#Inefficiency of #Sera from Mice Treated with Pseudotyped #SARS-CoV to Neutralize 2019-nCoV #Infection (Virol Sin., summary)

[Source: Virologica Sinica, full page: (LINK). Summary, edited.]

Inefficiency of Sera from Mice Treated with Pseudotyped SARS-CoV to Neutralize 2019-nCoV Infection

Zezhong Liu, Shuai Xia, Xinling Wang, Qiaoshuai Lan, Wei Xu, Qian Wang, Shibo Jiang & Lu Lu

Virologica Sinica (2020)

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Dear Editor, An outbreak of unusual pneumonia in Wuhan, China recently was caused by infection of a novel type of corona-virus. The virus and disease were denoted as 2019-nCoV and COVID-19, respectively, by the World Health Organization (WHO). Most recently, 2019-nCoV was renamed SARS-CoV-2 by Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV) (Gorbalenya et al.2020), or HCoV-19, as a common name for the consistence with COVID-19, by a group of virologists in China (Jiang et al.2020a, b). As of 7 March 2020, a total of 80,651 confirmed cases, including 3070 deaths, were reported in China (China CDC 2020). Global spread is undeniable with serious implications for public health, thus calling for rapid development of effective therapeutics and prophylatics (Jiang et al.2020a, b).

(…)

Keywords: SARS-CoV-2; SARS-CoV; COVID-19; Serotherapy; Animal models.

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#Infection and Rapid #Transmission of #SARS-CoV-2 in #Ferrets (Cell, abstract)

[Source: Cell Press, full page: (LINK). Abstract, edited.]

Journal pre-proof | DOI: 10.1016/j.chom.2020.03.023

This is a PDF file of an accepted peer-reviewed article but is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2020 The Author(s).

Infection and Rapid Transmission of SARS-CoV-2 in Ferrets

Young-Il Kim1,2, Seong-Gyu Kim1, Se-Mi Kim1, Eun-Ha Kim1,2, Su-Jin Park1,2 2 , Kwang-Min Yu1,2, Jae-Hyung Chang1, Eun Ji Kim1, Seunghun Lee1, Mark Anthony B. Casel1,2, Jiyee Um4 3 ,Min-Suk Song1,2, Hye Won Jeong1, Van Dam Lai3, Yeonjae Kim4, Bum Sik Chin4 4 , Jun-Sun Park4, Ki-Hyun Chung4, Suan-Sin Foo5, Haryung Poo6, In-pil Mo3, OK Jun Lee1 5 , Richard J Webby7, Jae U. Jung5,*, and Young Ki Choi1,2,8*

1 College of Medicine and Medical Research Institute, Chungbuk National University,
9 Cheongju, Republic of Korea; 2 Zoonotic Infectious Diseases Research Center, Chungbuk National University, Cheongju, Korea; 3College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea; 4 Research institute of Public Health, National Medical Center, Seoul, Republic of Korea; 5 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; 6Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, Republic of Korea; 7 Division of Virology, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; 8 Lead Contact

*Correspondence: jaeujung@med.usc.edu (J. J), choiki55@chungbuk.ac.kr (Y.K.C) *Jae U. Jung –  Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA

 

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory  syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 dissemination, understanding the in vivo characteristics of SARS-CoV 2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2- infected ferrets shed virus in nasal washes, saliva, urine and feces up to 8 days post infection. At 2 days post-contact, SARS-CoV-2 was detected in all naïve direct contact ferrets. Furthermore, a few naïve indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.

Keywords: 2019-novel coronavirus (2019-nCoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), novel coronavirus disease (COVID-19), virus shedding, transmission, ferrets

Keywords: SARS-CoV-2; COVID-19; Animal models.

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Higher #virulence of #swine #H1N2 #influenza viruses containing #avian-origin #HA and 2009 #pandemic PA and NP in #pigs and mice (Arch Virol., abstract)

[Source: Archives of Virology, full page: (LINK). Abstract, edited.]

Higher virulence of swine H1N2 influenza viruses containing avian-origin HA and 2009 pandemic PA and NP in pigs and mice

Yunyueng Jang, Taehyun Seo & Sang Heui Seo

Archives of Virology (2020)

 

Abstract

Pigs are capable of harbouring influenza A viruses of human and avian origin in their respiratory tracts and thus act as an important intermediary host to generate novel influenza viruses with pandemic potential by genetic reassortment between the two viruses. Here, we show that two distinct H1N2 swine influenza viruses contain avian-like or classical swine-like hemagglutinins with polymerase acidic (PA) and nucleoprotein (NP) genes from 2009 pandemic H1N1 influenza viruses that were found to be circulating in Korean pigs in 2018. Swine H1N2 influenza virus containing an avian-like hemagglutinin gene had enhanced pathogenicity, causing severe interstitial pneumonia in infected pigs and mice. The mortality rate of mice infected with swine H1N2 influenza virus containing an avian-like hemagglutinin gene was higher by 100% when compared to that of mice infected with swine H1N2 influenza virus harbouring classical swine-like hemagglutinin. Further, chemokines attracting inflammatory cells were strongly induced in lung tissues of pigs and mice infected by swine H1N2 influenza virus containing an avian-like hemagglutinin gene. In conclusion, it is necessary for the well-being of humans and pigs to closely monitor swine influenza viruses containing avian-like hemagglutinin with PA and NP genes from 2009 pandemic H1N1 influenza viruses.

Keywords: Influenza A; Avian Influenza; Swine Influenza; H1N1pdm09; H1N2; Reassortant strain; Pigs; Animal models.

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#Influenza A and B viruses with reduced #baloxavir susceptibility display attenuated in vitro #fitness but retain ferret #transmissibility (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility

Jeremy C. Jones, Philippe Noriel Q. Pascua, Thomas P. Fabrizio, Bindumadhav M. Marathe, Patrick Seiler, Subrata Barman, Richard J. Webby, Robert G. Webster, and Elena A. Govorkova

PNAS first published March 26, 2020 | DOI: https://doi.org/10.1073/pnas.1916825117

Contributed by Robert G. Webster, February 12, 2020 (sent for review October 2, 2019; reviewed by Rodney S. Daniels and Lieve Naesens)

 

Significance

The emergence of influenza viruses with reduced susceptibility to baloxavir marboxil (BXM) would limit the clinical utility of this novel antiviral. To assess the risk of such resistance emerging, we evaluated influenza A and B viruses carrying BXM-reduced susceptibility substitutions and compared their fitness to that of their drug-susceptible wild-type (I38-WT) counterparts. The 38T/F/M substitutions inhibited activity of the virus PA protein, and two of them (38T/F) hindered virus replication in cells. Even so, 38T/F/M viruses could transmit between ferrets, the gold-standard model for human transmission. These findings argue that there is a risk of transmission of BXM-resistant viruses from treated individuals. Whether such viruses could compete with WT viruses in spreading through the wider untreated community is less clear.

 

Abstract

Baloxavir marboxil (BXM) was approved in 2018 for treating influenza A and B virus infections. It is a first-in-class inhibitor targeting the endonuclease activity of the virus polymerase acidic (PA) protein. Clinical trial data revealed that PA amino acid substitutions at residue 38 (I38T/F/M) reduced BXM potency and caused virus rebound in treated patients, although the fitness characteristics of the mutant viruses were not fully defined. To determine the fitness impact of the I38T/F/M substitutions, we generated recombinant A/California/04/2009 (H1N1)pdm09, A/Texas/71/2017 (H3N2), and B/Brisbane/60/2008 viruses with I38T/F/M and examined drug susceptibility in vitro, enzymatic properties, replication efficiency, and transmissibility in ferrets. Influenza viruses with I38T/F/M substitutions exhibited reduced baloxavir susceptibility, with 38T causing the greatest reduction. The I38T/F/M substitutions impaired PA endonuclease activity as compared to that of wild-type (I38-WT) PA. However, only 38T/F A(H3N2) substitutions had a negative effect on polymerase complex activity. The 38T/F substitutions decreased replication in cells among all viruses, whereas 38M had minimal impact. Despite variable fitness consequences in vitro, all 38T/M viruses disseminated to naive ferrets by contact and airborne transmission, while 38F-containing A(H3N2) and B viruses failed to transmit via the airborne route. Reversion of 38T/F/M to I38-WT was rare among influenza A viruses in this study, suggesting stable retention of 38T/F/M genotypes during these transmission events. BXM reduced susceptibility-associated mutations had variable effects on in vitro fitness of influenza A and B viruses, but the ability of these viruses to transmit in vivo indicates a risk of their spreading from BXM-treated individuals.

influenza – endonuclease inhibitor – baloxavir marboxil – PA protein – I38T substitution

 

Footnotes

1 To whom correspondence may be addressed. Email: Jeremy.jones@stjude.org or robert.webster@stjude.org.

Author contributions: J.C.J., P.N.Q.P., T.P.F., R.J.W., R.G.W., and E.A.G. designed research; J.C.J., P.N.Q.P., B.M.M., and P.S. performed research; J.C.J., P.N.Q.P., T.P.F., and S.B. contributed new reagents/analytic tools; J.C.J., P.N.Q.P., T.P.F., and E.A.G. analyzed data; and J.C.J., P.N.Q.P., R.J.W., R.G.W., and E.A.G. wrote the paper.

Reviewers: R.S.D., The Francis Crick Institute; and L.N., Katholieke Universiteit Leuven.

Competing interest statement: E.A.G. reports receiving consultant fees and travel support from Genentech/Roche for serving on an advisory board. The other authors declare no conflicts of interest.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1916825117/-/DCSupplemental.

Published under the PNAS license.

Keywords: Seasonal Influenza; Antivirals; Drugs Resistance; Baloxavir.

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#Simulation of the #clinical and #pathological manifestations of #Coronavirus Disease 2019 (#COVID19) in golden Syrian #hamster #model: implications for disease pathogenesis and transmissibility (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases, full page: (LINK). Abstract, edited.]

Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility

Jasper Fuk-Woo Chan, Anna Jinxia Zhang, Shuofeng Yuan, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Andrew Chak-Yiu Lee, Wan-Mui Chan, Zhimeng Fan, Hoi-Wah Tsoi, Lei Wen, Ronghui Liang, Jianli Cao, Yanxia Chen, Kaiming Tang, Cuiting Luo, Jian-Piao Cai, Kin-Hang Kok, Hin Chu, Kwok-Hung Chan, Siddharth Sridhar, Zhiwei Chen, Honglin Chen, Kelvin Kai-Wang To, Kwok-Yung Yuen

Clinical Infectious Diseases, ciaa325, https://doi.org/10.1093/cid/ciaa325

Published: 26 March 2020

 

Abstract

Background

A physiological small animal model that resembles COVID-19 with low mortality is lacking.

Methods

Molecular docking on the binding between angiotensin-converting enzyme 2 (ACE2) of common laboratory mammals and the receptor-binding domain of the surface spike protein of SARS-CoV-2 suggested that the golden Syrian hamster is an option. Virus challenge, contact transmission, and passive immunoprophylaxis were performed. Serial organ tissues and blood were harvested for histopathology, viral load and titre, chemokine/cytokine assay, and neutralising antibody titre.

Results

The Syrian hamster could be consistently infected by SARS-CoV-2. Maximal clinical signs of rapid breathing, weight loss, histopathological changes from the initial exudative phase of diffuse alveolar damage with extensive apoptosis to the later proliferative phase of tissue repair, airway and intestinal involvement with virus nucleocapsid protein expression, high lung viral load, and spleen and lymphoid atrophy associated with marked cytokine activation were observed within the first week of virus challenge. The lung virus titre was between 105-107 TCID50/g. Challenged index hamsters consistently infected naïve contact hamsters housed within the same cage, resulting in similar pathology but not weight loss. All infected hamsters recovered and developed mean serum neutralising antibody titre ≥1:427 fourteen days post-challenge. Immunoprophylaxis with early convalescent serum achieved significant decrease in lung viral load but not in lung pathology. No consistent non-synonymous adaptive mutation of the spike was found in viruses isolated from infected hamsters.

Conclusions

Besides satisfying the Koch’s postulates, this readily available hamster model is an important tool for studying transmission, pathogenesis, treatment, and vaccination against SARS-CoV-2.

coronavirus, COVID-19, SARS-CoV-2, animal, transmission

Issue Section: Major Article

This content is only available as a PDF.

Author notes: J.F-W.C., A.J.Z., and S.Y. contributed equally to this work.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: SARS-CoV-2; COVID-19; Animal models.

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Evaluation of the #immune #response of a #H7N9 candidate #vaccine virus derived from the fifth wave A/Guangdong/17SF003/2016 (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Volume 177, May 2020, 104776

Evaluation of the immune response of a H7N9 candidate vaccine virus derived from the fifth wave A/Guangdong/17SF003/2016

Ji Dong a1, Peihai Chen bc1, Yang Wang a1, Yunhua Lv a, Ji Xiao a, Qinming Li a, Zhixia Li c, Beiwu Zhang c, Xuefeng Niu a, Chufang Li a, Weiqi Pan a, Ling Chen a

{a} State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; {b} Institute of Health Sciences and Technology, Anhui University, Hefei, China; {c} State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

Received 28 October 2019, Revised 4 February 2020, Accepted 16 March 2020, Available online 19 March 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104776

 

Highlights

  • Systemically evaluated the immune response to H7N9 CVV A/Guangdong/17SF003/2016 (GD/16) in mice and rhesus macaques.
  • GD/16 elicited robust neutralizing and IgG antibodies, but poor hemagglutination inhibition antibody titers.
  • Receptor binding avidity should be considered in interpretation of HI data for evaluation of influenza antigenic variation.

 

Abstract

Highly pathogenic influenza H7N9 viruses that emerged in the fifth wave of H7N9 outbreak pose a risk to human health. The World Health Organization has updated the candidate vaccine viruses for H7N9 viruses recently. In this study, we evaluated the immune response to an updated H7N9 candidate vaccine virus, which derived from the highly pathogenic A/Guangdong/17SF003/2016 (GD/16) in mice and rhesus macaques. GD/16 vaccination elicited robust neutralizing, virus-specific immunoglobulin G antibodies and effective protection, but poor hemagglutination inhibition antibody titers. Furthermore, mouse and rhesus macaque serum raised against the previous H7N9 CVV A/Anhui/1/2013 (AH/13) were tested for its cross-reactivity to GD/16 virus. We found that although AH/13-immune serum has poor hemagglutination inhibition reactivity against GD/16 virus, AH/13 elicit efficient cross-neutralizing antibodies and in vivo protection against GD/16. Further studies showed that the hemagglutinin of GD/16 has strong receptor binding avidity, which might be associated with the decreased hemagglutination inhibition assay sensitivity. This study underscores the point that receptor binding avidity should be taken into account when performing quantitative interpretation of hemagglutination inhibition data. A combination of multiple serological assays is required for accurate vaccine evaluation and antigenic analysis of influenza viruses.

Keywords: H7N9 influenza Virus – Vaccine – Immune response – Cross-reactivity – Haemagglutination inhibition – Receptor binding avidity

Keywords: Avian Influenza; H7N9; Vaccines.

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#Prophylactic and #therapeutic #remdesivir (GS-5734) #treatment in the rhesus #macaque model of #MERS #Coronavirus infection (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Emmie de Wit, Friederike Feldmann, Jacqueline Cronin, Robert Jordan, Atsushi Okumura, Tina Thomas, Dana Scott, Tomas Cihlar, and Heinz Feldmann

PNAS first published February 13, 2020 / DOI: https://doi.org/10.1073/pnas.1922083117

Edited by Michael B. A. Oldstone, Scripps Research Institute, La Jolla, CA, and approved February 7, 2020 (received for review December 16, 2019)

 

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.

 

Abstract

The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.

MERS-CoV – antiviral – animal model – remdesivir – therapy

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Keywords: Antivirals; Remdesivir; SARS-CoV-2; MERS-CoV; Coronavirus; Animal models.

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