Implementation and Extended Evaluation of the Euroimmun Anti-SARS-CoV-2 IgG Assay and Its Contribution to the United Kingdom’s COVID-19 Public Health Response

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ABSTRACT

In March 2020, the Rare and Imported Pathogens Laboratory at the UK Health Security Agency (UKHSA) (formerly Public Health England [PHE]) Porton Down, was tasked by the Department of Health and Social Care with setting up a national surveillance laboratory facility to study SARS-CoV-2 antibody responses and population-level sero-surveillance in response to the growing SARS-CoV-2 outbreak. In the following 12 months, the laboratory tested more than 160,000 samples, facilitating a wide range of research and informing UKHSA, DHSC, and UK government policy. Here we describe the implementation and use of the Euroimmun anti-SARS-CoV-2 IgG assay and provide an extended evaluation of its performance. We present a markedly improved overall sensitivity of 91.39% (≥14 days 92.74%, ≥21 days 93.59%) compared to our small-scale early study, and a specificity of 98.56%. In addition, we detail extended characteristics of the Euroimmun assay: intra- and interassay precision, correlation to neutralization, and assay linearity.

IMPORTANCE Serology assays have been useful in determining those with previous SARS-CoV-2 infection in a wide range of research and serosurveillance projects. However, assays vary in their sensitivity at detecting SARS-CoV-2 antibodies. Here, we detail an extended evaluation and characterization of the Euroimmun anti-SARS-CoV-2 IgG assay, one that has been widely used within the United Kingdom on over 160,000 samples to date.

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pROC: an open-source package for R and S+ to analyze and compare ROC curves

Xavier Robin, Natacha Turck, Alexandre Hainard … (2013)

Background Receiver operating characteristic (ROC) curves are useful tools to evaluate classifiers in biomedical and bioinformatics applications. However, conclusions are often reached through inconsistent use or insufficient statistical analysis. To support researchers in their ROC curves analysis we developed pROC, a package for R and S+ that contains a set of tools displaying, analyzing, smoothing and comparing ROC curves in a user-friendly, object-oriented and flexible interface. Results With data previously imported into the R or S+ environment, the pROC package builds ROC curves and includes functions for computing confidence intervals, statistical tests for comparing total or partial area under the curve or the operating points of different classifiers, and methods for smoothing ROC curves. Intermediary and final results are visualised in user-friendly interfaces. A case study based on published clinical and biomarker data shows how to perform a typical ROC analysis with pROC. Conclusions pROC is a package for R and S+ specifically dedicated to ROC analysis. It proposes multiple statistical tests to compare ROC curves, and in particular partial areas under the curve, allowing proper ROC interpretation. pROC is available in two versions: in the R programming language or with a graphical user interface in the S+ statistical software. It is accessible at http://expasy.org/tools/pROC/ under the GNU General Public License. It is also distributed through the CRAN and CSAN public repositories, facilitating its installation.

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COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study

Victoria Jane Hall, Sarah Foulkes, Ayoub Saei … (2021)

Background BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK from December, 2020. We aimed to determine the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in a cohort of health-care workers undergoing regular asymptomatic testing. Methods The SIREN study is a prospective cohort study among staff (aged ≥18 years) working in publicly-funded hospitals in the UK. Participants were assigned into either the positive cohort (antibody positive or history of infection [indicated by previous positivity of antibody or PCR tests]) or the negative cohort (antibody negative with no previous positive test) at the beginning of the follow-up period. Baseline risk factors were collected at enrolment, symptom status was collected every 2 weeks, and vaccination status was collected through linkage to the National Immunisations Management System and questionnaires. Participants had fortnightly asymptomatic SARS-CoV-2 PCR testing and monthly antibody testing, and all tests (including symptomatic testing) outside SIREN were captured. Data cutoff for this analysis was Feb 5, 2021. The follow-up period was Dec 7, 2020, to Feb 5, 2021. The primary outcomes were vaccinated participants (binary ever vacinated variable; indicated by at least one vaccine dose recorded by at least one of the two vaccination data sources) for the vaccine coverage analysis and SARS-CoV-2 infection confirmed by a PCR test for the vaccine effectiveness analysis. We did a mixed-effect logistic regression analysis to identify factors associated with vaccine coverage. We used a piecewise exponential hazard mixed-effects model (shared frailty-type model) using a Poisson distribution to calculate hazard ratios to compare time-to-infection in unvaccinated and vaccinated participants and estimate the impact of the BNT162b2 vaccine on all PCR-positive infections (asymptomatic and symptomatic). This study is registered with ISRCTN, number ISRCTN11041050, and is ongoing. Findings 23 324 participants from 104 sites (all in England) met the inclusion criteria for this analysis and were enrolled. Included participants had a median age of 46·1 years (IQR 36·0–54·1) and 19 692 (84%) were female; 8203 (35%) were assigned to the positive cohort at the start of the analysis period, and 15 121 (65%) assigned to the negative cohort. Total follow-up time was 2 calendar months and 1 106 905 person-days (396 318 vaccinated and 710 587 unvaccinated). Vaccine coverage was 89% on Feb 5, 2021, 94% of whom had BNT162b2 vaccine. Significantly lower coverage was associated with previous infection, gender, age, ethnicity, job role, and Index of Multiple Deprivation score. During follow-up, there were 977 new infections in the unvaccinated cohort, an incidence density of 14 infections per 10 000 person-days; the vaccinated cohort had 71 new infections 21 days or more after their first dose (incidence density of eight infections per 10 000 person-days) and nine infections 7 days after the second dose (incidence density four infections per 10 000 person-days). In the unvaccinated cohort, 543 (56%) participants had typical COVID-19 symptoms and 140 (14%) were asymptomatic on or 14 days before their PCR positive test date, compared with 29 (36%) with typical COVID-19 symptoms and 15 (19%) asymptomatic in the vaccinated cohort. A single dose of BNT162b2 vaccine showed vaccine effectiveness of 70% (95% CI 55–85) 21 days after first dose and 85% (74–96) 7 days after two doses in the study population. Interpretation Our findings show that the BNT162b2 vaccine can prevent both symptomatic and asymptomatic infection in working-age adults. This cohort was vaccinated when the dominant variant in circulation was B1.1.7 and shows effectiveness against this variant. Funding Public Health England, UK Department of Health and Social Care, and the National Institute for Health Research.

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Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals

Charlotte Manisty, Ashley D Otter, Thomas Treibel … (2021)

Rapid vaccine-induced population immunity is a key global strategy to control COVID-19. Vaccination programmes must maximise early impact, particularly with accelerated spread of new variants. 1 Most vaccine platforms use a two-dose prime-boost approach to generate an immune response against the virus S1 spike protein, the titres of which correlate with functional virus neutralisation and increase with boosting.2, 3 To enable larger numbers of people to receive the first dose, delayed administration of the second dose has been advocated and implemented by some. 1 The impact of previous SARS-CoV-2 infection on the need for boosting is not known. We reasoned that previous infection could be analogous to immune priming. As such, a first prime vaccine dose would effectively act as boost, so a second dose might not be needed. To test this, we undertook a nested case-control analysis of 51 participants of COVIDsortium,4, 5 an ongoing longitudinal observational study of health-care workers (HCWs) in London who underwent weekly PCR and quantitative serology testing from the day of the first UK lockdown on March 23, 2020, and for 16 weeks onwards. 24 of 51 HCWs had a previous laboratory-confirmed mild or asymptomatic SARS-CoV-2 infection, as confirmed by positive detection of antibodies against the SARS-CoV-2 nucleocapsid (Elecsys Anti-SARS-CoV-2 N ECLIA, Roche Diagnostics, Burgess Hill, UK) or the receptor binding domain of the SARS-CoV-2 S1 subunit of the spike protein (anti-S; Elecsys anti-SARS-CoV-2 spike ECLIA, Roche Diagnostics), whereas 27 HCWs remained seronegative. A median of 12·5 sampling timepoints per participant permitted the identification of peak antibody titres in seropositive individuals while avoiding false negatives. All participants received their first dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech, Mainz, Germany)2, 3 and were tested 19–29 days later (median 22 days, IQR 2). Among previously uninfected, seronegative individuals, anti-S titres after one vaccine dose were comparable to peak anti-S titres in individuals with a previous natural infection who had not yet been vaccinated. Among those with a previous SARS-CoV-2 infection, vaccination increased anti-S titres more than 140-fold from peak pre-vaccine levels (figure ). This increase appears to be at least one order of magnitude greater than reported after a conventional prime-boost vaccine strategy in previously uninfected individuals. 3 Figure Serological response to one dose of the BNT162b2 mRNA COVID-19 vaccine in individuals with and without laboratory-confirmed previous SARS-CoV-2 infection SARS-CoV-2 anti-S antibody titres in individuals with no previous infection are similar to titres in individuals who have had a mild SARS-CoV-2 infection. Anti-S titres in those with previous SARS-CoV-2 infection are more than 140-fold greater than at time of peak infection. Statistical analysis was by unpaired two-tailed t test. U=unit. NS=non-significant. These serological data suggest that for individuals receiving the BNT162b2 mRNA vaccine, a potential approach is to include serology testing at or before the time of first vaccination to prioritise use of booster doses for individuals with no previous infection. This could potentially accelerate vaccine rollout. With increasing variants (UK, South Africa, Brazil), wider coverage without compromising vaccine-induced immunity could help reduce variant emergence. Furthermore, reactogenicity after unnecessary boost risks an avoidable and unwelcome increase in vaccine hesitancy. Whether enhanced vaccine-induced antibody responses among previously seropositive individuals will show differential longevity compared to boosted vaccines remains to be seen. In the meantime, our findings provide a rationale for serology-based vaccine dosing to maximise coverage and impact.

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Author and article information

Contributors

Ashley David Otter:

ORCID: https://orcid.org/0000-0002-8317-9194

Manjula Kalia: Role: Editor

Journal

Journal ID (nlm-ta): Microbiol Spectr

Journal ID (iso-abbrev): Microbiol Spectr

Journal ID (publisher-id): spectrum

Title: Microbiology Spectrum

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2165-0497

Publication date (Electronic, pub): 23 February 2022

Publication date (Electronic, collection): Jan-Feb 2022

Publication date PMC-release: 23 February 2022

Volume: 10

Issue: 1

Electronic Location Identifier: e02289-21

Affiliations

[a ] Diagnostic Support, Science Group, UK Health Security Agency, Porton, Porton Down, United Kingdom

[b ] SARS-CoV-2 Serosurveillance Laboratory, UK Health Security Agency, Porton, Porton Down, United Kingdom

[c ] Rare and Imported Pathogens Laboratory, UK Health Security Agency, Porton, Porton Down, United Kingdom

[d ] NHS Blood and Transfusion, Microbiology Services, Colindale, United Kingdom

[e ] UK Health Security Agency, Colindale, United Kingdom

[f ] Seroepidemiology Unit, UK Health Security Agency, Manchester, United Kingdom

[g ] Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

[h ] Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom

[i ] Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

[j ] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

[k ] UK Health Security Agency (UKHSA), Porton, Porton Down, United Kingdom

[l ] Pathogen Immunology, UK Health Security Agency (UKHSA), Porton, Porton Down, United Kingdom

Regional Centre for Biotechnology

Author notes

[*]

Complete list of authors listed in the Acknowledgment section.

The authors declare no conflict of interest.

Author information

Ashley David Otter https://orcid.org/0000-0002-8317-9194

Article

Publisher ID: 02289-21 Publisher ID: spectrum.02289-21

DOI: 10.1128/spectrum.02289-21

PMC ID: 8865481

PubMed ID: 35196807

SO-VID: b67f9ca9-1020-472e-9f83-872918bb5d66

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 17 November 2021

Date accepted : 2 February 2022

Page count

supplementary-material: 1, Figures: 6, Tables: 2, Equations: 0, References: 33, Pages: 13, Words: 6643

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cover-date January/February 2022

Keywords: sars-cov-2,assay development,coronavirus,immunoassays,neutralizing antibodies

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Keywords: sars-cov-2, assay development, coronavirus, immunoassays, neutralizing antibodies

Implementation and Extended Evaluation of the Euroimmun Anti-SARS-CoV-2 IgG Assay and Its Contribution to the United Kingdom’s COVID-19 Public Health Response

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Most cited references 31

pROC: an open-source package for R and S+ to analyze and compare ROC curves

COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study

Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals

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