, Saudi Arabia. 35 Critical Care Medicine Department, Cairo University Hospital, Cairo, Egypt. 36 Internal Medicine Department, King Fahad General Hospital, Ministry of Health, Jeddah, Saudi Arabia.

 

Abstract

The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.

KEYWORDS: Antiviral; Clinical trial; Coronavirus; Interferon-β1b; Lopinavir/ritonavir; MERS; Protocol; Statistical analysis plan

PMID: 31900204 DOI: 10.1186/s13063-019-3846-x

Keywords: MERS-CoV; Antivirals; Interferons; Ritonavir; Lopinavir.

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Deducing the #Crystal #Structure of #MERS-CoV #Helicase (Methods Mol Biol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Methods Mol Biol. 2020;2099:69-85. doi: 10.1007/978-1-0716-0211-9_6.

Deducing the Crystal Structure of MERS-CoV Helicase.

Cui S1, Hao W2.

Author information: 1 NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China. Cui.sheng@ipb.pumc.edu.cn. 2 NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.

 

Abstract

RNA virus encodes a helicase essential for viral RNA transcription and replication when the genome size is larger than 7 kb. Coronavirus (CoV) has an exceptionally large RNA genome (~30 kb) and it encodes an essential replicase, the nonstructural protein 13 (nsp13), a member of superfamily 1 helicases. Nsp13 is among the evolutionary most conserved proteins not only in CoVs but also in nidovirales. Thus, it is considered as an important drug target. However, the high-resolution structure of CoV nsp13 remained unavailable even until more than a decade after the outbreak of the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, which hindered the structure-based drug design. This is in part due to the intrinsic flexibility of nsp13. Here, we describe protocols of deducing the crystal structure of Middle East respiratory syndrome coronavirus (MERS-CoV) helicase in detail, which include protein expression, purification, crystallization, enzymatic characterization, and structure determination. With these methods, catalytically active recombinant MERS-CoV nsp13 protein can be prepared and crystallized and the crystal structure can be solved.

KEYWORDS: Coronavirus; Crystallization; Helicase; Structure determination; nsp13

PMID: 31883088 DOI: 10.1007/978-1-0716-0211-9_6

Keywords: MERS-CoV.

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#Crystallization and Structural Determination of the #RBD of #MERS-CoV #Spike Glycoprotein (Methods Mol Biol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Methods Mol Biol. 2020;2099:39-50. doi: 10.1007/978-1-0716-0211-9_4.

Crystallization and Structural Determination of the Receptor-Binding Domain of MERS-CoV Spike Glycoprotein.

Zhou H1, Zhang S1, Wang X2.

Author information: 1 School of Life Sciences, Tsinghua University, Beijing, China. 2 School of Life Sciences, Tsinghua University, Beijing, China. xinquanwang@mail.tsinghua.edu.cn.

 

Abstract

Three-dimensional structures of the receptor-binding domain (RBD) of MERS-CoV spike glycoprotein bound to cellular receptor and monoclonal antibodies (mAbs) have been determined by X-ray crystallography, providing structural information about receptor recognition and neutralizing mechanisms of mAbs at the atomic level. In this chapter, we describe the purification, crystallization, and structure determination of the MERS-CoV RBD.

KEYWORDS: Crystallization; MERS-CoV; RBD; Spike; Structure determination; X-ray crystallography

PMID: 31883086 DOI: 10.1007/978-1-0716-0211-9_4

Keywords: MERS-CoV.

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Studying #Evolutionary #Adaptation of #MERS-CoV (Methods Mol Biol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Methods Mol Biol. 2020;2099:3-8. doi: 10.1007/978-1-0716-0211-9_1.

Studying Evolutionary Adaptation of MERS-CoV.

Letko M1, Munster V2.

Author information: 1 Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, National Institutes of Health, Hamilton, MT, USA. michael.letko@nih.gov. 2 Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, National Institutes of Health, Hamilton, MT, USA.

 

Abstract

Forced viral adaptation is a powerful technique employed to study the ways viruses may overcome various selective pressures that reduce viral replication. Here, we describe methods for in vitro serial passaging of Middle East respiratory syndrome coronavirus (MERS-CoV) to select for mutations which increase replication on semi-permissive cell lines as described in Letko et al., Cell Rep 24, 1730-1737, 2018.

KEYWORDS: Cell culture; Experimental evolution; Forced adaptation; Host restriction; MERS-CoV; Semi-permissive cell line; Species barrier

PMID: 31883083 DOI: 10.1007/978-1-0716-0211-9_1

Keywords: MERS-CoV; Evolution.

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