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      Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity

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      Proceedings of the National Academy of Sciences of the United States of America
      National Academy of Sciences
      antiviral therapy, SARS-CoV-2, preclinical model, favipiravir, hydroxychloroquine

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          Significance

          The previous lack of consensus around the use of hydroxychloroquine for COVID-19 patients underlines the need to thoroughly assess the in vivo efficacy of drugs against SARS-CoV-2. Small animal infection models, such as the hamster model, have a pivotal place herein. We here show in vivo preclinical results with favipiravir which indicate that antiviral efficacy against SARS-CoV-2 might only be achieved with a very high dose. Hydroxychloroquine, on the other hand, completely lacks antiviral activity, thus providing no scientific basis for its further use in COVID-19 patients. With this study on two key antiviral candidates, we establish the baseline for SARS-CoV-2 antiviral treatment, which will allow us to identify superior antiviral candidates in the near future.

          Abstract

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2−infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

            Dear Editor, In December 2019, a novel pneumonia caused by a previously unknown pathogen emerged in Wuhan, a city of 11 million people in central China. The initial cases were linked to exposures in a seafood market in Wuhan. 1 As of January 27, 2020, the Chinese authorities reported 2835 confirmed cases in mainland China, including 81 deaths. Additionally, 19 confirmed cases were identified in Hong Kong, Macao and Taiwan, and 39 imported cases were identified in Thailand, Japan, South Korea, United States, Vietnam, Singapore, Nepal, France, Australia and Canada. The pathogen was soon identified as a novel coronavirus (2019-nCoV), which is closely related to sever acute respiratory syndrome CoV (SARS-CoV). 2 Currently, there is no specific treatment against the new virus. Therefore, identifying effective antiviral agents to combat the disease is urgently needed. An efficient approach to drug discovery is to test whether the existing antiviral drugs are effective in treating related viral infections. The 2019-nCoV belongs to Betacoronavirus which also contains SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Several drugs, such as ribavirin, interferon, lopinavir-ritonavir, corticosteroids, have been used in patients with SARS or MERS, although the efficacy of some drugs remains controversial. 3 In this study, we evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir (GS-5734) and favipiravir (T-705) against a clinical isolate of 2019-nCoV in vitro. Standard assays were carried out to measure the effects of these compounds on the cytotoxicity, virus yield and infection rates of 2019-nCoVs. Firstly, the cytotoxicity of the candidate compounds in Vero E6 cells (ATCC-1586) was determined by the CCK8 assay. Then, Vero E6 cells were infected with nCoV-2019BetaCoV/Wuhan/WIV04/2019 2 at a multiplicity of infection (MOI) of 0.05 in the presence of varying concentrations of the test drugs. DMSO was used in the controls. Efficacies were evaluated by quantification of viral copy numbers in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR) and confirmed with visualization of virus nucleoprotein (NP) expression through immunofluorescence microscopy at 48 h post infection (p.i.) (cytopathic effect was not obvious at this time point of infection). Among the seven tested drugs, high concentrations of three nucleoside analogs including ribavirin (half-maximal effective concentration (EC50) = 109.50 μM, half-cytotoxic concentration (CC50) > 400 μM, selectivity index (SI) > 3.65), penciclovir (EC50 = 95.96 μM, CC50 > 400 μM, SI > 4.17) and favipiravir (EC50 = 61.88 μM, CC50 > 400 μM, SI > 6.46) were required to reduce the viral infection (Fig. 1a and Supplementary information, Fig. S1). However, favipiravir has been shown to be 100% effective in protecting mice against Ebola virus challenge, although its EC50 value in Vero E6 cells was as high as 67 μM, 4 suggesting further in vivo studies are recommended to evaluate this antiviral nucleoside. Nafamostat, a potent inhibitor of MERS-CoV, which prevents membrane fusion, was inhibitive against the 2019-nCoV infection (EC50 = 22.50 μM, CC50 > 100 μM, SI > 4.44). Nitazoxanide, a commercial antiprotozoal agent with an antiviral potential against a broad range of viruses including human and animal coronaviruses, inhibited the 2019-nCoV at a low-micromolar concentration (EC50 = 2.12 μM; CC50 > 35.53 μM; SI > 16.76). Further in vivo evaluation of this drug against 2019-nCoV infection is recommended. Notably, two compounds remdesivir (EC50 = 0.77 μM; CC50 > 100 μM; SI > 129.87) and chloroquine (EC50 = 1.13 μM; CC50 > 100 μM, SI > 88.50) potently blocked virus infection at low-micromolar concentration and showed high SI (Fig. 1a, b). Fig. 1 The antiviral activities of the test drugs against 2019-nCoV in vitro. a Vero E6 cells were infected with 2019-nCoV at an MOI of 0.05 in the treatment of different doses of the indicated antivirals for 48 h. The viral yield in the cell supernatant was then quantified by qRT-PCR. Cytotoxicity of these drugs to Vero E6 cells was measured by CCK-8 assays. The left and right Y-axis of the graphs represent mean % inhibition of virus yield and cytotoxicity of the drugs, respectively. The experiments were done in triplicates. b Immunofluorescence microscopy of virus infection upon treatment of remdesivir and chloroquine. Virus infection and drug treatment were performed as mentioned above. At 48 h p.i., the infected cells were fixed, and then probed with rabbit sera against the NP of a bat SARS-related CoV 2 as the primary antibody and Alexa 488-labeled goat anti-rabbit IgG (1:500; Abcam) as the secondary antibody, respectively. The nuclei were stained with Hoechst dye. Bars, 100 μm. c and d Time-of-addition experiment of remdesivir and chloroquine. For “Full-time” treatment, Vero E6 cells were pre-treated with the drugs for 1 h, and virus was then added to allow attachment for 2 h. Afterwards, the virus–drug mixture was removed, and the cells were cultured with drug-containing medium until the end of the experiment. For “Entry” treatment, the drugs were added to the cells for 1 h before viral attachment, and at 2 h p.i., the virus–drug mixture was replaced with fresh culture medium and maintained till the end of the experiment. For “Post-entry” experiment, drugs were added at 2 h p.i., and maintained until the end of the experiment. For all the experimental groups, cells were infected with 2019-nCoV at an MOI of 0.05, and virus yield in the infected cell supernatants was quantified by qRT-PCR c and NP expression in infected cells was analyzed by Western blot d at 14 h p.i. Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV 5 ) infection in cultured cells, mice and nonhuman primate (NHP) models. It is currently under clinical development for the treatment of Ebola virus infection. 6 Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination. 7 Our time-of-addition assay showed remdesivir functioned at a stage post virus entry (Fig. 1c, d), which is in agreement with its putative anti-viral mechanism as a nucleotide analogue. Warren et al. showed that in NHP model, intravenous administration of 10 mg/kg dose of remdesivir resulted in concomitant persistent levels of its active form in the blood (10 μM) and conferred 100% protection against Ebola virus infection. 7 Our data showed that EC90 value of remdesivir against 2019-nCoV in Vero E6 cells was 1.76 μM, suggesting its working concentration is likely to be achieved in NHP. Our preliminary data (Supplementary information, Fig. S2) showed that remdesivir also inhibited virus infection efficiently in a human cell line (human liver cancer Huh-7 cells), which is sensitive to 2019-nCoV. 2 Chloroquine, a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad-spectrum antiviral drug. 8,9 Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. 10 Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells (Fig. 1c, d). Besides its antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo. Chloroquine is widely distributed in the whole body, including lung, after oral administration. The EC90 value of chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM, which can be clinically achievable as demonstrated in the plasma of rheumatoid arthritis patients who received 500 mg administration. 11 Chloroquine is a cheap and a safe drug that has been used for more than 70 years and, therefore, it is potentially clinically applicable against the 2019-nCoV. Our findings reveal that remdesivir and chloroquine are highly effective in the control of 2019-nCoV infection in vitro. Since these compounds have been used in human patients with a safety track record and shown to be effective against various ailments, we suggest that they should be assessed in human patients suffering from the novel coronavirus disease. Supplementary information Supplementary information, Materials and Figures
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              The trinity of COVID-19: immunity, inflammation and intervention

              Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract — severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc Natl Acad Sci U S A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                27 October 2020
                9 October 2020
                9 October 2020
                : 117
                : 43
                : 26955-26965
                Affiliations
                [1] aLaboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven , B-3000 Leuven, Belgium;
                [2] bBiomedical MRI and Molecular Small Animal Imaging Centre, Department of Imaging and Pathology, Katholieke Universiteit Leuven , B-3000 Leuven, Belgium;
                [3] cDrug Delivery & Disposition, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven , 3000 Leuven, Belgium;
                [4] dUnité des Virus Emergents, Aix Marseille University, Institut de Recherche pour le Développement (IRD) 190, Institut National de la Santé et de la Recherche Médicale (INSERM) 1207 , 13005 Marseille, France;
                [5] eUCL Great Ormond Street Institute of Child Health, University College London , WC1N 1EH London, United Kingdom;
                [6] f Molecular Small Animal Imaging Centre, Department of Imaging and Pathology, Katholieke Universiteit Leuven , B-3000 Leuven, Belgium;
                [7] gDepartment of Laboratory Medicine, Ghent University Hospital , 9000 Ghent, Belgium;
                [8] hNuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Katholieke Universiteit Leuven , B-3000 Leuven, Belgium;
                [9] iAssistance Publique–Hôpitaux de Marseille, Aix-Marseille University, Unité des Virus Emergents, Institut de Recherche pour le Développement (IRD) 190, Institut National de la Santé et de la Recherche Médicale (INSERM) 1207, Laboratoire de Pharmacocin é tique et Toxicologie , 13005 Marseille, France;
                [10] jTranslational Cell and Tissue Research, Department of Imaging and Pathology, Katholieke Universiteit Leuven , B-3000 Leuven, Belgium;
                [11] kPharmacy Department, University Hospitals Leuven , 3000 Leuven, Belgium;
                [13] lDepartment of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven–University of Leuven , 3000 Leuven, Belgium;
                [12] mGlobal Virus Network , Baltimore, MD 21201
                Author notes

                Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved September 3, 2020 (received for review July 9, 2020)

                Author contributions: S.J.F.K., J.R.-P., and L.D. designed research; S.J.F.K., S.J., L. Langendries, L.S., S.t.H., L. Liesenborghs, V.V., E.H., K.B., E.M., C.D.K., L.B., J.R., T.V.B., X.Z., R.W., R.B., and J.W. performed research; S.J.F.K., L.S., B.H., R.A., J.P., H.J.T., K.D., P. Augustijns, N.V., C.C., J.B., C.S., B.W., P. Annaert, I.S., G.V.V., J.N., J.R.-P., and L.D. analyzed data; S.J.F.K., S.J., S.t.H., J.R.-P., and L.D. wrote the paper; V.V., E.H., and C.C. provided and facilitated access to essential infrastructure; H.J.T., K.D., and J.N. provided advice on the interpretation of data; and I.S. provided essential reagents.

                2S.J., L. Langendries, and L.S. contributed equally to this work.

                3J.R.-P. and L.D. contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-7935-0219
                https://orcid.org/0000-0001-8657-6841
                https://orcid.org/0000-0001-6450-6324
                https://orcid.org/0000-0002-9562-2923
                https://orcid.org/0000-0001-7981-6376
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                https://orcid.org/0000-0003-2595-388X
                https://orcid.org/0000-0002-8275-0125
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                https://orcid.org/0000-0001-8246-0534
                https://orcid.org/0000-0002-0943-9648
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                https://orcid.org/0000-0002-8874-675X
                Article
                202014441
                10.1073/pnas.2014441117
                7604414
                33037151
                39595c20-19a8-4eda-9d7d-59832bf5e568
                Copyright © 2020 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

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                Pages: 11
                Funding
                Funded by: KU Leuven (Katholieke Universiteit Leuven) 501100004040
                Award ID: COVID FUND
                Award Recipient : Suzanne J. F. Kaptein Award Recipient : Sofie Jacobs Award Recipient : Lana Langendries Award Recipient : Laura Seldeslachts Award Recipient : Sebastiaan Ter Horst Award Recipient : Laurens Liesenborghs Award Recipient : Elke Maas Award Recipient : Lindsey Bervoets Award Recipient : Jasper Rymenants Award Recipient : Tina Van Buyten Award Recipient : Hendrik Jan Thibaut Award Recipient : Kai Dallmeier Award Recipient : Robbert Boudewijns Award Recipient : Birgit Weynand Award Recipient : Greetje Vande Velde Award Recipient : Johan Neyts Award Recipient : Joana Rocha-Pereira Award Recipient : Leen Delang
                Funded by: Fonds Wetenschappelijk Onderzoek (FWO) 501100003130
                Award ID: G0G4820N
                Award Recipient : Suzanne J. F. Kaptein Award Recipient : Sofie Jacobs Award Recipient : Lana Langendries Award Recipient : Laura Seldeslachts Award Recipient : Sebastiaan Ter Horst Award Recipient : Laurens Liesenborghs Award Recipient : Bart Hens Award Recipient : Elke Maas Award Recipient : Lindsey Bervoets Award Recipient : Jasper Rymenants Award Recipient : Tina Van Buyten Award Recipient : Hendrik Jan Thibaut Award Recipient : Kai Dallmeier Award Recipient : Robbert Boudewijns Award Recipient : Christopher Cawthorne Award Recipient : Birgit Weynand Award Recipient : Greetje Vande Velde Award Recipient : Johan Neyts Award Recipient : Joana Rocha-Pereira Award Recipient : Leen Delang
                Funded by: EC | H2020 | H2020 Societal Challenges (H2020 Priority Societal Challenges) 100010676
                Award ID: 101003627
                Award Recipient : Johan Neyts
                Funded by: Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation) 100000865
                Award ID: INV-00636
                Award Recipient : Johan Neyts
                Funded by: KU Leuven (Katholieke Universiteit Leuven) 501100004040
                Award ID: C24/17/061
                Award Recipient : Suzanne J. F. Kaptein Award Recipient : Sofie Jacobs Award Recipient : Lana Langendries Award Recipient : Laura Seldeslachts Award Recipient : Sebastiaan Ter Horst Award Recipient : Laurens Liesenborghs Award Recipient : Elke Maas Award Recipient : Lindsey Bervoets Award Recipient : Jasper Rymenants Award Recipient : Tina Van Buyten Award Recipient : Hendrik Jan Thibaut Award Recipient : Kai Dallmeier Award Recipient : Robbert Boudewijns Award Recipient : Birgit Weynand Award Recipient : Greetje Vande Velde Award Recipient : Johan Neyts Award Recipient : Joana Rocha-Pereira Award Recipient : Leen Delang
                Funded by: Fonds Wetenschappelijk Onderzoek (FWO) 501100003130
                Award ID: 1001719N
                Award Recipient : Suzanne J. F. Kaptein Award Recipient : Sofie Jacobs Award Recipient : Lana Langendries Award Recipient : Laura Seldeslachts Award Recipient : Sebastiaan Ter Horst Award Recipient : Laurens Liesenborghs Award Recipient : Bart Hens Award Recipient : Elke Maas Award Recipient : Lindsey Bervoets Award Recipient : Jasper Rymenants Award Recipient : Tina Van Buyten Award Recipient : Hendrik Jan Thibaut Award Recipient : Kai Dallmeier Award Recipient : Robbert Boudewijns Award Recipient : Christopher Cawthorne Award Recipient : Birgit Weynand Award Recipient : Greetje Vande Velde Award Recipient : Johan Neyts Award Recipient : Joana Rocha-Pereira Award Recipient : Leen Delang
                Funded by: Fonds Wetenschappelijk Onderzoek (FWO) 501100003130
                Award ID: 1S21918N
                Award Recipient : Suzanne J. F. Kaptein Award Recipient : Sofie Jacobs Award Recipient : Lana Langendries Award Recipient : Laura Seldeslachts Award Recipient : Sebastiaan Ter Horst Award Recipient : Laurens Liesenborghs Award Recipient : Bart Hens Award Recipient : Elke Maas Award Recipient : Lindsey Bervoets Award Recipient : Jasper Rymenants Award Recipient : Tina Van Buyten Award Recipient : Hendrik Jan Thibaut Award Recipient : Kai Dallmeier Award Recipient : Robbert Boudewijns Award Recipient : Christopher Cawthorne Award Recipient : Birgit Weynand Award Recipient : Greetje Vande Velde Award Recipient : Johan Neyts Award Recipient : Joana Rocha-Pereira Award Recipient : Leen Delang
                Funded by: KU Leuven (Katholieke Universiteit Leuven) 501100004040
                Award ID: internal funds
                Award Recipient : Suzanne J. F. Kaptein Award Recipient : Sofie Jacobs Award Recipient : Lana Langendries Award Recipient : Laura Seldeslachts Award Recipient : Sebastiaan Ter Horst Award Recipient : Laurens Liesenborghs Award Recipient : Elke Maas Award Recipient : Lindsey Bervoets Award Recipient : Jasper Rymenants Award Recipient : Tina Van Buyten Award Recipient : Hendrik Jan Thibaut Award Recipient : Kai Dallmeier Award Recipient : Robbert Boudewijns Award Recipient : Birgit Weynand Award Recipient : Greetje Vande Velde Award Recipient : Johan Neyts Award Recipient : Joana Rocha-Pereira Award Recipient : Leen Delang
                Funded by: Fonds Wetenschappelijk Onderzoek (FWO) 501100003130
                Award ID: 12R2119N
                Award Recipient : Suzanne J. F. Kaptein Award Recipient : Sofie Jacobs Award Recipient : Lana Langendries Award Recipient : Laura Seldeslachts Award Recipient : Sebastiaan Ter Horst Award Recipient : Laurens Liesenborghs Award Recipient : Bart Hens Award Recipient : Elke Maas Award Recipient : Lindsey Bervoets Award Recipient : Jasper Rymenants Award Recipient : Tina Van Buyten Award Recipient : Hendrik Jan Thibaut Award Recipient : Kai Dallmeier Award Recipient : Robbert Boudewijns Award Recipient : Christopher Cawthorne Award Recipient : Birgit Weynand Award Recipient : Greetje Vande Velde Award Recipient : Johan Neyts Award Recipient : Joana Rocha-Pereira Award Recipient : Leen Delang
                Funded by: James Black Charitable foundation
                Award ID: 559133
                Award Recipient : Juanita Pang Award Recipient : Rachel Williams Award Recipient : Judith Breuer
                Funded by: Rosetrees studentship
                Award ID: M876
                Award Recipient : Juanita Pang Award Recipient : Rachel Williams Award Recipient : Judith Breuer
                Funded by: NIHR UCL/UCLH biomedical Research Centre
                Award ID: No number
                Award Recipient : Juanita Pang Award Recipient : Rachel Williams Award Recipient : Judith Breuer
                Categories
                530
                Biological Sciences
                Microbiology
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                antiviral therapy,sars-cov-2,preclinical model,favipiravir,hydroxychloroquine

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