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. 2024 Dec 19;12(12):e70114. doi: 10.1002/iid3.70114

Diagnostic Efficacy of 11 SARS‐CoV‐2 Serological Assays for COVID‐19: A Meta‐Analysis and Adjusted Indirect Comparison of Diagnostic Test Accuracy

Ying Zhao 1, Minjie Zhang 1, Weiwei Liang 2,✉, Lijiang Fang 3
PMCID: PMC11656407  PMID: 39698931

ABSTRACT

Objective

In the past 5 years, a large number of serological assays for large‐scale detection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) antigen emerged. Serological assays for SARS‐CoV‐2 were needed to support clinical diagnosis and epidemiological investigations. However, there were limited data on the diagnostic accuracy of these serological assays. We aimed to compare the diagnostic accuracy of 11 commercial serological assays for coronavirus disease‐2019 (COVID‐19) by taking the reverse transcriptase polymerase chain reaction (RT‐PCR) assays as the reference standard, which served as the control arm to conduct an indirect comparison of diagnostic accuracy for 11 different SARS‐CoV‐2 serological assays.

Methods

This meta‐analysis was conducted following the PRISMA 2020 reporting guideline. Electronic searches were performed using the Cochrane Library, PubMed, Embase, Web of Science, Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), WANFANG, and Chinese Weipu (VIP) databases. Fifty‐seven articles, including 11 serologic‐based IgG, IgM, and total antibodies assays for SARS‐CoV‐2, published before June 2024, were included in this meta‐analysis. The main outcome of this meta‐analysis used to evaluate the performance of 11 assays included pooled diagnostic odds ratio (DOR), area under the summary receiver operating characteristic (AUC), and summary receiver operating characteristic curve (SROC). The R software was used for adjusted indirect comparison to calculate the relative diagnostic odds ratio (RDOR) with corresponding 95% confidence intervals (CIs), and indirect comparison forest plots showed the results.

Results

A total of 57 articles met the eligibility criteria for inclusion in our meta‐analysis. The pooled DOR and the AUC for access SARS‐CoV‐2 IgG were 564.28 (95% CI 229.58−1386.91) and 1.00, and as for EDI novel coronavirus COVID‐19 IgG those were 85.27 (95% CI 53.99−134.68) and 0.95, for EDI novel coronavirus COVID‐19 IgM were 49.42 (95% CI 16.47−148.30) and 0.86, for iFlash‐SARS‐CoV‐2 IgG were 652.31 (95% CI 362.32−1174.41) and 0.97, for iFlash‐SARS‐CoV‐2 IgM were 36.72 (95% CI 12.42−108.54) and 0.76, for MAGLUMI 2019‐nCoV IgG were 145.44 (95% CI 59.37−356.30) and 0.90, for MAGLUMI 2019‐nCoV IgM were 21.59 (95% CI 14.27−32.67) and 0.59, for ortho‐clinical anti‐SARS‐CoV‐2 IgG were 719.46 (95% CI 262.34−1973.13) and 1.00, for ortho‐clinical anti‐SARS‐CoV‐2 total were 1104.60 (95% CI 395.64−3083.99) and 1.00, for Siemens SARS‐CoV‐2 total (COV2T) were 1143.37 (95% CI 316.49−4130.62) and 0.99, for Wantai SARS‐CoV‐2 total Ab were 1014.98 (95% CI 618.48−1665.66) and 1.00. The pooled DOR for assays‐based IgG (n = 43), assays‐based total antibody (n = 35), and assays‐based IgM (n = 20) was 242.88 (95% CI 157.66−374.16), 1215.90 (95% CI 547.14−2702.07), and 40.99 (95% CI 22.63−74.25). The diagnostic accuracy of assays‐based total antibody performed better than those of assays‐based IgG and assays‐based IgM; assays‐based IgG performed better than assays‐based IgM.

Conclusion

This study suggested that the Siemens SARS‐CoV‐2 total (COV2T), ortho‐clinical anti‐SARS‐CoV‐2 total, and Wantai SARS‐CoV‐2 total had the best overall diagnostic accuracy. The diagnostic efficacy of the assays‐based total antibody had statistically significantly higher accuracy than those of assays‐based IgG and assays‐based IgM for COVID‐19.

Keywords: adjusted indirect comparison, COVID‐19, meta‐analysis, SARS‐CoV2, serological assays

We aimed to compare the diagnostic accuracy of 11 commercial serological assays for coronavirus disease‐2019 (COVID‐19) by taking the reverse transcriptase polymerase chain reaction (RT‐PCR) assays as reference standard, which served as control arm to conduct an indirect comparison of diagnostic accuracy for 11 different SARS‐CoV‐2 serological assays.

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1. Introduction

Severe acute respiratory coronavirus 2 (SARS‐CoV‐2), a novel coronavirus that caused coronavirus disease 2019 (COVID‐19), has become a pandemic threat in which serological testing from diagnosis to epidemiologic surveillance has been indispensable in the past 5 years. The molecular testing with real‐time reverse transcription polymerase chain reaction (RT‐PCR) for the detection of SARS‐CoV‐2 was the reference standard for COVID‐19 diagnosis. Besides SARS‐CoV‐2 RT‐PCR testing, serological testing comprising the detection of IgM, IgA, or IgG antibodies to SARS‐CoV‐2‐specific epitopes has the potential to play an important role in the confirmation in individual patients with suspected COVID‐19 symptoms, or for the past SARS‐CoV‐2 infections [1]. Immune response to SARS‐CoV‐2 included cell‐mediated and antibody‐mediated immunity [2]. The spike (S) glycoproteins with their receptor‐binding domain (RBD) and the nucleocapsid (N) protein were widely used as the most common antigens in commercial serological assays for the detection of specific antibodies [3, 4]. In specific contexts, serological testing might be instrumental for acute diagnostic purposes, particularly when the RT‐PCR fails to identify SARS‐CoV‐2, for example, in patients who are greater than 14 days from their onset of symptoms [5]. Freund et al. reported that serological markers as part of medical follow‐up of symptomatic COVID‐19 patients can be used for prognostication; the study found anti‐S levels were significantly associated with previous severe COVID‐19 [6]. In addition, serological testing has been reported to be significant and important for personalized vaccination plans. Vaccines are designed to induce antibodies to the S antigen or RBD [7]; vaccine‐induced antibodies may arise in response to the S antigen and are, therefore, potentially detectable by any assay using the S antigen or RBD. Freund et al. also reported that the trajectory of anti‐S IgG levels after vaccination was found to predict the response to future COVID vaccinations, and the determination of the characteristics of the humoral response to COVID‐19 vaccinations is significant in predicting the humoral response to the booster vaccines [8]. Serological testing also has potential utility for tracking the course of the SARS‐CoV‐2 pandemic in the community. Screening of individuals who may be a source for prophylactic or therapeutic neutralizing antibodies is another application of serological testing [9]. Multiple manufacturers offered various high‐throughput serological assays differing not only in their antibody isotypes (i.e., IgA, IgM, IgG, or total antibody) but also targeted SARS‐CoV‐2 antigens (i.e., the S1 subunit of the spike protein, N protein, or RBD). Due to urgency and demand in the initial days of the COVID‐19 pandemic, numerous serological assays were rapidly developed and have been validated on a limited number of samples. The diagnostic efficacy of serological assays varies greatly; few studies were conducted to compare the performance of these assays on a large scale. This study aimed to evaluate the analytic performance and diagnostic characteristics of 11 commercial serological assays for the detection of SARS‐CoV‐2 specific IgG, IgM, and total antibodies. The 11‐assays comparison included the access SARS‐CoV‐2 IgG assay from Beckman Coulter (USA), EDI novel coronavirus COVID‐19 IgG and EDI novel coronavirus COVID‐19 IgM assays from Epitope Diagnostics (San Diego, CA, USA), iFlash‐SARS‐CoV‐2 IgG and iFlash‐SARS‐CoV‐2 IgM from Shenzhen YHLO Biotech (Shenzhen, China), MAGLUMI 2019‐nCoV IgG and MAGLUMI 2019‐nCoV IgM assays from Snibe Diagnostic (Shenzhen, China), ortho‐clinical anti‐SARS‐CoV‐2 IgG and ortho‐clinical anti‐SARS‐CoV‐2 total assays from Ortho Clinical Diagnostics (France), Siemens SARS‐CoV‐2 total (COV2T) assay from Siemens (Munich, Germany), and Wantai SARS‐CoV‐2 total Ab assay from Wantai Biological Pharmacy Enterprise (Beijing, China). Meanwhile we assessed the diagnostic accuracy of antibody isotypes by meta‐analysis and indirect comparison.

2. Materials and Methods

2.1. Search Strategy

Studies were identified by searching the Cochrane Library, PubMed, Embase, Web of Science, Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), WANFANG, and Chinese Weipu (VIP) databases. The search terms used were (“2019‐nCoV” OR “coronavirus disease 2019 virus” OR “2019 novel coronavirus” OR “COVID‐19” OR “COVID‐19 diagnostic testing” OR “COVID‐19 serological test” OR “SARS‐CoV‐2” OR “severe acute respiratory syndrome coronavirus 2” OR “Anti‐SARS‐CoV‐2”) AND (“Access SARS‐CoV‐2 IgG” OR “EDI Novel Coronavirus COVID‐19” OR “iFlash‐SARS‐CoV‐2” OR “MAGLUMI 2019‐nCoV” OR “Ortho‐Clinical anti‐SARS‐CoV‐2” OR “Siemens SARS‐CoV‐2” OR “Siemens SARS‐CoV‐2 Total (COV2T)” OR “Wantai SARS‐CoV‐2”). The searches were limited to articles published in Chinese or English.

2.2. Inclusion and Exclusion Criteria

We included studies that evaluated the performance of the above‐mentioned 11 anti‐SARS‐CoV‐2 antibody serological assays. The 11‐assay comparison for inclusion in the data analysis met the following inclusion criteria: (1) Studies which included the COVID‐19 patients' serum samples and negative control serum samples reporting both sensitivity and specificity of serological assays for COVID‐19; (2) the diagnosis of SARS‐CoV‐2 (COVID‐19) by taking RT‐PCR as the reference standard meanwhile based on clinical symptoms and imaging diagnosis; (3) stored pre‐COVID‐19 blood samples collected from the healthy blood donors and the individuals with a history of PCR‐confirmed non‐COVID‐19 infection within the previous 6 months were used as negative control; (4) the number of true positive (TP), true negative (TN), false positive (FP), and false negative (FN) were then abstracted, or data that could transform into above information were reported.

The exclusion criteria: (1) The studies evaluated the performance of in‐house developed antibody assay for the diagnosis of COVID‐19 instead of any commercial serological assay; (2) the studies evaluated the serological assays for the detection of antibodies generated by vaccines against SARS‐CoV‐2; (3) the studies whose COVID‐19 patients were diagnosed without at least one positive RT‐PCR test carried out; (4) studies in which serological assays were evaluated without providing enough information for the immunoglobulin classes (IgG, IgA, IgM, or total antibody), the targeting antigen, manufacturer/platform or the method; (5) studies with negative control sample sizes or patients serums samples less than 30.

2.3. Data Extraction and Quality Assessment

Articles were independently assessed for inclusion by the two authors of this paper (Ying Zhao and Minjie Zhang), and data from included studies were extracted using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool for the domains of patient selection, performance of the index test, performance of the reference test, and flow and timing (for risk of bias only). The extracted data included the name of the first author of the article, publication year, manufacturer, method, assay, immunoglobulin isotypes (IgM, IgG, or total antibody), type of antigen (S, N, or RBD), COVID‐19 patients sample size, and the negative control sample size. The TP, FP, TN, and FN results of each arm were reported separately.

2.4. Statistical Analysis

The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the summary receiver operating characteristic curves (SROC) with corresponding 95% (confidence intervals, CI) were measured. The SROC curve (based on 2 × 2 contingency tables) was established to show the sensitivity and specificity for each individual arm, and the area under the curve (AUC) was used to determine diagnostic accuracy. Review Manager 5.3 (Cochrane Collaboration) analysis software was used to build the area under the SROC curve (AUC) graphics by making use of different colors for different serological assays. The relative diagnostic odds ratio (RDOR) of indirect comparison was used to compare the diagnostic accuracy of different assays and different immunoglobulin isotypes. The RDOR outcomes were summarized and exhibited in paired forest plots by R software (Parametric Technology Corporation). When the 95% CI of the RDOR contains 1, it indicates that the difference between the two comparison objects was not statistically significant; alternatively, when its 95% CI exceeds 1, suggesting that the difference between the two comparison objects was statistically significant. The Deek's test was used to evaluate whether there was publication bias.

3. Results

3.1. Study Characteristics

A PRISMA flow chart in Figure 1 was used. A total of 1781 pieces of literature were identified after the removal of duplicate articles. One hundred after full‐text review were assessed for eligibility. Fifty‐seven articles were included finally in the systematic review [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66]. The detailed characteristics of the articles included in this study are shown in Table 1.

Figure 1.

Figure 1

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Flow diagram of selecting the literature and screening process.

Table 1.

Characteristics of the included studies.

Author Year Method Manufacturer/platform Assay Antigen Antibody type COVID‐19 patient samples (n) Controls (n)
A Bown [10] 2020 CLIA Siemens Atellica Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 536 976
Al‐Jighefee HT [11] 2021 ELISA NA EDI novel coronavirus COVID‐19 IgG N IgG 291 119
ELISA NA EDI novel coronavirus COVID‐19 IgM N IgM 291 119
Andrey DO [12] 2021 ELISA DYNEX DSX EDI novel coronavirus COVID‐19 IgG N IgG 172 185
Bundschuh C [13] 2020 ELISA Serion Diagnostics EDI novel coronavirus COVID‐19 IgG N IgG 104 456
ELISA Serion Diagnostics EDI novel coronavirus COVID‐19 IgM N IgM 104 456
Chiereghin A [14] 2020 CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgG N and S IgG 207 130
CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgM N and S IgM 207 130
Chua KYL [15] 2020 CLIA Vitros 5600 Ortho‐clinical anti‐SARS‐CoV‐2 IgG S1 IgG 86 95
CLIA Beckman Unicel DxI 800 Access SARS‐CoV‐2 IgG S1‐RBD IgG 86 95
Davidson N [16] 2020 ELISA NA EDI novel coronavirus COVID‐19 IgG N IgG 71 138
ELISA NA EDI novel coronavirus COVID‐19 IgM N IgM 71 138
Deng Jielun [17] 2021 CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgG N and S IgG 69 73
CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgM N and S IgM 69 73
Egger M [18] 2020 ELISA NA EDI novel coronavirus COVID‐19 IgG N IgG 104 200
ELISA NA EDI novel coronavirus COVID‐19 IgM N IgM 104 200
Florin L [19] 2021 CLIA Siemens Atellica IM1300 Siemens SARS‐CoV‐2 total (COV2T) S1‐RBD Total Ab 175 90
Garnett E [20] 2020 CLIA Vitros 5600 Ortho‐clinical anti‐SARS‐CoV‐2 total S Total antibody 79 57
Gdoura M [21] 2022 CLIA Beckman Coulter Access SARS‐CoV‐2 IgG S1‐RBD IgG 72 119
Han Xiaoyan [22] 2023 CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgG N and S IgG 123 41
CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgM N and S IgM 123 41
Harritshøj LH [23] 2021 CLIA Siemens Atellica IM Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 148 596
CLIA Siemens Dimension Vista 500 Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 147 596
CLIA Maglumi 4000+ MAGLUMI 2019‐nCoV IgG Unspecified IgG 148 1173
CLIA Maglumi 800 MAGLUMI 2019‐nCoV IgM Unspecified IgM 150 1184
CLIA Vitros 3600 Ortho‐clinical anti‐SARS‐CoV‐2 IgG S1 IgG 150 600
CLIA Vitros 3600 Ortho‐clinical anti‐SARS‐CoV‐2 total S1 Total antibody 150 605
ELISA Tecan Sunrise Wantai SARS‐CoV‐2 total Ab S Total antibody 150 659
CLIA iFlash 1800 iFlash‐SARS‐CoV‐2 IgG N and S IgG 150 586
CLIA iFlash 1800 iFlash‐SARS‐CoV‐2 IgM N and S IgM 150 585
Heffernan E [24] 2021 ELISA Dynex DS2 Wantai SARS‐CoV‐2 total Ab S Total antibody 137 100
Herroelen PH [25] 2020 ELISA Bio‐Rad Version EIA 0_16 Wantai SARS‐CoV‐2 total Ab S1‐RBD Total antibody 169 57
Hörber S [26]a 2020 CLIA Siemens ADVIA Centaur XPT Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 186 123
Horn MP [27] 2022 ELISA DYNEX DSX EDI novel coronavirus COVID‐19 IgG N IgG 192 3462
Igawa G [28] 2021 CLIA Siemens Dimension EXL 200 Siemens SARS‐CoV‐2 total (COV2T) S1‐RBD Total Ab 236 98
Ikegami S [29] 2021 CLIA Beckman Coulter Access SARS‐CoV‐2 IgG S1‐RBD IgG 97 100
Irsara C [30] 2021 CLIA Siemens ADVIA Centaur XPT Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 195 288
Kubota K [31] 2021 CLIA Vitros 3600 Ortho‐clinical anti‐SARS‐CoV‐2 IgG S IgG 66 148
CLIA Vitros 3600 Ortho‐clinical anti‐SARS‐CoV‐2 total S1 Total antibody 66 148
Kundu D [32] 2022 CLIA Siemens ADVIA Centaur XPT Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 153 150
Lapić I [33] 2020 CLIA Maglumi 800 MAGLUMI 2019‐nCoV IgG N and S IgG 42 48
Lester SN [34] 2024 CLIA Vitros ECi/ECiQ/3600 and Vitros 5600/XT 7600 Ortho‐clinical anti‐SARS‐CoV‐2 total S1 Total antibody 87 117
Li Ping [35] 2020 CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgG N and S IgG 116 134
CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgM N and S IgM 116 134
Mafi S [36] 2023 ELISA NA Wantai SARS‐CoV‐2 total Ab S1 Total antibody 110 120
Mairesse A [37] 2020 CLIA iFlash 1800 iFlash‐SARS‐CoV‐2 IgG N and S IgG 178 75
CLIA iFlash 1800 iFlash‐SARS‐CoV‐2 IgM N and S IgM 178 75
Manthei DM [38] 2021 CLIA Siemens Centaur XP Siemens SARS‐CoV‐2 total (COV2T) S1‐RBD Total Ab 131 188
Marlet J [39] 2020 ELISA NA Wantai SARS‐CoV‐2 total Ab S Total Ab 58 89
Montesinos I [40] 2020 CLIA Maglumi 800 MAGLUMI 2019‐nCoV IgG Unspecified IgG 126 72
CLIA Maglumi 800 MAGLUMI 2019‐nCoV IgM Unspecified IgM 126 72
Naaber P [41] 2020 CLIA Maglumi 1000 MAGLUMI 2019‐nCoV IgG Unspecified IgG 97 100
ELISA Dynex Agility EDI novel coronavirus COVID‐19 IgG N IgG 97 100
Nedelcu I [42] 2021 ELISA Dynex DSX EDI novel coronavirus COVID‐19 IgG N IgG 528 161
ELISA Dynex DSX EDI novel coronavirus COVID‐19 IgM N IgM 528 161
Nicholson S [43] 2021 ELISA NA Wantai SARS‐CoV‐2 total Ab S1 Total antibody 96 209
Nyagwange J [44] 2022 ELISA NA Wantai SARS‐CoV‐2 total Ab S1 Total antibody 149 327
Oved K [45] 2020 CLIA Beckman Coulter Access SARS‐CoV‐2 IgG S1‐RBD IgG 162 318
2020 CLIA Siemens ADVIA Centaur XPT Siemens SARS‐CoV‐2 total (COV2T) S1‐RBD Total Ab 156 432
Padoan A [46] 2020 CLIA Vitros ECi/ECiQ/3600 and Vitros 5600/XT 7600 Ortho‐clinical anti‐SARS‐CoV‐2 IgG S IgG 130 54
CLIA Vitros ECi/ECiQ/3600 and Vitros 5600/XT 7600 Ortho‐clinical anti‐SARS‐CoV‐2 total S1 Total antibody 130 54
Parai D [47] 2021 CLIA iFlash 1800 iFlash‐SARS‐CoV‐2 IgG N and S IgG 594 100
Pérez‐García F [48] 2021 CLIA Siemens Atellica Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 50 60
Pflüger LS [49] 2020 CLIA Siemens Atellica Siemens SARS‐CoV‐2 total (COV2T) S1 Total Ab 75 320
ELISA Euroimmun Analyzer I‐2 P Wantai SARS‐CoV‐2 total Ab S1 Total Ab 75 320
Piec I [50] 2021 ELISA Dynex Agility EDI novel coronavirus COVID‐19 IgG N IgG 43 152
Riester E [51] 2021 CLIA iFlash 1800 iFlash‐SARS‐CoV‐2 IgG N and S IgG 104 928
CLIA iFlash 1800 iFlash‐SARS‐CoV‐2 IgM N and S IgM 104 928
Rikhtegaran Tehrani Z [52] 2020 ELISA NA EDI novel coronavirus COVID‐19 IgG N IgG 97 288
ELISA NA EDI novel coronavirus COVID‐19 IgM N IgM 95 299
Sekirov I [53] 2021 CLIA Vitros XT 7600 Ortho‐clinical anti‐SARS‐CoV‐2 IgG S IgG 42 65
CLIA Vitros XT 7600 Ortho‐clinical anti‐SARS‐CoV‐2 total S1 Total antibody 42 65
CLIA Siemens ADVIA Centaur XPT Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 42 65
Şener B [54] 2022 CMIA Beckman Coulter Access SARS‐CoV‐2 IgG S1‐RBD IgG 125 50
CMIA Siemens Atellica Siemens SARS‐CoV‐2 total (COV2T) S1‐RBD Total Ab 131 50
Serre‐Miranda C [55] 2021 CLIA NA MAGLUMI 2019‐nCoV IgG N and S IgG 117 35
CLIA NA MAGLUMI 2019‐nCoV IgM N and S IgM 117 35
Soleimani R [56] 2021 CLIA Maglumi 800 MAGLUMI 2019‐nCoV IgG N and S IgG 176 100
2021 CLIA Maglumi 800 MAGLUMI 2019‐nCoV IgM N and S IgM 176 100
Syre H [57] 2022 ELISA DYNEX DS2 system Wantai SARS‐CoV‐2 total Ab S Total antibody 211 320
Tan SS [58] 2020 CLIA Beckman Unicel DxI 800 Access SARS‐CoV‐2 IgG S1‐RBD IgG 173 163
CLIA Siemens ADVIA Centaur XPT Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 173 163
CLIA Vitros 3600 Ortho‐clinical anti‐SARS‐CoV‐2 total S1 Total antibody 173 163
Theel ES [59] 2020 ELISA Dynex Agility EDI novel coronavirus COVID‐19 IgG N IgG 61 149
CLIA Vitros 3600 Ortho‐clinical anti‐SARS‐CoV‐2 IgG S IgG 61 149
Tolan NV [60] 2023 ELISA NA EDI novel coronavirus COVID‐19 IgG N IgG 105 55
ELISA NA EDI novel coronavirus COVID‐19 IgM N IgM 103 57
Van Elslande J [61] 2020 CLIA Maglumi 800 MAGLUMI 2019‐nCoV IgG Unspecified IgG 223 113
Velay A [62] 2020 ELISA NA EDI novel coronavirus COVID‐19 IgG N IgG 198 100
ELISA NA EDI novel coronavirus COVID‐19 IgM N IgM 198 100
Ward MD [63] 2021 CLIA Siemens Atellica Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 112 2030
CLIA Siemens EXL Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 112 2030
Wu Lianpeng [64] 2021 CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgG N and S IgG 179 50
CLIA iFlash 3000 iFlash‐SARS‐CoV‐2 IgM N and S IgM 179 50
Yassine HM [65] 2021 ELISA Epoch 2 EDI novel coronavirus COVID‐19 IgG N IgG 101 70
Zilla M [66] 2021 CLIA Beckman Coulter Access SARS‐CoV‐2 IgG S1‐RBD IgG 154 184
CLIA Siemens Centaur XP Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 154 184
CLIA Siemens Vista 1500 Siemens SARS‐CoV‐2 total (COV2T) S1 Total antibody 154 184
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a

If borderline results were considered positive.

Abbreviations: CLIA, chemiluminescent immunoassay; ELISA, enzyme immunoassay; N, nucleocapsid antigen; NA, not specified; RBD, receptor‐binding domain; S1, S1 domain of viral spike protein; S1/S2, recombinant S1 and S2 antigens.

3.2. Quality Assessment

The assessment was performed using the Review Manager Software version 5.3. Figure 2 summarized the QUADA‐2 assessment. Five articles were judged as “high” in the patient selection domain of the risk of bias (including Al‐Jighefee, Chiereghin, Ikegami, Naaber, and Nedelcu). Among the above five articles, two or three questions of a domain were answered as “no”; therefore, the level of risk of bias was judged as “high” in the patient selection domain. For the index test domain of the risk of bias, it was found that the first question of the domain was answered as “no” on account of the serological assays being evaluated not in blind; therefore, all articles were judged as “unclear”. Six articles (including Chiereghin, Harritshøj, Horn, Ikegami, Naaber, and Padoan) whose patients had been diagnosed with COVID‐19 by positive SARS‐CoV‐2 RT‐PCR regardless of clinical symptoms or contained recovered COVID‐19 patients were judged as “unclear” in the reference standard domain of the risk of bias. Thirteen articles (including Chiereghin, Chua, Davidson, Egger, Garnett, Horn, Igawa, Marlet, Riester, Sekirov, Syre, Tan, and Ward) were judged as “high” in the flow and timing domain. The applicability judgment results for the patient selection domain were consistent with the reference standard domain; six articles (including Al‐Jighefee, Chiereghin, Horn, Naaber, Padoan, and Pflüger), including asymptomatic COVID‐19 patients were judged as “high,” and nine articles (including Harritshøj, Ikegami, Irsara, Lapić, Oved, Parai, Theel, Tolan, and Yassine) including recovered COVID‐19 patients were judged as “unclear.”

Figure 2.

Figure 2

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Risk of bias and applicability concerns summary.

3.3. Data Synthesis and Meta‐Analysis

First, we evaluated the diagnostic accuracy of immunoglobulin isotypes (IgM, IgG, and total antibody). Due to significant heterogeneity in the analysis of three immunoglobulin isotypes, a random effects model was used. A forest plot of DOR with 95% CIs for immunoglobulin isotypes is shown in Figure 3A. The pooled DOR for IgG (242.88 [95% CI 157.66−374.16]), IgM (40.99 [95% CI 22.63−74.25]), and total antibody (1215.90 [95% CI 547.14−2702.07]) showed that assays‐based total antibody had the better diagnostic accuracy compared to assays‐based IgG and assays‐based IgM with significant difference. Moreover, indirect comparison results of RDOR with 95% CIs showed that assays‐based total antibody and assays‐based IgG showed significantly better diagnostic accuracy than assays‐based IgM (as shown in Figure 3B).

Figure 3.

Figure 3

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(A) Pooled DOR with 95% CIs of immunoglobulin classes. (B) Indirect comparison forest plots of RDOR with 95% CIs for all three pairwise immunoglobulin comparisons. CIs, confidence intervals; DOR, diagnostic odds ratio; RDOR, relative diagnostic odds ratio.

As mentioned above, the diagnostic efficacy of the assays‐based total antibody had statistically significantly higher accuracy than those of assays‐based IgG and assays‐based IgM. We assessed the diagnostic accuracy of assays‐based IgM separately. Meta‐analyses evaluating the parameters of the accuracy of the reported assays were performed, and results are shown in Table 2. Forest plots of coupled sensitivity and specificity with 95% CIs for 11 serological assays are shown in Figure 4. We also constructed the SROC curves for all 11 serological assays (as shown in Figure 5A). The pooled DOR results of 11 serological assays were shown by forest plots (as shown in Figure 5B). There was no significant heterogeneity for access SARS‐CoV‐2 IgG, iFlash‐SARS‐CoV‐2 IgG, MAGLUMI 2019‐nCoV IgM, ortho‐clinical anti‐SARS‐CoV‐2 IgG, ortho‐clinical anti‐SARS‐CoV‐2 total, and Wantai SARS‐CoV‐2 total Ab, and a fixed effects model was used. The results of RDOR with 95% CIs were exhibited in the indirect comparison forest plot by R software. From the pooled DOR and the SROC curves, the overall diagnostic accuracy of the Siemens SARS‐CoV‐2 total (COV2T) (1143.37 [95% CI 316.49−4130.62]), ortho‐clinical anti‐SARS‐CoV‐2 total (1104.60 [95% CI 395.64−3083.99]), Wantai SARS‐CoV‐2 total Ab (1014.98 [95% CI 618.48−1665.66]), and ortho‐clinical anti‐SARS‐CoV‐2 IgG (719.46 [95% CI 262.34−1973.13]) performed better than the other serological assays; indirect comparison results of RDOR with 95% CIs for these four pairwise assays showed that there was no significant difference between them. Meanwhile, the RDOR results suggested that the diagnostic accuracy of these four assays was statistically significantly higher than EDI novel coronavirus COVID‐19 IgG. The RDOR value of EDI novel coronavirus COVID‐19 IgG versus iFlash‐SARS‐CoV‐2 IgG was 0.19 (95% CI 0.04−0.94), which suggested that the diagnostic accuracy of iFlash‐SARS‐CoV‐2 IgG was statistically significantly higher than EDI novel coronavirus COVID‐19 IgG (as shown in Figure 6). The diagnostic accuracy of the three IgM assays had no significant difference (as shown in Figure 5C).

Table 2.

Summary table of the diagnostic accuracy.

Assay Pooled analysis results (95% CI) Heterogeneity Deek's test
Pooled sensitivity Pooled specificity Pooled PLR Pooled NLR AUC DOR I 2 (%) p t p
Access SARS‐CoV‐2 IgG 0.78 (0.64−0.87) 1.00 (0.99−1.00) 275.20 (82.90−914.00) 0.22 (0.13−0.38) 1.00 564.28 (229.58−1386.91)a 0 0.56 −0.53 0.618
EDI novel coronavirus COVID‐19 IgG 0.67 (0.60−0.74) 0.98 (0.97−0.99) 36.10 (21.90−59.50) 0.34 (0.27−0.41) 0.95 85.27 (53.99−134.68) 55 < 0.01 −0.18 0.859

EDI novel coronavirus COVID‐19 IgG

(omitting Davidson)

 0.68 (0.60−0.74) 0.98 (0.97−0.99) 38.20 (24.10−60.70) 0.33 (0.26−0.41) 0.97 87.61 (67.43−113.81)a 32 0.13 0.25 0.806
EDI novel coronavirus COVID‐19 IgM 0.41 (0.30−0.52) 0.99 (0.97−1.00) 47.20 (12.80−173.40) 0.60 (0.49−0.73) 0.86 49.42 (16.47−148.30) 76 < 0.01 0.32 0.758

EDI novel coronavirus COVID‐19 IgM

(omitting Davidson)

 0.44 (0.33−0.55) 0.99 (0.98−1.00) 63.60 (18.40−219.30) 0.57 (0.46−0.70) 0.91 67.86 (25.55−180.22) 57 0.03 1.12 0.315
iFlash‐SARS‐CoV‐2 IgG 0.87 (0.82−0.90) 1.00 (0.98−1.00) 195.10 (44.00−865.00) 0.13 (0.10−0.18) 0.97 652.31 (362.32−1174.41)a 48 0.05 −2.52 0.040b
iFlash‐SARS‐CoV‐2 IgM 0.52 (0.49−0.55) 0.98 (0.97−0.99) 18.37 (5.71−59.05) 0.52 (0.45−0.60) 0.76 36.72 (12.42−108.54) 87 < 0.01 −3.41 0.014b

iFlash‐SARS‐CoV‐2 IgM

(omitting Han Xiaoyan)

 0.50 (0.41−0.60) 0.98 (0.96−0.99) 32.30 (15.70−66.20) 0.50 (0.42−0.61) 0.86 49.19 (31.92−75.81)a 51 0.06 −2.37 0.064
MAGLUMI 2019‐nCoV IgG 0.69 (0.62−0.74) 0.99 (0.97−1.00) 71.30 (22.80−223.00) 0.32 (0.26−0.38) 0.90 145.44 (59.37−356.30) 57 0.03 −1.26 0.263

MAGLUMI 2019‐nCoV IgG

(omitting Harritshøj)

 0.66 (0.60−0.72) 0.99 (0.95−1.00) 59.30 (13.40−261.50) 0.34 (0.29−0.40) 0.83 83.80 (42.86−163.85)a 0 0.72 0.12 0.912
MAGLUMI 2019‐nCoV IgM 0.55 (0.51−0.59) 0.97 (0.96−0.98) 23.77 (4.96−113.88) 0.45 (0.36−0.57) 0.59 21.59 (14.27−32.67)a 53 0.09 0.74 0.534
Ortho‐clinical anti‐SARS‐CoV‐2 IgG 0.86 (0.64−0.96) 1.00 (0.99−1.00) 330.20 (69.80−1562.30) 0.14 (0.04−0.42) 1.00 719.46 (262.34−1973.13)a 56 0.05 −0.68 0.536

Ortho‐clinical anti‐SARS‐CoV‐2 IgG

(omitting Harritshøj)

 0.85 (0.54‐0.96) 0.99 (0.98‐1.00) 139.20 (44.90−431.50) 0.16 (0.04−0.56) 1.00 459.87 (156.30−1353.00)a 33 0.20 1.13 0.340
Ortho‐clinical anti‐SARS‐CoV‐2 total 0.88 (0.70−0.96) 1.00 (0.98−1.00) 1036.40 (55.80−19258.80) 0.12 (0.04−0.34) 1.00 1104.60 (395.64−3083.99)a 33 0.18 −1.28 0.256
Siemens SARS‐CoV‐2 total (COV2T) 0.85 (0.78−0.90) 1.00 (0.99−1.00) 521.80 (135.30−2011.80) 0.15 (0.10−0.22) 0.99 1143.37 (316.49−4130.62) 91 < 0.01 −4.11 0.001b

Siemens SARS‐CoV‐2 total (COV2T)

(omitting Kundu)

 0.85 (0.78−0.90) 1.00 (1.00−1.00) 301.60 (196.80−462.10) 0.15 (0.10−0.22) 1.00 1581.39 (837.31−2986.72) 45 0.02 −4.90 0.000b
Wantai SARS‐CoV‐2 total Ab 0.93 (0.88−0.96) 0.99 (0.98−1.00) 107.80 (50.80−229.00) 0.07 (0.04−0.12) 1.00 1014.98 (618.48−1665.66)a 33 0.15 −0.10 0.919
Open in a new tab
a

The pooled DOR was calculated with a fixed effects model.

b

Significant publication bias was observed.

Figure 4.

Figure 4

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Forest plots of coupled sensitivity and specificity with 95% confidence intervals for 11 serological assays. Harritshøj (A): Siemens Vista assay was performed, Harritshøj (B): Siemens Atellica assay was performed; Ward (A): Siemens Atellica assay was used, Ward (B): Siemens EXL systems were used; Zilla (A): Siemens Centaur assay was performed; Zilla (B): Siemens Vista assay was performed.

Figure 5.

Figure 5

Open in a new tab

(A) SROC curve of the 11 serological assays. (B) Pooled DOR with 95% CIs of the 11 serological assays. (C) Indirect comparison forest plots of RDOR with 95% CIs for three IgM assays pairwise comparisons. CIs, confidence intervals; DOR, diagnostic odds ratio; RDOR, relative diagnostic odds ratio; SROC, summary receiver operating characteristics.

Figure 6.

Figure 6

Open in a new tab

Indirect comparison forest plots of RDOR with 95% CIs for IgG and total antibody assays pairwise comparisons. CIs, confidence intervals; RDOR, relative diagnostic odds ratio.

3.4. Heterogeneity Test and Sensitivity Analysis

We investigated heterogeneity for 11 serological assays; significant high heterogeneity was observed for EDI novel coronavirus COVID‐19 IgG, EDI novel coronavirus COVID‐19 IgM, iFlash‐SARS‐CoV‐2 IgM, MAGLUMI 2019‐nCoV IgG, and Siemens SARS‐CoV‐2 total. To determine the possible source of heterogeneity, sensitivity analysis was performed. Omitting a single study did not significantly affect the pooled DOR. Nevertheless, no significant heterogeneity was observed for EDI novel coronavirus COVID‐19 IgG (p = 0.13, I 2 = 32%) when the study “Davidson 2020” was removed as well as for iFlash‐SARS‐CoV‐2 IgM (p = 0.06, I 2 = 51%) when study “Han Xiaoyan 2023” was removed and for ortho‐clinical anti‐SARS‐CoV‐2 IgG (p = 0.20, I 2 = 33%) when study “Harritshøj 20213” was removed. The heterogeneity decreased for EDI novel coronavirus COVID‐19 IgM (p = 0.03, I 2 = 57%) when study “Davidson 2020” was removed as well as for Siemens SARS‐CoV‐2 total (p = 0.02, I 2 = 45%) when study “Kundu 2022” was removed. While “Harritshøj 2021” was the primary cause of the heterogeneity for MAGLUMI 2019‐nCoV IgG (p = 0.72, I 2 = 0%, omitting “Harritshøj 2021”) (as shown in Table 2).

3.5. Risk of Bias Assessment

The Deek's test was performed to detect publication bias for iFlash‐SARS‐CoV‐2 IgG, iFlash‐SARS‐CoV‐2 IgM, and Siemens SARS‐CoV‐2 total, and the results of publication bias showed that the p value for aromatase was < 0.05, indicating that significant publication bias was observed (as shown in Table 2).

4. Discussion

Since the start of the COVID‐19 pandemic, an increasing number of serological SARS‐CoV‐2 assays have been introduced to the diagnostic market. We have demonstrated a comprehensive evaluation of 11 commercially available anti‐SARS‐CoV‐2 antibody assays. First, we evaluated the diagnostic efficiency of eight assays for detecting IgG and total antibodies against SARS‐CoV‐2. Taking into account the manufacturer's threshold, the pooled sensitivity among the evaluated eight assays ranged from 67% to 93%. Wantai SARS‐CoV‐2 total Ab and ortho‐clinical anti‐SARS‐CoV‐2 total assays had the best pooled sensitivity, followed by the iFlash‐SARS‐CoV‐2 IgG, ortho‐clinical anti‐SARS‐CoV‐2 IgG, and Siemens SARS‐CoV‐2 total (COV2T) assays. The high sensitivity of the two assays could be due to the ability of the two assays to detect all immunoglobulin classes. The pooled sensitivity of the EDI Novel Coronavirus COVID‐19 IgG and MAGLUMI 2019‐nCoV IgG assays was the lowest with a positive rate of 67% and 69% in the neglect of the three assays‐based IgM conditions, the pooled sensitivity of the three IgM assays varied from 41% to 55%. The overall sensitivity of the IgM assays was low, suggesting that there was limited utility in testing for IgM assays. Other studies have suggested development of IgM may occur earlier using a nucleocapsid antigen target compared to the spike glycoproteins [67, 68]. The pooled specificity of MAGLUMI 2019‐nCoV IgM was low compared to the other assays; all other assays demonstrated pooled specificity exceeding 98%. Besides the sensitivity and specificity, the pooled PLR (1036.40 and 521.80) and pooled NLR (0.12 and 0.15) for ortho‐clinical anti‐SARS‐CoV‐2 total and Siemens SARS‐CoV‐2 Total (COV2T) assays were also better than those for the other assays. Nevertheless, the pooled NLR (0.07) for Wantai SARS‐CoV‐2 total Ab displayed the best performance. The pooled DOR of Siemens SARS‐CoV‐2 total (COV2T), ortho‐clinical anti‐SARS‐CoV‐2 total, and Wantai SARS‐CoV‐2 total Ab assays were sharply higher compared to the other assays. We also constructed the SROC curves using RevMan 5.3 software and calculated the AUC using STATA software (version 12). The AUC was 1.00 for access SARS‐CoV‐2 IgG, ortho‐clinical anti‐SARS‐CoV‐2 IgG, ortho‐clinical anti‐SARS‐CoV‐2 total, and Wantai SARS‐CoV‐2 total Ab, 0.99 for Siemens SARS‐CoV‐2 total (COV2T). The results of the SROC curve and the AUC suggested that the diagnostic accuracy of those three assays (Siemens SARS‐CoV‐2 total, ortho‐clinical anti‐SARS‐CoV‐2 total, and Wantai SARS‐CoV‐2 total Ab) were relatively higher than the other assays.

Subsequently, we used RT‐PCR as the reference standard and conducted an indirect comparison between the 11 assays by calculating the RDOR value using R software. The adjustment indirect comparison forest plots of RDOR showed that the diagnostic accuracy of the four assays (Siemens SARS‐CoV‐2 total, ortho‐clinical anti‐SARS‐CoV‐2 total, Wantai SARS‐CoV‐2 total Ab, and ortho‐clinical anti‐SARS‐CoV‐2 IgG) had no significant difference and we also did not observe a significant difference between the other three assays (EDI novel coronavirus COVID‐19 IgM, iFlash‐SARS‐CoV‐2 IgM, and MAGLUMI 2019‐nCoV IgM) in the diagnostic accuracy of COVID‐19. We also constructed an indirect comparison to compare the diagnostic accuracy of immunoglobulin classes recognized (IgM, IgG, and total antibody). In our study, the pooled DOR of assays‐based IgM were low compared to the assays‐based IgG and the assays‐based total antibody. Independent of the serological method, the diagnostic performance of the IgM‐specific assays was lower than that of IgG and total antibody‐specific assays. Another study reported that SARS‐CoV‐2‐specific IgM is detected mostly in the early infection phase but only in rare cases [69, 70]. The antibodies assessed in these assays refer to structural antigenic proteins of SARS‐CoV‐2; the 11 serological assays differ in the type of immunoglobulin classes recognized as well as the nature of the antigen used for antibody recognition. At present, many studies have performed a structured systematic review and meta‐analysis to evaluate the diagnostic characteristics of serological testing for the detection of SARS‐CoV‐2 antibodies. Most of them provided the pooled analysis results (e.g., sensitivities and specificities) regarding the accuracy parameters of the reported serological assays. There are a limited number of comparable serological assays in the studies performed head‐to‐head comparisons. Under the condition of insufficient direct comparative study, we conducted an indirect comparison of the diagnostic efficacy of 11 assays; our data provide the overall diagnostic efficacy of 11 assays, as well as the antibody isotypes. Additionally, it is important to point out that our study took RT‐PCR as a reference standard and conducted an indirect comparison to compare the efficacy of antibody assays by calculating the RDOR value between them. To visualize results, we provide forest plots showing the RDOR with 95% CI of the 11‐assay comparison by R software.

This meta‐analysis also had some limitations. Due to the included studies differing in terms of method, manufacturer, and period of blood collection, we found high heterogeneity rates among trials. The expression change of antibodies against SARS‐CoV‐2 and the methods used for the detection of antibodies may have an effect on the overall diagnostic accuracy of serological assays. Because few articles included in this meta‐analysis have provided the data regarding the TP, FP, FN, and TN values at different sampling times, we could not directly address whether or not the sampling time affects the assay performance. The second is related to the methodological qualities of the primary studies. In the eligibility criteria, we did not set very strict definitions for the diagnosis of COVID‐19; in some studies, asymptomatic COVID‐19 and recovered COVID‐19 patient's serum samples comprise a large proportion. Specifically, the methods used for diagnosing COVID‐19 were not described in most studies. Another limitation was that this meta‐analysis had high heterogeneity, and sensitivity analysis indicated that the heterogeneity may be derived from a single study.

5. Conclusions

This study suggested that the Siemens SARS‐CoV‐2 total (COV2T), ortho‐clinical anti‐SARS‐CoV‐2 total, and Wantai SARS‐CoV‐2 total had high diagnostic efficiency. The diagnostic efficacy of the assays‐based total antibody had statistically significantly higher accuracy than those of assays‐based IgG and assays‐based IgM for COVID‐19.

Author Contributions

Ying Zhao and Minjie Zhang: conception, design, and administrative support. Weiwei Liang, Lijiang Fang, and Ying Zhao: data analysis and interpretation. Minjie Zhang, Weiwei Liang, and Lijiang Fang: manuscript writing, collection, and assembly of data. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Requests for any data can be made to the authors.

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