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      Potential Antiviral Options against SARS-CoV-2 Infection

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          Abstract

          As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here, we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified the most potent sera from recovered patients for the treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against the SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that a combination of orally available virus-directed nelfinavir and host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.

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          Most cited references59

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          Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

          Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.
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            Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

            Could administration of convalescent plasma transfusion be beneficial in the treatment of critically ill patients with coronavirus disease 2019 (COVID-19)? In this uncontrolled case series of 5 critically ill patients with COVID-19 and acute respiratory distress syndrome (ARDS), administration of convalescent plasma containing neutralizing antibody was followed by an improvement in clinical status. These preliminary findings raise the possibility that convalescent plasma transfusion may be helpful in the treatment of critically ill patients with COVID-19 and ARDS, but this approach requires evaluation in randomized clinical trials. Coronavirus disease 2019 (COVID-19) is a pandemic with no specific therapeutic agents and substantial mortality. It is critical to find new treatments. To determine whether convalescent plasma transfusion may be beneficial in the treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Case series of 5 critically ill patients with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; P ao 2 /F io 2 <300; and mechanical ventilation. All 5 were treated with convalescent plasma transfusion. The study was conducted at the infectious disease department, Shenzhen Third People's Hospital in Shenzhen, China, from January 20, 2020, to March 25, 2020; final date of follow-up was March 25, 2020. Clinical outcomes were compared before and after convalescent plasma transfusion. Patients received transfusion with convalescent plasma with a SARS-CoV-2–specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 days after admission. Changes of body temperature, Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness), P ao 2 /F io 2 , viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after convalescent plasma transfusion. All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and P ao 2 /F io 2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2–specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion. In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials. This case series describes clinical outcomes in 5 Chinese patients with laboratory-confirmed COVID-19, ARDS, and high viral loads despite antiviral treatment who were given human plasma with SARS-CoV-2 antibodies obtained from previously infected and recovered patients.
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              Effectiveness of convalescent plasma therapy in severe COVID-19 patients

              Significance COVID-19 is currently a big threat to global health. However, no specific antiviral agents are available for its treatment. In this work, we explore the feasibility of convalescent plasma (CP) transfusion to rescue severe patients. The results from 10 severe adult cases showed that one dose (200 mL) of CP was well tolerated and could significantly increase or maintain the neutralizing antibodies at a high level, leading to disappearance of viremia in 7 d. Meanwhile, clinical symptoms and paraclinical criteria rapidly improved within 3 d. Radiological examination showed varying degrees of absorption of lung lesions within 7 d. These results indicate that CP can serve as a promising rescue option for severe COVID-19, while the randomized trial is warranted.
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                Author and article information

                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                13 June 2020
                June 2020
                : 12
                : 6
                : 642
                Affiliations
                [1 ]Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7028 Trondheim, Norway; aleksandr.ianevski@ 123456ntnu.no (A.I.); rouany@ 123456stud.ntnu.no (R.Y.); svetlana.biza@ 123456yandex.ru (S.B.); Hilde.Lysvand@ 123456ntnu.no (H.L.); kirsti.loseth@ 123456ntnu.no (K.L.); veslemoy.m.landsem@ 123456ntnu.no (V.M.L.); valentyn.oksenych@ 123456ntnu.no (V.O.); sten.e.erlandsen@ 123456ntnu.no (S.E.E.); per.a.aas@ 123456ntnu.no (P.A.A.); lars.hagen@ 123456ntnu.no (L.H.); caroline.h.pettersen@ 123456ntnu.no (C.H.P.); jan.afset@ 123456ntnu.no (J.E.A.); svein.a.nordbo@ 123456ntnu.no (S.A.N.); magnar.bjoras@ 123456ntnu.no (M.B.)
                [2 ]Department of Medical Microbiology, St. Olavs Hospital, 7006 Trondheim, Norway; Mona.Hoyseter.Fenstad@ 123456stolav.no (M.H.F.); Janne.Fossum.Malmring@ 123456stolav.no (J.F.M.)
                [3 ]Department of Immunology and Transfusion Medicine, St. Olavs Hospital, 7006 Trondheim, Norway
                [4 ]Institute of Technology, University of Tartu, 50090 Tartu, Estonia; Eva.Zusinaite@ 123456ut.ee (E.Z.); tanel.tenson@ 123456ut.ee (T.T.)
                [5 ]Institute of Genomics Core Facility, University of Tartu, 51010 Tartu, Estonia; tuuli.reisberg@ 123456ut.ee
                Author notes
                [* ]Correspondence: denis.kainov@ 123456ntnu.no ; Tel./Fax: +358-405-490-220
                Author information
                https://orcid.org/0000-0002-5088-3791
                https://orcid.org/0000-0002-7620-4355
                Article
                viruses-12-00642
                10.3390/v12060642
                7354438
                32545799
                4629bec0-a1ef-43d2-9b20-201128624e90
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 May 2020
                : 11 June 2020
                Categories
                Article

                Microbiology & Virology
                antivirals,broad-spectrum antivirals,antiviral drug combinations
                Microbiology & Virology
                antivirals, broad-spectrum antivirals, antiviral drug combinations

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