Antigen tests are an essential part of SARS-CoV-2 testing strategies. Rapid antigen tests are easy to use but less sensitive compared to nucleic acid amplification tests (NAT) and less suitable for large-scale testing. In contrast, laboratory-based antigen tests are suitable for high-throughput immunoanalyzers. Here we evaluated the diagnostic performance of the laboratory-based Siemens Healthineers SARS-CoV-2 Antigen (CoV2Ag) assay.
In a public test center, from 447 individuals anterior nasal swab specimens as well as nasopharyngeal swab specimens were collected. The nasal swab specimens were collected in sample inactivation medium and measured using the CoV2Ag assay. The nasopharyngeal swab specimens were measured by RT-PCR. Additionally, 9,046 swab specimens obtained for screening purposes in a tertiary care hospital were analyzed and positive CoV2Ag results confirmed by NAT.
In total, 234/447 (52.3%) participants of the public test center were positive for SARS-CoV-2-RNA. Viral lineage B1.1.529 was dominant during the study. Sensitivity and specificity of the CoV2Ag assay were 88.5% (95%CI: 83.7–91.9%) and 99.5% (97.4–99.9%), respectively. Sensitivity increased to 93.7% (97.4–99.9%) and 98.7% (97.4–99.9%) for swab specimens with cycle threshold values <30 and <25, respectively. Out of 9,046 CoV2Ag screening tests from hospitalized patients, 21 (0.2%) swab specimens were determined as false-positive by confirmatory NAT.
Using sample tubes containing inactivation medium the laboratory-based high-throughput CoV2Ag assay is a very specific and highly sensitive assay for detection of SARS-CoV-2 antigen in nasal swab specimens including the B1.1.529 variant. In low prevalence settings confirmation of positive CoV2Ag results by SARS-CoV-2-RNA testing is recommended.
Fast and reliable detection of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), particularly in the context of (mass) screenings, is key to limit healthcare burden related to the COVID-19 pandemic . Although viral nucleic acid amplification tests (NAT), e.g. by quantitative reverse transcription PCR (RT-PCR), remains the gold-standard for diagnosis, considerable disadvantages such as assay duration and costs have given greater importance to alternative diagnostic tools such as immunoassays detecting viral protein. Therefore, numerous point-of-care tests (POCT) have been developed and are widely available by now . However, potential downsides such as inconsistent performance, low-throughput and difficulties to interpret results could be prevented by using fully-automated systems [1, 3, 4]. Furthermore, test results can be directly incorporated into digital patient records which strengthens transparency and traceability. There is an increasing demand for high-throughput SARS-CoV-2 antigen-assays, not only in hospital settings but also for large corporations in general. Fully automated tests could therefore help to identify infected persons and limit the spread of COVID-19 . Collection of nasopharyngeal swab specimens, the gold-standard for SARS-CoV-2 testing, is time-consuming. Thus, alternative swab sample types, such as nasal swab specimens, are needed for large-scale testing strategies .
As new variants of concern (VOC) might evolve and potentially evade antibody-mediated detection in immunoassays, it is of great importance that every assay is carefully evaluated for the ability to detect newly evolved strains [7, 8]. So far, several automated (semi-)quantitative SARS-CoV-2 antigen tests from different vendors have been evaluated ranging from chemiluminescence immunoassays (CLIA) to enzyme-linked immunosorbent assay (ELISA) and others , , . In our study we evaluated the fully-automated Siemens Healthineers SARS-CoV-2 Antigen (CoV2Ag) assay on the Atellica Solution Analyzer, a chemiluminescence based one-step-sandwich-immunoassay which utilizes five monoclonal anti-nucleocapsid antibodies for viral detection. CoV2Ag results from fresh anterior nasal swab specimens were correlated with NAT (e.g. RT-PCR) results to determine the diagnostic performance of the laboratory-based SARS-CoV-2 antigen assay. In addition, we determined the false positivity rate of the assay in more than 9,000 screening samples obtained in a large university hospital with low SARS-CoV-2 infection prevalence.
Materials and methods
The study was conducted as part of the diagnostic evaluation of a SARS-CoV-2 antigen assay as screening test for hospitalized patients at the University Hospital Tübingen. The study was composed of two parts: First, the diagnostic performance of the antigen assay was evaluated using anterior nasal swab specimens (n=447) collected at a public COVID-19 test center in Tübingen, Germany from January 26, 2022 to February 18, 2022. Second, the antigen assay was evaluated as screening test in the University Hospital Tübingen using anterior nasal swab specimens collected twice a week from hospitalized patients (n=9,046) from January 3, 2022 to March 28, 2022. The study was conducted according to the declaration of Helsinki and its later amendments and in accordance with the local Ethics Committee of the Medical Faculty of the University of Tübingen (project number: 015/2022BO2). Informed written consent was obtained from all participants before swab specimen collection for the study.
Swab specimens and sample collection
For SARS-CoV-2 antigen testing anterior nasal (AN) swab specimens were collected in Sample Inactivation Media tubes provided by the manufacturer (Siemens Healthineers, Tarrytown, USA) containing virus inactivation medium. Samples were transported within 4 h to the central laboratory of the Institute for Clinical Chemistry and Pathobiochemistry. At the public test center AN swabs for the CoV2Ag assay were taken immediately after collection of nasopharyngeal swab specimens for RT-PCR testing (DNA/RNA Shield™ collection tubes [Zymo Research, Freiburg, Germany]).
In the second part of the study (University Hospital Screening) positive antigen tests using AN swab specimens collected in Sample Inactivation Media tubes were verified by NAT testing at the Institute of Medical Virology using subsequently collected oropharyngeal swab specimens (ESwab®, Copan Diagnostics, California, USA).
SARS-CoV-2 antigen assay – CoV2Ag
The CoV2Ag assay (Siemens Healthineers, Eschborn, Germany) is a SARS-CoV-2 specific antigen assay detecting the nucleocapsid protein (NCP). It is a fully automated one-step-sandwich-immunoassay using acridinium ester chemiluminescent technology on an Atellica Solution immunoanalyzer (Siemens Healthineers). The CoV2Ag assay is approved for nasopharyngeal and anterior nasal swab specimens and is compatible with the Sample Inactivation Media. CoV2Ag results are reported as Index values and results are considered as negative (Index value<1.0) or positive (Index value≥1.0) for the detection of the SARS-CoV-2 NCP according to the manufacturer. The measuring range of the CoV2Ag assay is specified as 0.10–1,000 Index. The manufacturer claims a specificity of 100% (95%-Confidence Interval: 96.92–100%) and a sensitivity of 84.07% (95%-Confidence Interval: 76.00–90.28%) using anterior nasal swab samples collected from symptomatic individuals compared to RT-PCR testing. Using the Atellica Solution immunoanalyzer a sample volume of 100 µL is needed and the measuring time is 26 min.
SARS-CoV-2 molecular testing
Detection of SARS-CoV-2 RNA at the public test center was done by using the MagMAX™ Viral/Pathogen Nucleic Acid Isolation Kit and the TaqPath™ COVID-19 RT-PCR Kit (both Applied Biosystems, Massachusetts, USA) on a KingFisher™ Purification System and a QuantStudio 12K Flex RT-PCR system (both ThermoFisher Scientific, Massachusetts, USA). Cycle threshold (Ct) values were quantified by targeting the viral ORF1ab and n genes. SARS-CoV-2-RNA testing of hospitalized patients was done at the Institute for Medical Virology by using the Aptima® SARS-CoV-2 or the Aptima® SARS-CoV-2/Flu transcription-mediated amplification (TMA) assays on a Panther® system (Hologic) or the Xpert® Xpress SARS-CoV-2 real-time RT-PCR assay on a GeneXpert® platform (Cepheid). Due to the range of different SARS-CoV-2 NAT assays at the hospital only qualitative results were used for this study. For SARS-CoV-2 whole genome sequencing RNA of SARS-CoV-2 positive respiratory swab specimens were extracted using standard protocols (e.g. Qiagen QIAamp Viral RNA Mini Kit, Qiagen GmbH, Hilden, Germany) followed by library preparation (Illumina COVIDSeq Test, Illumina Inc., San Diego, USA) and sequencing on a Illumina machine (NextSeq500, Illumina Inc.) using NextSeq 500/550 Mid Output KT v2.5, 150 cycles chemistry (Illumina, Inc.). The SARS-CoV-2 lineage was then identified and classified using Phylogenetic Assignment of Named Global Outbreak LINeages (Pangolin) (https://cov-lineages.org/pangolin.html)  and Nextclade (https://clades.nextstrain.org/) each in the latest updated version.
To assess the analytical performance of the CoV2Ag antigen assay the within-run and between-run precision was determined using quality control samples and pooled samples of study participants. Within-run and between-run precision were calculated using antigen results of samples measured in series (n=10) or on five consecutive days according to the CLSI guideline protocol EP15-A3. The within-run precision analysis revealed variation of coefficients of 2.1% (252 ± 5.3 Index) and 9.7% (7.9 ± 0.8 Index). The between-run precision of the CoV2Ag was 2.3% (331 ± 7.5 Index) and 18.3% (7.3 ± 1.3 Index). Using the negative control sample a mean Index of 0.11 ± 0.12 and 0.11 ± 0.03 was obtained for measurements in series and between runs, respectively (results below the limit of detection were set as 0.1 Index).
Results of antigen measurements were evaluated according to the manufacturers’ cut-off indices as positive (Index≥1.0) or negative (Index<1.0). Diagnostic sensitivity and specificity were calculated as follows: all samples which are positive by RT-PCR were considered as true positives. Negative RT-PCR results were considered as true negatives. The non-parametric Spearman rank correlation coefficient was performed to correlate Index results of the CoV2Ag and Ct values. A p-value <0.05 was considered as statistically significant. ROC curve analysis and Youden’s Index were used to determine optimal thresholds for the CoV2Ag antigen assay. All analyses were performed using Analyse-it Software and JMP 14 (SAS Institute, Cary, United States). Figures were created using Analyse-it, JMP 14 and Microsoft Office PowerPoint (Microsoft, Washington, USA).
Diagnostic performance of the CoV2Ag antigen assay
In the first part of the study anterior nasal (AN) swab specimens from 447 participants were included in the analysis. Participants were tested at a public test center for the following reasons: 220 participants (49%) had a previously positive rapid antigen test, 117 (26%) reported close contact to a COVID-19 infected person and 112 (25%) needed a certificate for traveling or for other reasons. Among all participants, 21 (5%) were symptomatic with suspicion for COVID-19 (mean duration of symptoms: 1.5 days). 426 (95%) participants were asymptomatic. A variant of concern (VOC) analysis was performed for 12 swab specimens collected during the first part of the study and all of them were positive for the Omicron variant.
The results of the diagnostic performance evaluation of the CoV2Ag antigen assay are shown in Table 1. A total of 207 AN swab specimens were considered positive using the CoV2Ag assay and had a median Index of 569 (interquartile range: 26.4–1,000; see Figure 1 and Table 2). Comparing antigen results with RT-PCR, the CoV2Ag revealed a specificity of 99.5% (97.4–99.9%). One sample was detected as false-positive by the CoV2Ag assay (Index of 8.6). This participant reported to be asymptomatic and was tested due to a close contact to a SARS-CoV-2 infected person. The overall sensitivity of the CoV2Ag assay was 88.5% (83.7–91.9%). Among the participants with COVID-19 suspicious symptoms, 15 of 21 participants were confirmed SARS-CoV-2 RNA positive. 13 out of these samples were considered positive using the CoV2Ag assay. Considering the viral load (Ct values) determined by RT-PCR, the sensitivity of the CoV2Ag increased for swab specimens with lower Ct values, i.e. corresponding to a high viral concentration in the sample (see Table 2). Regarding samples with Ct values <30 as true positive, the sensitivity of the CoV2Ag assay increased to 94.4% (90.4–96.7%; see Table 3). For RT-PCR positive swab specimens with Ct values <20, the CoV2Ag showed 100% (96.7–100%) sensitivity. Comparing Index results of the CoV2Ag assay and Ct values, an acceptable correlation was found (rS=0.75; p<0.0001). Similarly, Cohen’s Kappa showed good agreement between the CoV2Ag antigen assay and RT-PCR (0.875; 95% CI: 0.831–0.920).
|SARS-CoV-2 RT-PCR result|
|CoV2Ag antigen result||Positive||Negative|
A total of 447 anterior nasal swab specimens from a public test center were compared to RT-PCR results of nasopharyngeal swab specimens. Shown are the numbers of positive and negative results for each test and the results of the sensitivity/specificity analysis and the agreement analysis. Sensitivity: 88.5% (83.7–91.9%). Specificity: 99.5% (97.4–99.9%). Cohen’s kappa: 0.875 (0.831–0.920).
|RT-PCR (+) Ct<20||RT-PCR (+) Ct 20–25||RT-PCR (+) Ct 25–30||RT-PCR (+) Ct >30||RT-PCR (+) all samples|
|Number of swab specimens||111||66||36||21||234|
|Median ± IQR (Index)||1,000 (783–1,000)||240 (28.5–1,000)||14.8 (1.0–87.7)||0.1 (0.1–5.9)||569 (26.4–1,000)|
Shown is the distribution of CoV2Ag Indices (median ± interquartile range (IQR)) in RT-PCR positive participants stratified by the cycle threshold (Ct) value.
|RT-PCR Ct value||RT-PCR positive results||CoV2Ag antigen positive results||Sensitivity (95%-CI)|
Sensitivity and 95%-Confidence Interval (CI) was determined in different subgroups stratified by RT-PCR based cycle threshold (Ct) values.
To determine an optimal threshold for the CoV2Ag antigen assay ROC curve analysis was performed and revealed an area under the curve (AUC) of 0.951 (0.932–0.970; see Figure 2). Based on the analyzed data Youden’s Index determined an optimal threshold of 0.18 Index. Using this threshold, the sensitivity increased to 90.2% and the specificity decreased to 98.6%.
Performance of the CoV2Ag assay as screening test in a university hospital
In the second part of the study, the intended use of the CoV2Ag assay as screening test for hospitalized patients was evaluated. A total of 9046 AN swab specimens were collected during the study period and included in the analysis (see Figure 3). 92 swab specimens (1.0%) were considered positive using the CoV2Ag assay. 71 of these swab specimens (0.8%) were confirmed as true positive by SARS-CoV-2 RNA detection, while 21 swab specimens (0.2%) could not be confirmed, and thus were considered as false-positive antigen results. The false-positive antigen results ranged between an Index of 1.0 and 2.9. VOC analysis was available for 46 true positive samples (64%) and revealed B1.1.529 variant (Omicron) in all samples. Among them, 24 samples (52%) were positive for the Omicron sublineage BA.1 and 22 samples (48%) for the sublineage BA.2.
In the present study, the diagnostic performance of the CoV2Ag, a laboratory-based SARS-CoV-2 antigen assay from Siemens Healthineers, was evaluated using anterior nasal (AN) swab specimens. To our knowledge, this is the first evaluation of the CoV2Ag assay.
AN swab specimens were collected in commercially available, prefilled tubes containing virus inactivation medium to ensure the inactivation of SARS-CoV-2 virus particles prior to sample handling. No additional manual steps, such as adding of lysis reagent, are necessary. This is important, since the safe handling of swab specimen material is a prerequisite for the broad implementation of laboratory-based SARS-CoV-2 antigen testing. The rapid inactivation process (incubation time according to the manufacturer: 10 min) is within the normal transportation time in a hospital workflow process, thereby enabling the safe handling of a large number of COVD-19 suspected samples within a short period of time. Consequently, prefilled inactivation tubes improve and facilitate sample processing and contributes to the broad implementation of high-throughput SARS-CoV-2 antigen assays in clinical laboratories and other locations.
In this study, AN swab specimens were used for antigen testing and compared to nasopharyngeal (NP) swab specimens for RT-PCR testing. Since collection of NP swab specimens is uncomfortable and time-consuming, alternative swab specimens are needed, especially for large-scale testing . Several studies demonstrated good agreements between AN and NP collected swab specimens [13, 14]. Nevertheless, NP swab specimens are still regarded as gold-standard for SARS-CoV-2 testing . However, AN swab specimen collection has several advantages compared to NP swab collection : it is easy to use, less invasive and therefore more tolerated by patients compared to NP swab collection. This is especially important for mass screenings and testing strategies where people such as healthcare workers are repeatedly tested and therefore preferring less invasive methods.
The diagnostic evaluation of the CoV2Ag antigen assay in the first part of the study revealed a very good overall specificity (99.5%) and sensitivity (88.5%) in detecting SARS-CoV-2 viral protein. Only one swab specimen was considered false positive by the CoV2Ag. Regarding the sensitivity of the CoV2Ag assay in specimens with high viral load (Ct value <30) the sensitivity was very good (>94%) and further increased for specimens with Ct value <25 (sensitivity >98%). ROC curve analysis and Youden’s Index only marginally improved sensitivity of the CoV2Ag assay but reduced specificity thereby increasing the number of false-positive results.
In total, results of the diagnostic performance evaluation are in accordance with the manufacturer’s claims and demonstrate that the CoV2Ag assay exhibits a comparable performance as RT-PCR testing in specimens with high viral load. Due to the advantages of antigen testing, such as shorter turnaround times, improved cost-effectiveness and its suitability for mass testing, laboratory-based antigen assays are true alternatives to NAT testing in identifying persons with high viral load. Since the majority of the participants were asymptomatic, the present results indicate that the CoV2Ag assay is a valuable tool to detect viral protein in asymptomatic persons. Moreover, screening studies showed that repeated antigen testing, for example twice a week, can reduce the incidence of new SARS-CoV-2 infections . In symptomatic participants the sensitivity of the CoV2Ag assay was slightly reduced in the present study. However, only a small number of symptomatic participants was included and the mean duration of symptoms was very short. Therefore, a reliable analysis concerning symptomatic SARS-CoV-2 virus carriers cannot be conducted.
In the second part of the study, which investigated the role of the CoV2Ag as SARS-CoV-2 screening test for hospitalized patients, the high specificity of the CoV2Ag was confirmed. Measuring >9,000 swab specimens from hospitalized patients, 21 out of 92 CoV2Ag positive cases could not be confirmed by SARS-CoV-2 RNA detection, i.e. only 0.2% of all screening swab specimens were considered as false-positive by the CoV2Ag. Given the expectedly much lower prevalence of SARS-CoV-2 infections in the screening population in the university hospital compared to the participant group from the public test center, this false positive rate seems quite acceptable. Nevertheless, confirmation of positive CoV2Ag results by molecular testing is highly recommended in such a low prevalence setting. Sensitivity could not be assessed in the second part of the study because SARS-CoV-2 NAT was not done in parallel for all screened individuals at the hospital.
The high-throughput laboratory-based antigen CoV2Ag assay can be run on widely available immunoanalyzer platforms. Such assays address the need for large-scale antigen testing and overcome the disadvantages of rapid antigen tests (e.g. lateral flow immunoassays), such as low-throughput, inconsistent performance and reduced sensitivities [1, 5]. Furthermore, antigen results generated by automated platforms can be directly transmitted to medical records thereby significantly reducing the workload. A main area of application for laboratory-based antigen testing is in the hospital setting, where central laboratories can accomplish high-throughput testing using broadly available and existing laboratory automation and fully automated analyzers in combination with short transportation times. Moreover, at public gatherings, such as airports, schools or sport events, high-throughput testing can be of great interest and may optimize testing strategies and work-flow processes. However, only few laboratory-based COVID-19 antigen tests are currently available on the market and have been evaluated in detail. In a pooled analysis the Roche Elecsys SARS-CoV-2 antigen assay showed a high pooled diagnostic specificity (99%) and acceptable sensitivity (68%) in detecting SARS-CoV-2 viral protein . Another pooled analysis regarded the ultrasensitive S-Plex SARS-CoV-2 electrochemiluminescence antigen assay and revealed a pooled specificity and sensitivity of 92 and 87%, respectively . Two other studies investigated the laboratory-based antigen assay from DiaSorin and demonstrated an excellent overall specificity (both 100%) but low sensitivity (65.7 and 40.2%) compared to RT-PCR results [18, 19]. Considering samples with high viral load using the DiaSorin antigen assay, sensitivity substantially increased (>90%). Of note, these evaluation studies mainly investigated nasopharyngeal swab specimens and thus the comparability with the present study is limited.
During the first part of the study the SARS-CoV-2 variant of concern (VOC) B1.1.529 (Omicron) was dominant in Germany and particular in Baden-Wuerttemberg (>90%; see Table 4). Representative data from the Robert Koch Institute revealed that Omicron sublineage BA.1 was the dominant sublineage during the first part of the study (week 04/2022: BA.1 87.2%, BA.2 10.6%; see Table 4). The proportion of sublineage BA.2 increased during the following weeks (week 07/2022: BA.1 61.9%, BA.2 37.5%). In the first part of the study, VOC analysis was performed in only a small number of swab specimens (n=12), but all analyzed samples resembled the Omicron variant. However, data on sublineages of samples collected in the first part of the study are not available and therefore the evaluation of the CoV2Ag assay concerning differences in detection of sublineages BA.1 and BA.2 is limited. In the majority of SARS-CoV-2 positive samples obtained during the hospital screening study the proportion of Omicron sublineages BA.1 (52%) and BA.2 (48%) were similar. For the intended use of the CoV2Ag assay, the identification of subjects with a high viral load, the detection of BA.1 and BA.2 at high viral load levels may be sufficient, even the antigen binding is not perfect. Since additional mutations may appear in the nucleocapsid protein in novel variants which potentially contribute to an evasion in immunoassays, future studies are needed to comprehensively address the diagnostic performance of the CoV2Ag assay in detecting new sublineages and virus variants .
|Omicron (B.1.1.529 + sublineages of B.1.1.529)
|Omicron (BA.2) Germany||Omicron (B.1.1.529 + sublineages of B.1.1.529)
Further limitations of the study include the small number of symptomatic participants in the first part of the study and the lack of follow-up swab specimens of SARS-CoV-2 positive participants or of antigen negative and symptomatic participants. Therefore, precise data evaluating the sensitivity of the CoV2Ag assay in context of time of symptoms onset is limited and needs to be evaluated in further studies.
In conclusion, the laboratory-based CoV2Ag assay is a very specific and highly sensitive immunoassay for the detection of SARS-CoV-2 viral protein in AN swab specimens. In low-prevalence settings confirmation of positive results by SARS-CoV-2 RNA testing is recommended to recognize occasionally occurring false-positive antigen test results. Using sample inactivation medium tubes for swab specimen collection will facilitate and optimize the workflow process in laboratories. Therefore, CoV2Ag is a valuable tool for large scale and long-term COVID-19 testing and may improve screening strategies for healthcare facilities and public gatherings.
We thank all participants of the study and we are grateful to the contribution of A. Guirguis, A. K. Horlacher, K. Schweitzer, M. Weisser, R. Werner and the staff of the COVID-19 test center for the excellent support.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed written consent was obtained from all participants before swab specimen collection for the study.
Ethical approval: This study complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by the local ethics committee (project number: 015/2022BO2).
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