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      Potently neutralizing and protective human antibodies against SARS-CoV-2

      1 , 1 , 3 , 1 , 2 , 3 , 4 , 5 , 1 , 1 , 1 , 1 , 1 , 5 , 6 , 6 , 1 , 1 , 1 , 3 , 2 , 3 , 2 , 3 , 3 , 3 , 7 , 7 , 8 , 4 , 4 , 9 , 10 , 10 , 10 , 3 , 3 , 11 , 3 , 11 , 4 , 5 , 5 , 3 , 2 , 3 , 12 , 13 , 1 , 14 , ** , 1 , 6 , 14 , **
      Coronavirus, SARS-CoV-2, SARS-CoV, COVID-19, Antibodies, Monoclonal, Human, Adaptive Immunity

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          The COVID-19 pandemic is a major threat to global health 1 for which there are limited medical countermeasures 2, 3 . Moreover, we currently lack a thorough understanding of mechanisms of humoral immunity 4 . From a larger panel of human monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein 5 , we identified several that exhibited potent neutralizing activity and fully blocked the receptor-binding domain of S (S RBD) from interacting with human ACE2 (hACE2). Competition-binding, structural, and functional studies allowed clustering of the mAbs into classes recognizing distinct epitopes on the S RBD as well as distinct conformational states of the S trimer. Potent neutralizing mAbs recognizing non-overlapping sites, COV2-2196 and COV2-2130, bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. In two mouse models of SARS-CoV-2 infection, passive transfer of either COV2-2196 or COV2-2130 alone or a combination of both mAbs protected mice from weight loss and reduced viral burden and inflammation in the lung. In addition, passive transfer of each of two of the most potently ACE2 blocking mAbs (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on S RBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutics.

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          Most cited references54

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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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            Is Open Access

            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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              SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

              Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

                Author and article information

                16 October 2020
                15 July 2020
                August 2020
                15 January 2021
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                [1 ]Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
                [2 ]Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [3 ]Department of Medicine, Washington University School of Medicine, St. Louis, 63110, MO, USA
                [4 ]Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
                [5 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
                [6 ]Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
                [7 ]Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA
                [8 ]Leipzig University Medical School, Institute for Drug Discovery, 04103 Leipzig, Germany
                [9 ]Antibody Discovery and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, 20878, USA
                [10 ]Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, 20878, USA
                [11 ]Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
                [12 ]Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [13 ]Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [14 ]Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
                Author notes
                Contact information: James E. Crowe, Jr., M.D. Departments of Pediatrics, Pathology, Microbiology, and Immunology, and the Vanderbilt Vaccine Center, Vanderbilt Vaccine Center, 11475 Medical Research Building IV, 2213 Garland Avenue, Nashville, TN 37232-0417, USA, Telephone (615) 343-8064, james.crowe@ 123456vumc.org
                [** ]Corresponding authors. James Crowe, james.crowe@ 123456vumc.org ; Robert Carnahan, Robert.carnahan@ 123456vumc.org .

                Author contributions. Conceived of the project: S.J.Z., P.G., R.H.C., L.B.T., M.S.D., J.E.C.; Obtained funding: J.E.C. and M.S.D. Performed laboratory experiments: S.J.Z., P.G., J.B.C., E.B., R.E.C., J.P.N., A.S., J.X.R., A.T., R.S.N., R.E.S., N.S., D.R.M., L.E.W., A.O.H., N.M.K., E.S.W., J.M.F., S.S., B.K.M., A.C., N.B.M., J.J.S., K.R., Y.-M.L., S.P.K., M.J.H., L.E.G.; Performed computational work: E.C.C., T.J., S.D., L.M., B.T.M; Supervised research: J.M, N.L.K, D.H.B., R.S.B., L.B.T., M.S.D., R.H.C., J.E.C. Wrote the first draft of the paper: S.J.Z., P.G., R.H.C., J.E.C.; All authors reviewed and approved the final manuscript.


                These authors contributed equally


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                coronavirus,sars-cov-2,sars-cov,covid-19,antibodies, monoclonal,human,adaptive immunity
                coronavirus, sars-cov-2, sars-cov, covid-19, antibodies, monoclonal, human, adaptive immunity


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