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      Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge

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          Abstract

          Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.

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          Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

          Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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            Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

            Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
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              Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity

              Another host factor for SARS-CoV-2 Virus-host interactions determine cellular entry and spreading in tissues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the earlier SARS-CoV use angiotensin-converting enzyme 2 (ACE2) as a receptor; however, their tissue tropism differs, raising the possibility that additional host factors are involved. The spike protein of SARS-CoV-2 contains a cleavage site for the protease furin that is absent from SARS-CoV (see the Perspective by Kielian). Cantuti-Castelvetri et al. now show that neuropilin-1 (NRP1), which is known to bind furin-cleaved substrates, potentiates SARS-CoV-2 infectivity. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial and epithelial cells. Daly et al. found that the furin-cleaved S1 fragment of the spike protein binds directly to cell surface NRP1 and blocking this interaction with a small-molecule inhibitor or monoclonal antibodies reduced viral infection in cell culture. Understanding the role of NRP1 in SARS-CoV-2 infection may suggest potential targets for future antiviral therapeutics. Science, this issue p. 856, p. 861; see also p. 765
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                Author and article information

                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                The Authors. Published by Elsevier B.V.
                2352-3964
                1 April 2021
                April 2021
                1 April 2021
                : 66
                : 103291
                Affiliations
                [a ]Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Robert-Koch-Str. 40, 37085 Göttingen, Germany
                [b ]Laboratory of Flow Cytometry, Centre of Postgraduate Medical Education, Warsaw, Poland
                [c ]Dept. of Anesthesiology and Intensive Care Medicine & Center for Sepsis Control and Care (CSCC), Jena University Hospital-Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
                [d ]Center for Clinical Studies, Jena University Hospital, 07747 Jena, Germany
                [e ]Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Sweden
                [f ]French National Research Agency (ANR), Paris, France
                [g ]Intensive Care Department and Shock, Organ Dysfunction and Resuscitation Research Group, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, Barcelona, 08035, Spain
                [h ]Centro de Investigación Biomedica En Red-Enfermedades Respiratorias (CibeRes, CB06/06/0028), Instituto de salud Carlos III (ISCIII), Av. de Monforte de Lemos, 5, 28029 Madrid, Spain
                [i ]Department of Trauma, Hand, and Reconstructive Surgery, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany
                [j ]Pediatric Critical Care Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
                [k ]4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens 12462, Greece
                [l ]Department of Anesthesia and Intensive Care, University Hospital of Modena, Italy
                [m ]Department of Intensive Care Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands
                [n ]Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
                [o ]Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany
                [p ]Multidisciplinary Intensive Care Research Organization (MICRO), St. James's Hospital, James's St N, Ushers, Dublin, D03 VX82, Ireland
                [q ]Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
                [r ]Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland
                [s ]Pneumology Department, Respiratory Institute (ICR), Hospital Clinic of Barcelona - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) - University of Barcelona (UB), Spain
                [t ]Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
                [u ]Hospices Civils de Lyon, Immunology Laboratory, Edouard Herriot Hospital, 5 Place d'Arsonval, 69003 Lyon, France
                [v ]EA 7426 "Pathophysiology of Injury-Induced Immunosuppression - PI3", Université Claude Bernard Lyon 1/bioMérieux/Hospices Civils de Lyon, Edouard Herriot Hospital, 5 Place d'Arsonval, 69003 Lyon, France
                [w ]Institute for Infectious Disease and Infection Control, Jena University Hospital-Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
                [x ]Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital-Friedrich Schiller University, Bachstrasse 18, 07743 Jena, Germany
                [y ]Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Donaueschingenstrasse 13, 1200, Vienna, Austria
                Author notes
                [* ]Corresponding author.
                [#]

                shared first authorship

                Article
                S2352-3964(21)00084-0 103291
                10.1016/j.ebiom.2021.103291
                8016444
                376c8951-5e5d-4027-8771-7cfb2f22ae63
                © 2021 The Authors

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 19 December 2020
                : 22 February 2021
                : 5 March 2021
                Categories
                Review

                covid-19,animal model,pre-clinical research,pandemic,clinical trial,vaccine

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