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      Clinical and laboratory evaluation of SARS-CoV-2 lateral flow assays for use in a national COVID-19 seroprevalence survey

      research-article
      1 , 2 , , 1 , 1 , 1 , 1 , 1 , 1 , 3 , 1 , 3 , 4 , 4 , 2 , 4 , 1 , 5 , 5 , 3 , 1 , 1 , 1 , 1 , 6 , 1 , 1 , 5 , 7 , 8 , 8 , 8 , 8 , 9 , 1 , 1 , 1 , 10 , 1 , 2 , 4 , 2 , 5 , 2 , 11 , 1 , 1 , 2
      Thorax
      BMJ Publishing Group
      viral infection, clinical epidemiology, respiratory infection

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          Abstract

          Background

          Accurate antibody tests are essential to monitor the SARS-CoV-2 pandemic. Lateral flow immunoassays (LFIAs) can deliver testing at scale. However, reported performance varies, and sensitivity analyses have generally been conducted on serum from hospitalised patients. For use in community testing, evaluation of finger-prick self-tests, in non-hospitalised individuals, is required.

          Methods

          Sensitivity analysis was conducted on 276 non-hospitalised participants. All had tested positive for SARS-CoV-2 by reverse transcription PCR and were ≥21 days from symptom onset. In phase I, we evaluated five LFIAs in clinic (with finger prick) and laboratory (with blood and sera) in comparison to (1) PCR-confirmed infection and (2) presence of SARS-CoV-2 antibodies on two ‘in-house’ ELISAs. Specificity analysis was performed on 500 prepandemic sera. In phase II, six additional LFIAs were assessed with serum.

          Findings

          95% (95% CI 92.2% to 97.3%) of the infected cohort had detectable antibodies on at least one ELISA. LFIA sensitivity was variable, but significantly inferior to ELISA in 8 out of 11 assessed. Of LFIAs assessed in both clinic and laboratory, finger-prick self-test sensitivity varied from 21% to 92% versus PCR-confirmed cases and from 22% to 96% versus composite ELISA positives. Concordance between finger-prick and serum testing was at best moderate (kappa 0.56) and, at worst, slight (kappa 0.13). All LFIAs had high specificity (97.2%–99.8%).

          Interpretation

          LFIA sensitivity and sample concordance is variable, highlighting the importance of evaluations in setting of intended use. This rigorous approach to LFIA evaluation identified a test with high specificity (98.6% (95%CI 97.1% to 99.4%)), moderate sensitivity (84.4% with finger prick (95% CI 70.5% to 93.5%)) and moderate concordance, suitable for seroprevalence surveys.

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          Most cited references17

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          Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections

          The clinical features and immune responses of asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been well described. We studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Asymptomatic individuals were admitted to the government-designated Wanzhou People's Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15-26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6-10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8-38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.
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            Convergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals

            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 1–5 . 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 (IC50s) 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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              Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study

              Summary Background Spain is one of the European countries most affected by the COVID-19 pandemic. Serological surveys are a valuable tool to assess the extent of the epidemic, given the existence of asymptomatic cases and little access to diagnostic tests. This nationwide population-based study aims to estimate the seroprevalence of SARS-CoV-2 infection in Spain at national and regional level. Methods 35 883 households were selected from municipal rolls using two-stage random sampling stratified by province and municipality size, with all residents invited to participate. From April 27 to May 11, 2020, 61 075 participants (75·1% of all contacted individuals within selected households) answered a questionnaire on history of symptoms compatible with COVID-19 and risk factors, received a point-of-care antibody test, and, if agreed, donated a blood sample for additional testing with a chemiluminescent microparticle immunoassay. Prevalences of IgG antibodies were adjusted using sampling weights and post-stratification to allow for differences in non-response rates based on age group, sex, and census-tract income. Using results for both tests, we calculated a seroprevalence range maximising either specificity (positive for both tests) or sensitivity (positive for either test). Findings Seroprevalence was 5·0% (95% CI 4·7–5·4) by the point-of-care test and 4·6% (4·3–5·0) by immunoassay, with a specificity–sensitivity range of 3·7% (3·3–4·0; both tests positive) to 6·2% (5·8–6·6; either test positive), with no differences by sex and lower seroprevalence in children younger than 10 years ( 10%) and lower in coastal areas (<3%). Seroprevalence among 195 participants with positive PCR more than 14 days before the study visit ranged from 87·6% (81·1–92·1; both tests positive) to 91·8% (86·3–95·3; either test positive). In 7273 individuals with anosmia or at least three symptoms, seroprevalence ranged from 15·3% (13·8–16·8) to 19·3% (17·7–21·0). Around a third of seropositive participants were asymptomatic, ranging from 21·9% (19·1–24·9) to 35·8% (33·1–38·5). Only 19·5% (16·3–23·2) of symptomatic participants who were seropositive by both the point-of-care test and immunoassay reported a previous PCR test. Interpretation The majority of the Spanish population is seronegative to SARS-CoV-2 infection, even in hotspot areas. Most PCR-confirmed cases have detectable antibodies, but a substantial proportion of people with symptoms compatible with COVID-19 did not have a PCR test and at least a third of infections determined by serology were asymptomatic. These results emphasise the need for maintaining public health measures to avoid a new epidemic wave. Funding Spanish Ministry of Health, Institute of Health Carlos III, and Spanish National Health System.
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                Author and article information

                Journal
                Thorax
                Thorax
                thoraxjnl
                thorax
                Thorax
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0040-6376
                1468-3296
                August 2020
                12 August 2020
                : thoraxjnl-2020-215732
                Affiliations
                [1 ] departmentDepartment of Infectious Disease, Faculty of Medicine , Imperial College London , London, UK
                [2 ] departmentNIHR BRC , Imperial College NHS Trust , London, UK
                [3 ] Imperial College Healthcare NHS Trust , London, UK
                [4 ] departmentDepartment of Epidemiology and Public Health , Imperial College London , London, UK
                [5 ] departmentInstitute of Global Health Innovation , Imperial College London , London, UK
                [6 ] departmentSynthetic Biology Group , MRC London Institute of Medical Sciences, Imperial College London , London, UK
                [7 ] departmentCentre for Defence Pathology , British Army , Birmingham, UK
                [8 ] Chelsea and Westminster Healthcare NHS Trust , London, UK
                [9 ] departmentNIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance , Imperial College London , London, UK
                [10 ] departmentDepartment of Surgery and Cancer , Imperial College London , London, UK
                [11 ] departmentDepartment of Epidemiology and Biostatistics, School of Public Health , Imperial College London , London, United Kingdom
                Author notes
                [Correspondence to ] Dr Barnaby Flower, Infectious Disease, Department of Medicine, Imperial College London, London W2 1NY, UK; b.flower@ 123456imperial.ac.uk
                Author information
                http://orcid.org/0000-0002-2659-544X
                http://orcid.org/0000-0001-6849-3962
                http://orcid.org/0000-0002-9465-5299
                http://orcid.org/0000-0001-7095-7922
                Article
                thoraxjnl-2020-215732
                10.1136/thoraxjnl-2020-215732
                7430184
                32796119
                0cc9d11d-4034-4ce0-9f65-8160bd13af58
                © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

                This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

                History
                : 06 July 2020
                : 22 July 2020
                : 25 July 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100014013, UK Research and Innovation;
                Award ID: MC_PC_19078
                Funded by: FundRef http://dx.doi.org/10.13039/100013986, Government of the United Kingdom;
                Categories
                Respiratory Infection
                2474
                2313
                Original research
                Custom metadata
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                Surgery
                viral infection,clinical epidemiology,respiratory infection
                Surgery
                viral infection, clinical epidemiology, respiratory infection

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