Evaluation of Nucleocapsid and Spike Protein-based ELISAs for detecting antibodies against SARS-CoV-2

Liu, Wanbing; Liu, Lei; Kou, Guomei; Zheng, Yaqiong; Ding, Yinjuan; Ni, Wenxu; Wang, Qiongshu; Tan, Li; Wu, Wanlei; Tang, Shi; Xiong, Zhuo; Zheng, Shangen

doi:10.1101/2020.03.16.20035014

Cited by 112 publications

(158 citation statements)

References 17 publications

(18 reference statements)

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“…Moreover, irrespective of the method, a combined IgG/IgM test seems to be a better choice in terms of sensitivity than measuring either antibody type alone. The analyses also showed that tests that use the S antigen are more sensitive than N antigen-based tests probably due to higher sensitivity and earlier immune response to the S antigen 52 and more specific perhaps due to less cross-reactivity with less conserved regions of spike proteins existing in other coronaviruses (SARS-CoV) 17,55,64 . Combining N and S antigens further improves sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Antibody tests in detecting SARS-CoV-2 infection: a meta-analysis

Kontou

Braliou

Dimou

et al. 2020

Preprint

127

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With the emergence of SARS-CoV-2 and the associated Coronavirus disease 2019 (COVID-19), there is an imperative need for diagnostic tests that can identify the infection. Although Nucleic Acid Test (NAT) is considered to be the gold standard, serological tests based on antibodies could be very helpful. However, individual studies measuring the accuracy of the various tests are usually underpowered and inconsistent, thus, a comparison of different tests is needed. We performed a systematic review and meta-analysis following the PRISMA guidelines. We conducted the literature search in PubMed, medRxiv and bioRxiv. For the statistical analysis we used the bivariate method for meta-analysis of diagnostic tests pooling sensitivities and specificities. We evaluated IgM and IgG tests based on Enzyme-linked immunosorbent assay (ELISA), Chemiluminescence Enzyme Immunoassays (CLIA), Fluorescence Immunoassays (FIA) and the point-of-care (POC) Lateral Flow Immunoassays (LFIA) that are based on immunochromatography. In total, we identified 38 eligible studies that include data from 7,848 individuals. The analyses showed that tests using the S antigen are more sensitive than N antigen-based tests. IgG tests perform better compared to IgM ones, and show better sensitivity when the samples were taken longer after the onset of symptoms. Moreover, irrespective of the method, a combined IgG/IgM test seems to be a better choice in terms of sensitivity than measuring either antibody type alone. All methods yielded high specificity with some of them (ELISA and LFIA) reaching levels around 99%. ELISA- and CLIA-based methods performed better in terms of sensitivity (90-94%) followed by LFIA and FIA with sensitivities ranging from 80% to 86%. ELISA tests could be a safer choice at this stage of the pandemic. POC tests (LFIA), that are more attractive for large seroprevalence studies show high specificity but lower sensitivity and this should be taken into account when designing and performing seroprevalence studies.

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Section: Discussionmentioning

confidence: 99%

Antibody tests in detecting SARS-CoV-2 infection: a meta-analysis

Kontou

Braliou

Dimou

et al. 2020

Preprint

127

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“…Studies on SARS-CoV-1 showed that most patients seroconverted after infection but this was delayed (17-21 days) compared to a typical time course for seroconversion with other 325 respiratory viruses 30,31 . Several studies demonstrate seroconversion of IgG antibodies against the spike protein 1-3 weeks after infection with SARS-CoV-2 [32][33][34][35][36] 38 . Similarly, the median time for seroconversion to IgG in hospitalized patients was found to be 14 days in a study of 173 patients in China, with some taking up to 1 month to generate antibody detectable in a commercial ELISA test 39 .…”

Section: The Relationship Between Seroprevalence and Sars-cov-2 Exposmentioning

confidence: 99%

Detection of neutralising antibodies to SARS coronavirus 2 to determine population exposure in Scottish blood donors between March and May 2020

Thompson

Grayson

Paton

et al. 2020

Preprint

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Background. The extent of spread of SARS coronavirus 2 (SARS-CoV-2) in the UK and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of recent blood donors in Scotland to detect antibodies to SARS-CoV-2 as a marker of past infection. Methods. A pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study group comprised samples from 1000 blood donors collected in Scotland during March, 2020. Controls were collected from 100 donors in Scotland during 2019. Findings. All samples collected on the 17th March, 2020 (n=500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in 5 of the 500 samples collected 21st to 23rd March; one further sample was reactive in an anti-spike ELISA. Interpretation. Although we cannot use the rise in numbers seropositive to infer the contemporary seroprevalence or the growth rate of the epidemic, we note that they are consistent with frequency of reported diagnosed infections and SARS-CoV-2-associated deaths reported in that time period in Scotland, given that seroconversion takes up to 2-3 weeks. It should also be noted that blood donors are not representative of the general population; in particular, those with a history of recent respiratory infections are deferred. Finally, it is unknown what proportion of infected individuals seroconvert and become reactive in the assays used. Serial follow up studies are needed to track infection and seroconversion in this and other similar populations However, these data indicate that sero-surveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic like the current SARS-CoV-2 outbreak.

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“…Open Meta-Analyst showed that IgM based serological assays that use the S antigen are more sensitive than IgM based serological assays that used the N antigen-based tests probably due to higher sensitivity and earlier immune response to the S antigen 33 . However subgroup meta-analysis showed that IgG based serological assays that use N antigen are more sensitive than IgG based serological assays that use S antigen.…”

Section: Heterogeneity Investigationsmentioning

confidence: 99%

A Systematic and Meta-Analysis Review on the Diagnostic Accuracy of Antibodies in the Serological Diagnosis of COVID-19.

Vengesai

Midzi

Kasambala

et al. 2020

Preprint

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Background: Serological testing based on different antibody types are an alternative method being used to diagnose SARS-CoV-2 and has the potential of having higher diagnostic accuracy compared to the current gold standard RT-PCR. Therefore, the objective of this review was to evaluate the diagnostic accuracy of IgG and IgM based Point-of-care (POC) lateral flow immunoassays (LFIA), chemiluminescence enzyme immunoassay (CLIA), fluorescence enzyme-linked immunoassay (FIA) and ELISA systems that detect SARS-CoV-2 antigens.Method: A systematic literature search was carried out in PubMed, Medline complete and MedRxiv. Studies evaluating the diagnostic accuracy of serological assays for SARS-CoV-2 were eligible. Study selection and data-extraction were done by two authors independently. QUADAS-2 checklist tool was used to assess the quality of the studies. The bivariate model and the hierarchical summary receiver operating characteristic curve model were performed to evaluate the diagnostic accuracy of the serological tests. Subgroup meta-analysis analyses was performed to explore the heterogeneity. Results: The pooled sensitivity for IgG, IgM and IgG-IgM based LFIA tests were 0.5856, 0.4637 and 0.6886 respectively compared to RT-PCR method. The pooled sensitivity for IgG and IgM based CLIA tests were 0.9311 and 0.8516 respectively compared to RT-PCR. The pooled sensitivity the IgG, IgM and IgG-IgM based ELISA tests were 0.8292, 0.8388 and 0.8531 respectively compared to RT-PCR. All tests displayed high specificities ranging from 0.9693 to 0.9991. Among the evaluated tests, IgG based CLIA expressed the highest sensitivity signifying its accurate detection of the largest proportion of infections identified by RT-PCR. ELISA and CLIA tests performed better in terms of sensitivity compared to LFIA. IgG based tests performed better compared to IgM ones expect for the ELISA. Conclusions: We report that IgG-IgM based ELISA tests have the best overall diagnostic test accuracy. Moreover, irrespective of the method, a combined IgG/IgM test seems to be a better choice in terms of sensitivity than measuring either antibody type independently. Given the poor performances of the current LFIA devices there is need for more research on the development of highly sensitivity and specific POC LFIA that are adequate for most individual patient applications and attractive for large sero-prevalence studies.Systematic review registration: PROSPERO Registration Number is: CRD42020179112

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Evaluation of Nucleocapsid and Spike Protein-based ELISAs for detecting antibodies against SARS-CoV-2

Cited by 112 publications

References 17 publications

Antibody tests in detecting SARS-CoV-2 infection: a meta-analysis

Antibody tests in detecting SARS-CoV-2 infection: a meta-analysis

Detection of neutralising antibodies to SARS coronavirus 2 to determine population exposure in Scottish blood donors between March and May 2020

A Systematic and Meta-Analysis Review on the Diagnostic Accuracy of Antibodies in the Serological Diagnosis of COVID-19.

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