Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial

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Abstract

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy.

Methods

COVID-19 patients with moderate pneumonia (SpO ₂ ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO ₂), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions.

Results

A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference ( p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher.

Conclusions

The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered.

Trial registration

Clinicaltrials.jp number: JapicCTI-205238.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40121-021-00517-4.

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Most cited references 21

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Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Fei Zhou, Ting Yu, Ronghui Du … (2020)

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

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Virological assessment of hospitalized patients with COVID-2019

Roman Wölfel, Victor M Corman, Wolfgang Guggemos … (2020)

Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.

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Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Manli Wang, Ruiyuan Cao, Leike Zhang … (2020)

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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Author and article information

Contributors

Satoshi Iwata: siwata@ncc.go.jp

Journal

Journal ID (nlm-ta): Infect Dis Ther

Journal ID (iso-abbrev): Infect Dis Ther

Title: Infectious Diseases and Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 2193-8229

ISSN (Electronic): 2193-6382

Publication date (Electronic): 27 August 2021

Publication date PMC-release: 27 August 2021

Pages: 1-21

Affiliations

[1 ]Department of Respiratory Medicine, Tokyo Shinagawa Hospital, 6-3-22 Higashioi, Shinagawa-ku, Tokyo, 140-8522 Japan

[2 ]GRID grid.411731.1, ISNI 0000 0004 0531 3030, Department of Pulmonary Medicine, School of Medicine, , International University of Health and Welfare, ; 852 Hatakeda, Narita, Chiba 286-8520 Japan

[3 ]GRID grid.415474.7, Department of Otolaryngology, , Self-Defense Forces Central Hospital, ; 1-2-24 Ikejiri, Setagaya-ku, Tokyo, 154-8532 Japan

[4 ]GRID grid.419708.3, ISNI 0000 0004 1775 0430, Department of Respiratory Medicine, , Kanagawa Cardiovascular and Respiratory Center, ; 6-16-1 Tomiokahigashi, Kanazawa-ku, Yokohama, Kanagawa 236-0051 Japan

[5 ]GRID grid.430047.4, ISNI 0000 0004 0640 5017, Department of Infectious Disease and Infection control, , Saitama Medical University Hospital, ; 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495 Japan

[6 ]GRID grid.26091.3c, ISNI 0000 0004 1936 9959, Division of Pulmonary Medicine, Department of Medicine, School of Medicine, , Keio University, ; 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan

[7 ]GRID grid.411909.4, Department of Infectious Diseases, , Tokyo Medical University Hachioji Medical Center, ; 1163 Tatemachi, Hachioji, Tokyo 193-0998 Japan

[8 ]GRID grid.415479.a, Department of Infectious Diseases, , Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, ; 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677 Japan

[9 ]GRID grid.417363.4, Department of Respiratory Internal Medicine, , St. Marianna University Yokohama City Seibu Hospital, ; 1197-1 Yasashi-cho, Asahi-ku, Yokohama, Kanagawa 241-0811 Japan

[10 ]GRID grid.411205.3, ISNI 0000 0000 9340 2869, Department of Respiratory Medicine, , Kyorin University School of Medicine, ; 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 Japan

[11 ]GRID grid.416823.a, Division of Pulmonary Medicine, Department of Internal Medicine, , Tachikawa Hospital, ; 4-2-22 Nishiki-cho, Tachikawa, Tokyo 190-8531 Japan

[12 ]GRID grid.419430.b, Department of Respiratory Medicine, , Saitama Cardiovascular and Respiratory Center, ; 1696 Itai, Kumagaya, Saitama 360-0197 Japan

[13 ]GRID grid.412768.e, ISNI 0000 0004 0642 1308, Department of General Internal Medicine, , Tokai University Oiso Hospital, ; 21-1 Gakkyo, Oiso-machi, Naka-gun, Kanagawa, 259-0198 Japan

[14 ]GRID grid.410819.5, Department of Respiratory Internal Medicine, , Yokohama Rosai Hospital, ; 3211 Kozukue-cho, Kohoku-ku, Yokohama, Kanagawa 222-0036 Japan

[15 ]GRID grid.452399.0, ISNI 0000 0004 1757 1352, Department of Diabetes, Metabolism and Kidney Disease, , Edogawa Hospital, ; 2-24-18 Higashikoiwa, Edogawa-ku, Tokyo, 133-0052 Japan

[16 ]GRID grid.415388.3, ISNI 0000 0004 1772 5753, Department of General Medicine, , Kitakyushu Municipal Medical Center, ; 2-1-1 Bashaku, Kokurakita-ku, Kitakyushu, Fukuoka 802-8561 Japan

[17 ]GRID grid.411887.3, ISNI 0000 0004 0595 7039, Infection Control and Prevention Center, , Gunma University Hospital, ; 3-39-15 Showamachi, Maebashi, Gunma 371-8511 Japan

[18 ]GRID grid.417089.3, ISNI 0000 0004 0378 2239, Department of Respiratory Medicine, , Tokyo Metropolitan Tama Medical Center, ; 2-8-29 Musashidai, Fuchu, Tokyo 183-8524 Japan

[19 ]GRID grid.495549.0, ISNI 0000 0004 1764 8786, Department of Respiratory Medicine, , Nihon University Itabashi Hospital, ; 30-1 Oyaguchikami-cho, Itabashi-ku, Tokyo, 173-8610 Japan

[20 ]Department of General Internal Medicine, Kawasaki Municipal Tama Hospital, 1-30-37 Shukugawara, Tama-ku, Kawasaki, Kanagawa 214-8525 Japan

[21 ]Department of Respiratory and Infectious Diseases, Nagano Prefectural Shinshu Medical Center, 1332 Suzaka, Suzaka, Nagano 382-8577 Japan

[22 ]GRID grid.417092.9, Department of Cardiology, , Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, ; 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015 Japan

[23 ]Department of Internal Medicine, Nippon Koukan Hospital, 1-2-1 Kokandori, Kawasaki-ku, Kawasaki, Kanagawa 210-0852 Japan

[24 ]Department of Neurology, Higashiosaka City Medical Center, 3-4-5 Nishiiwata, Higashiosaka, Osaka 578-8588 Japan

[25 ]GRID grid.471500.7, ISNI 0000 0004 0649 1576, Department of Emergency and General Internal Medicine, , Fujita Health University Hospital, ; 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192 Japan

[26 ]GRID grid.410843.a, ISNI 0000 0004 0466 8016, Department of Respiratory Medicine, , Kobe City Medical Center General Hospital, ; 2-1-1 Minatojimaminamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan

[27 ]GRID grid.470350.5, Department of Infectious Diseases, , National Hospital Organization Fukuokahigashi Medical Center, ; 1-1-1 Chidori, Koga, Fukuoka 811-3195 Japan

[28 ]Department of Infectious Diseases, Sakai City Medical Center, 1-1-1 Ebarajicho, Nishi-ku, Sakai, Osaka 593-8304 Japan

[29 ]GRID grid.415474.7, Department of Internal Medicine, , Self-Defense Forces Central Hospital, ; 1-2-24 Ikejiri, Setagaya-ku, Tokyo, 154-8532 Japan

[30 ]GRID grid.410862.9, ISNI 0000 0004 1770 2279, Scientific Information Department, , FujiFilm Toyama Chemical Co., Ltd., ; 3-4-8 Hatchobori, Chuo-ku, Tokyo, 104-0032 Japan

[31 ]GRID grid.412764.2, ISNI 0000 0004 0372 3116, Department of Infectious Diseases, School of Medicine, , St. Marianna University, ; 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511 Japan

[32 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Department of Infectious Diseases, , National Cancer Center Hospital, ; 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan

Article

Publisher ID: 517

DOI: 10.1007/s40121-021-00517-4

PMC ID: 8396144

PubMed ID: 34453234

SO-VID: 5acbeef9-c041-417f-8b03-d2ae0b9d580c

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 21 May 2021

Date accepted : 27 July 2021

Funding

Funded by: FUJIFILM Toyama Chemical CO

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Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial

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Abstract

Introduction

Methods

Results

Conclusions

Trial registration

Supplementary Information

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Novel Coronavirus Disease COVID-19

Most cited references 21

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Virological assessment of hospitalized patients with COVID-2019

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

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