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      Convergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals

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      1 , 9 , 1 , 2 , 1 , 1 , 1 , 1 , 6 , 1 , 1 , 1 , 1 , 1 , 4 , 3 , 1 , 5 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 2 , 3 , 3 , 7 , 7 , 6 , 6 , 6 , 6 , 3 , 2 , 6 , 2 , 8 , 1 , 1 , 8
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          Abstract

          During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2 15 . Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titers: less than 1:50 in 33% and below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC 50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

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          Most cited references45

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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.
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            Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

            Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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              cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination

              A software tool, cryoSPARC, addresses the speed bottleneck in cryo-EM image processing, enabling automated macromolecular structure determination in hours on a desktop computer without requiring a starting model.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                13 June 2020
                18 June 2020
                August 2020
                18 December 2020
                : 584
                : 7821
                : 437-442
                Affiliations
                [1 ]Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
                [2 ]Laboratory of Retrovirology, The Rockefeller University, New York, NY 10065, USA
                [3 ]Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
                [4 ]Hospital Program Direction, The Rockefeller University, New York, NY 10065, USA
                [5 ]Hospital Clinical Research Office, The Rockefeller University, New York, NY 10065, USA
                [6 ]Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
                [7 ]Chan Zuckerberg Biohub, 499 Illinois Street, San Francisco, CA 94158, USA
                [8 ]Howard Hughes Medical Institute
                [9 ]present address: Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
                Author notes
                [*]

                Equal contribution

                Author Contributions: D.F.R., P.D.B., P.J.B., T.H., C.M.R. and M.C.N. conceived, designed and analyzed the experiments. D.F.R., M.C. and C.G. designed clinical protocols. F.M., J.C.C.L., Z.W., A.C., M.A., C.O.B., S.F., T.H., C.V., K.G., F.B., S.T.C., P.M., H.H., L.N., F.S., Y.W., H.-H.H., E.M., A.W.A., K.E.H.T., N.K. and P.R.H. carried out experiments. A.G. and M.C. produced antibodies. C.O.B., J.P. and E.W. produced SARS-CoV-2 proteins. A.H., R.K., J.H., K.G.M., C.G. and M.C. recruited participants and executed clinical protocols. R.P., J.D., M.P. and I.S. processed clinical samples. C.O.B. performed negative-stain EM analysis. T.Y.O., A.P.W. and V.R. performed bioinformatic analysis. D.F.R., P.D.B., P.J.B., T.H., C.M.R. and M.C.N. wrote the manuscript with input from all co-authors.

                [# ] Send correspondence to Paul D. Bieniasz: pbieniasz@ 123456rockefeller.edu , Marina Caskey: mcaskey@ 123456rockefeller.edu , Michel C. Nussenzweig: nussen@ 123456rockefeller.edu , Pamela Bjorkman bjorkman@ 123456caltech.edu , or Davide F. Robbiani: drobbiani@ 123456irb.usi.ch
                Article
                NIHMS1603863
                10.1038/s41586-020-2456-9
                7442695
                32555388
                32e3e793-a32b-420b-9868-ed17d6d1ec5b

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