Emerging preclinical evidence does not support broad use of hydroxychloroquine in COVID-19 patients

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Abstract

There is an urgent need for drugs, therapies and vaccines to be available to protect the human population against COVID-19. One of the first approaches taken in the COVID-19 global response was to consider repurposing licensed drugs. This commentary highlights an extraordinary international collaborative effort of independent researchers who have recently all come to the same conclusion—that chloroquine or hydroxchloroquine are unlikely to provide clinical benefit against COVID-19.

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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 Chan, Anna Zhang, Shuofeng Yuan … (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.

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Respiratory disease in rhesus macaques inoculated with SARS-CoV-2

Vincent J. Munster, Friederike Feldmann, Brandi N Williamson … (2020)

An outbreak of a novel coronavirus, named SARS-CoV-2, causing respiratory disease and a ~2% case fatality rate started in Wuhan, China in December 2019 1,2 . Following unprecedented global spread3, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8–16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.

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The Genome Landscape of the African Green Monkey Kidney-Derived Vero Cell Line

Naoki Osada, Arihiro Kohara, Toshiyuki Yamaji … (2014)

Continuous cell lines that originate from mammalian tissues serve as not only invaluable tools for life sciences, but also important animal cell substrates for the production of various types of biological pharmaceuticals. Vero cells are susceptible to various types of microbes and toxins and have widely contributed to not only microbiology, but also the production of vaccines for human use. We here showed the genome landscape of a Vero cell line, in which 25,877 putative protein-coding genes were identified in the 2.97-Gb genome sequence. A homozygous ∼9-Mb deletion on chromosome 12 caused the loss of the type I interferon gene cluster and cyclin-dependent kinase inhibitor genes in Vero cells. In addition, an ∼59-Mb loss of heterozygosity around this deleted region suggested that the homozygosity of the deletion was established by a large-scale conversion. Moreover, a genomic analysis of Vero cells revealed a female Chlorocebus sabaeus origin and proviral variations of the endogenous simian type D retrovirus. These results revealed the genomic basis for the non-tumourigenic permanent Vero cell lineage susceptible to various pathogens and will be useful for generating new sub-lines and developing new tools in the quality control of Vero cells.

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Author and article information

Contributors

S. G. P. Funnell:

ORCID: http://orcid.org/0000-0002-4254-2751

simon.funnell@phe.gov.uk

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 26 August 2020

Publication date PMC-release: 26 August 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 4253

Affiliations

[1 ]GRID grid.271308.f, ISNI 0000 0004 5909 016X, National Infection Service, , Public Health England, ; Porton Down, Manor Farm Road, Salisbury, Wiltshire SP40JG UK

[2 ]Coalition for Epidemic Preparedness Innovations, 1901 Pennsylvania Avenue, NW, Suite 1003, Washington, DC 20006 USA

[3 ]GRID grid.424065.1, ISNI 0000 0001 0701 3136, Bernhard Nocht Institute for Tropical Medicine, ; Bernhard Nocht Strasse. 74, 20359 Hamburg, Germany

[4 ]GRID grid.3575.4, ISNI 0000000121633745, World Health Organisation, ; Avenue Appia, 1211, Geneva, Switzerland

[5 ]GRID grid.38142.3c, ISNI 000000041936754X, Wyss Institute for Biologically Inspired Engineering, , Harvard University, ; CLSB5, 3 Blackfan Circle, Boston, MA 02115 USA

[6 ]Emulate Inc., 27 Drydock Avenue, 5th Floor, Boston, MA 02210 USA

[7 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, Global Virus Network, , KU Leuven, ; 3000 Leuven, Belgium

[8 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, , National Institute of Health, ; Hamilton, 59840 MT USA

[9 ]GRID grid.7429.8, ISNI 0000000121866389, Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases » (IMVA-HB/IDMIT), ; Fontenay-aux-Roses & Le Kremlin-Bicêtre, 92265 France

[10 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Department of Microbiology and Immunology, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA

[11 ]School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, NG7 2UH UK

Author information

S. G. P. Funnell http://orcid.org/0000-0002-4254-2751

D. E. Ingber http://orcid.org/0000-0002-4319-6520

L. Delang http://orcid.org/0000-0002-8874-675X

E. de Wit http://orcid.org/0000-0002-9763-7758

H. Feldmann http://orcid.org/0000-0001-9448-8227

P. Maisonnasse http://orcid.org/0000-0002-0555-207X

R. Le Grand http://orcid.org/0000-0002-4928-4484

M. B. Frieman http://orcid.org/0000-0003-0107-0775

Article

Publisher ID: 17907

DOI: 10.1038/s41467-020-17907-w

PMC ID: 7450055

PubMed ID: 32848158

SO-VID: 9c2f5009-17d9-4687-a021-4a26da3a5fd4

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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 26 May 2020

Date accepted : 25 July 2020

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Keywords: animal disease models,respiratory system models,sars-cov-2,preclinical research

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ScienceOpen disciplines: Uncategorized

Keywords: animal disease models, respiratory system models, sars-cov-2, preclinical research

Emerging preclinical evidence does not support broad use of hydroxychloroquine in COVID-19 patients

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Novel Coronavirus Disease COVID-19

Most cited references 4

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

Respiratory disease in rhesus macaques inoculated with SARS-CoV-2

The Genome Landscape of the African Green Monkey Kidney-Derived Vero Cell Line

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