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      The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients

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          Abstract

          The serum level of RBD-binding antibodies correlates with SARS-CoV-2 neutralization and can be used for population-level surveillance.

          Abstract

          The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD's performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people.

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          Most cited references 27

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          Origin and evolution of pathogenic coronaviruses

          Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two highly transmissible and pathogenic viruses that emerged in humans at the beginning of the 21st century. Both viruses likely originated in bats, and genetically diverse coronaviruses that are related to SARS-CoV and MERS-CoV were discovered in bats worldwide. In this Review, we summarize the current knowledge on the origin and evolution of these two pathogenic coronaviruses and discuss their receptor usage; we also highlight the diversity and potential of spillover of bat-borne coronaviruses, as evidenced by the recent spillover of swine acute diarrhoea syndrome coronavirus (SADS-CoV) to pigs.
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            Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

            Summary Background Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses. Methods We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection. Findings Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37–75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log10 copies per mL (IQR 4·1–7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope −0·15, 95% CI −0·19 to −0·11; R 2=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074–0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R 2>0·9). No genome mutations were detected on serial samples. Interpretation Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for high-risk individuals. Serological assay can complement RT-qPCR for diagnosis. Funding Richard and Carol Yu, May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, and Sanming Project of Medicine.
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              The spike protein of SARS-CoV — a target for vaccine and therapeutic development

              Key Points This Review provides an overview on the spike (S) protein of severe acute respiratory syndrome-coronavirus (SARS-CoV) as a target for the development of vaccines and therapeutics for the prevention and treatment of SARS. SARS is a newly emerging infectious disease, caused by SARS-CoV, a novel coronavirus that caused a global outbreak of SARS. SARS-CoV S protein mediates binding of the virus with its receptor angiotensin-converting enzyme 2 and promotes the fusion between the viral and host cell membranes and virus entry into the host cell. SARS-CoV S protein induces humoral and cellular immune responses against SARS-CoV. SARS S protein is the target of new SARS vaccines. These vaccines are based on SARS-CoV full-length S protein and its receptor-binding domain, including DNA-, viral vector- and subunit-based vaccines Peptides, antibodies, organic compounds and short interfering RNAs are additional anti-SARS-CoV therapeutics that target the S protein. The work on SARS-CoV S protein-based vaccines and drugs will be useful as a model for the development of prophylactic strategies and therapies against other viruses with class I fusion proteins that can cause emerging infectious diseases.
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                Author and article information

                Journal
                Sci Immunol
                Sci Immunol
                SciImmunol
                immunology
                Science Immunology
                American Association for the Advancement of Science
                2470-9468
                11 June 2020
                : 5
                : 48
                Affiliations
                [1 ]Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA
                [2 ]Department of Epidemiology, UNC Chapel Hill School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
                [3 ]Departments of Medicine, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA
                [4 ]Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA
                [5 ]Immunology/Histocompatibility and Immunogenetics Laboratories, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA
                [6 ]Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA
                [7 ]Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA
                [8 ]Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University, Decatur, Georgia, USA
                Author notes
                [* ] Correspondence should be addressed to Lakshmanane Premkumar ( prem@ 123456med.unc.edu ) or Aravinda M. de Silva ( aravinda_desilva@ 123456med.unc.edu )
                Article
                abc8413
                10.1126/sciimmunol.abc8413
                7292505
                32527802
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: 75N9301900065
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: T32 AI007151
                Funded by: doi http://dx.doi.org/10.13039/100000861, Burroughs Wellcome Fund;
                Funded by: doi http://dx.doi.org/10.13039/100007890, University of North Carolina at Chapel Hill;
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