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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 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 5

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          An Outbreak of Human Coronavirus OC43 Infection and Serological Cross-reactivity with SARS Coronavirus.

          In summer 2003, a respiratory outbreak was investigated in British Columbia, during which nucleic acid tests and serology unexpectedly indicated reactivity for severe acute respiratory syndrome coronavirus (SARS-CoV).
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            The important role of serology for COVID-19 control

            As of April 14, 2020, just under 2 million cases of coronavirus disease 2019 (COVID-19) have been reported worldwide. 1 With the pandemic growing at an alarming rate and national governments struggling to control local epidemics because of scant diagnostics and impermanent non-pharmaceutical interventions, we should look to additional epidemiological solutions. Locations such as Singapore and Taiwan have been successful in slowing epidemic growth by using intensive surveillance with broader testing strategies to identify and contain cases.2, 3 In The Lancet Infectious Diseases, Sarah Ee Fang Yong and colleagues 4 report three clusters of COVID-19 cases identified in Singapore in early 2020 by active case-finding and contact tracing and confirmed with RT-PCR. One cluster from a church (Church A) was previously identified 5 and linked to two imported cases from Wuhan, China. The two additional clusters (Church B and a family gathering) were attributable to community transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by one individual interacting with both clusters. Serological platforms were developed and assessed for confirmation of SARS-CoV-2-specific antibody responses to capture past infections. By serological analysis, Yong and colleagues identified the missing link between the Church A cluster and the other two clusters—an individual who had twice tested negative by RT-PCR. By linking all three clusters, Yong and colleagues highlight the success of such surveillance measures to capture many cases and effectively slow the spread of COVID-19 in Singapore. This investigation exemplifies the failings of RT-PCR as a sole diagnostic method in surveillance, because of its inability to detect past infection, and the added value of serological testing, which if captured within the correct timeframe after disease onset can detect both active and past infections.6, 7 In public health practice, serological analysis can be useful for rapid case-identification and the subsequent chain of events to actively identify close contacts, recommend quarantine, and define clusters of cases. Contact tracing, which is a necessary but insufficient means of disease control, needs careful effort and is sensitive to timing to be effective, particularly in highly dense populations. As shown in Singapore, serological analysis can be useful for contact tracing in urban environments and linking clusters of cases retrospectively to delineate transmission chains and ascertain how long transmission has been ongoing or to estimate the proportion of asymptomatic individuals in the population. Beyond the immediate use of serological data to identify and contain cases, these data can also be used to set control policies. Population serological testing (specifically measuring SARS-CoV-2-specific IgG antibody titres) can estimate the total number of infections by assessing the number of individuals who have mounted an immune response, regardless of whether an infection was subclinical or happened in the recent past (current data suggest antibodies persist for at least 4 weeks). 8 By providing estimates of who is and is not immune to SARS-CoV-2, serological data can be used in at least four ways. First, to estimate epidemiological variables, such as the attack rate or case-fatality rate, which are necessary to assess how much community transmission has occurred and its burden. Second, to strategically deploy immune health-care workers to reduce exposure of the virus to susceptible individuals. Third, to assess the effect of non-pharmaceutical interventions at the population-level and inform policy changes to release such measures, Fourth, to identify individuals who mounted a strong immunological response to the virus and whose antibody isolates can be used to treat patients via plasma therapy. 9 Although the potential for serological assays to help control the COVID-19 pandemic is substantial, the complexity of developing and validating a diagnostic test is not fully elucidated by Yong and colleagues. 4 Serological assays are currently being developed for widespread use. 10 Yet, several challenges remain: first, assessing the sensitivity and specificity of tests, particularly for determining disease during the acute phase of infection; second, verifying the test is not detecting cross-reactivity with other viral pathogens that result in false-positive results; third, understanding antibody kinetics over time to distinguish thresholds of immunity, because we do not know how long immunity to this novel coronavirus might last; and finally, ensuring the test is reliable for distribution and is cost-efficient. Although RT-PCR diagnostics will still be vital for identifying acute infection, as the SARS-CoV-2 pandemic continues to spread and cases accumulate, serological testing and data will prove increasingly important to understand the pandemics' past and predict its future. © 2020 Flickr - Roberto Herdiyanto 2020 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.
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              Rapid point-of-care testing for SARS-CoV-2 in a community screening setting shows low sensitivity

              Objective With the current SARS-CoV2 outbreak, countless tests need to be performed on potential symptomatic individuals, contacts and travellers. The gold standard is a quantitative polymerase chain reaction (qPCR)–based system taking several hours to confirm positivity. For effective public health containment measures, this time span is too long. We therefore evaluated a rapid test in a high-prevalence community setting. Study design Thirty-nine randomly selected individuals at a COVID-19 screening centre were simultaneously tested via qPCR and a rapid test. Ten previously diagnosed individuals with known SARS-CoV-2 infection were also analysed. Methods The evaluated rapid test is an IgG/IgM–based test for SARS-CoV-2 with a time to result of 20 min. Two drops of blood are needed for the test performance. Results Of 49 individuals, 22 tested positive by repeated qPCR. In contrast, the rapid test detected only eight of those positive correctly (sensitivity: 36.4%). Of the 27 qPCR-negative individuals, 24 were detected correctly (specificity: 88.9%). Conclusion Given the low sensitivity, we recommend not to rely on an antibody-based rapid test for public health measures such as community screenings.
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                Author and article information

                Journal
                Science Immunology
                Sci. Immunol.
                American Association for the Advancement of Science (AAAS)
                2470-9468
                June 11 2020
                June 11 2020
                June 11 2020
                June 11 2020
                : 5
                : 48
                : eabc8413
                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 ]Immunology/Histocompatibility and Immunogenetics Laboratories, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA
                [5 ]Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA
                [6 ]Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University, Decatur, Georgia, USA
                [7 ]Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA
                [8 ]Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA
                Article
                10.1126/sciimmunol.abc8413
                7292505
                32527802
                © 2020

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