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      Longitudinal Isolation of Potent Near-Germline SARS-CoV-2-Neutralizing Antibodies from COVID-19 Patients

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      1 , 19 , 1 , 19 , 1 , 1 , 1 , 2 , 3 , 2 , 3 , 1 , 1 , 4 , 5 , 1 , 6 , 1 , 7 , 8 , 1 , 2 , 3 , 2 , 3 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 17 , 18 , 9 , 1 , 4 , 2 , 3 , 1 , 4 , 11 , 20 ,
      Cell
      The Author(s). Published by Elsevier Inc.
      SARS-CoV-2, 2019-nCoV, COVID-19, neutralizing antibody, monoclonal antibody, single B cell analysis

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          Summary

          The SARS-CoV-2 pandemic has unprecedented implications for public health, social life, and the world economy. Because approved drugs and vaccines are limited or not available, new options for COVID-19 treatment and prevention are in high demand. To identify SARS-CoV-2-neutralizing antibodies, we analyzed the antibody response of 12 COVID-19 patients from 8 to 69 days after diagnosis. By screening 4,313 SARS-CoV-2-reactive B cells, we isolated 255 antibodies from different time points as early as 8 days after diagnosis. Of these, 28 potently neutralized authentic SARS-CoV-2 with IC 100 as low as 0.04 μg/mL, showing a broad spectrum of variable (V) genes and low levels of somatic mutations. Interestingly, potential precursor sequences were identified in naive B cell repertoires from 48 healthy individuals who were sampled before the COVID-19 pandemic. Our results demonstrate that SARS-CoV-2-neutralizing antibodies are readily generated from a diverse pool of precursors, fostering hope for rapid induction of a protective immune response upon vaccination.

          Graphical Abstract

          Highlights

          • Isolation of highly potent SARS-CoV-2-neutralizing antibodies

          • Longitudinal sampling reveals early class-switched neutralizing response

          • SARS-CoV-2 S-protein-reactive antibodies show little somatic mutation over time

          • Potential antibody precursor sequences identified in SARS-CoV-2-naive individuals

          Abstract

          In a longitudinal analysis of SARS-CoV-2-infected people, Kreer et al. find highly potent neutralizing antibodies that use a broad spectrum of variable (V) genes and show low levels of somatic mutations. They also identify potential precursor sequences of these SARS-CoV-2-neutralizing antibodies from virus-naive individuals, sampled before the COVID-19 pandemic. This could indicate that neutralizing antibodies can be readily generated from existing germline antibody sequences found in the general population.

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          Most cited references52

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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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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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                The Author(s). Published by Elsevier Inc.
                0092-8674
                1097-4172
                13 July 2020
                13 July 2020
                Affiliations
                [1 ]Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
                [2 ]Institute of Virology, Faculty of Medicine, Philipps University Marburg, 35043 Marburg, Germany
                [3 ]German Center for Infection Research, Partner Site Gießen-Marburg-Langen, 35043 Marburg, Germany
                [4 ]German Center for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany
                [5 ]Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
                [6 ]Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50935 Cologne, Germany
                [7 ]Department I of Internal Medicine, Center for Integrated Oncology (CIO) Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany
                [8 ]Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
                [9 ]Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel
                [10 ]Institute for Dental Research and Oral Musculoskeletal Biology and Center for Biochemistry, University of Cologne, 50931 Cologne, Germany
                [11 ]Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
                [12 ]Faculty of Medicine, University of Würzburg, 97080 Würzburg, Germany
                [13 ]Institute for Translational Bioinformatics, University Hospital Tübingen and University of Tübingen, 72076 Tübingen, Germany
                [14 ]Faculty of Medicine, University of Tübingen, 72076 Tübingen, Germany
                [15 ]Methods in Medical Informatics, Department of Computer Science, University of Tübingen, 72076 Tübingen, Germany
                [16 ]German Center for Infection Research, Partner Site Tübingen, 72076 Tübingen, Germany
                [17 ]Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
                [18 ]Department of Infectious Diseases and Tropical Medicine, Munich Clinic Schwabing, Academic Teaching Hospital, Ludwig Maximilians University, 80804 Munich, Germany
                Author notes
                []Corresponding author florian.klein@ 123456uk-koeln.de
                [19]

                These authors contributed equally

                [20]

                Lead Contact

                Article
                S0092-8674(20)30821-7
                10.1016/j.cell.2020.06.044
                7355337
                32673567
                875e3a80-c014-4cc4-ba4e-df0454030e68
                © 2020 The Author(s)

                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.

                Categories
                Article

                Cell biology
                sars-cov-2,2019-ncov,covid-19,neutralizing antibody,monoclonal antibody,single b cell analysis

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