Abstract
Background
Nucleic acid detection represents limitations due to its false-negative rate and technical complexity in the COVID-19 pandemic. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests are widely spread all over the world presently. However, there is no report on the effectiveness of anti-SARS-CoV-2 antibody testing methods in China.
Methods
We gathered 10776 serum samples from close contacts of the SARS-CoV-2 infections in Fujian of China and used 2 chemiluminescence immunoassays (Wantai Bio., Yahuilong Bio.) and 2 lateral flow immunoassays (Lizhu Bio. and Dongfang Bio.) to perform the anti-SARS-CoV-2 antibody tests in China.
Results
The 4 antibody tests have great diagnostic value for infected or uninfected, especially in the neutralizing antibodies tests, the AUC can reach 0.939 (Wantai Bio.) and 0.916 (Yahuilong Bio.). Furthermore, we used pseudoviruses and euvirus neutralization assay to validate the effectiveness of these antibody test, the results of pseudoviruses neutralization assay or euvirus neutralization assay shows a considerable correlation with the 4 antibody detection respectively, particularly in euvirus neutralization assay, neutralizing antibodies detected by Wantai Bio. or Yahuilong Bio., the correlation can get the level of 0.93 or 0.82.
Conclusions
The findings of this study demonstrate that the detections of antibodies have profound value in the diagnosis of COVID-19.
Keywords: COVID-19, Antibody test, SARS-CoV-2, Lateral flow immunoassays, Chemiluminescence immunoassays, Pseudoviruses neutralization assay, Euvirus neutralization assay
1. Introduction
A novel coronavirus disease, abbreviated to COVID-19, is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1], resulting in a pandemic that was defined by the Director-General of the World Health Organization (WHO) on March 11, 2020 [2]. The responsible pathogen is a virus that has a high sequence identity (i.e., up to 80 %) with the homologous virus that led to the 2003 SARS outbreak [1], [3]. SARS-CoV-2 contains several arbovirus subgenera that can cause mild to severe human disease [4], which manifest in clinical manifestations of dry cough, fever, fatigue, even severe pneumonia, and nearly-one‐third of the patients developing acute respiratory distress syndrome [5], [6]. The complexities and severity of disease remain a tremendous knowledge gap since its frequent mutate that include alpha (α), beta (β), gamma (γ), delta (δ), and omicron (o) of virus till date [7], [8]. Nevertheless, there is no specific therapy for COVID-19 by far [9].
Nucleic acid detection is still the currently mainstream clinical diagnosis for the COVID-19 [10], which bases on the samples from nasopharyngeal and throat swabs of patients [11]. Though its vital role in identifying SARS-CoV-2 infection in patients at the beginning of the outbreak of a virus, the limitations of this method are becoming more and more obvious [12]. Such as, one recent article made a point that RT‐PCR got a positive rate of 38 % in a test include 4880 specimens with a significant number of false-negative cases [13]. The principal reason for this case is that the diagnostic accuracy of RT-PCT relies on many factors, such as sample types and collection, transportation and storage conditions, as well as the quality and consistency of the PCR assays being used [14], [15]. In addition, many patients may be asymptomatic, which results in increasing the uncertainty of the diagnostic work-up [16]. Hence, it is urgent to develop more effective diagnostic methods that can rapidly identify infected patients with high accuracy.
The production of specific antibodies, especially anti-SARS-CoV-2 IgM, IgG, and neutralizing antibodies tests are better be used as an alternative non-invasive method for clinical diagnosis of acute COVID-19 [17], particularly in patients with a low viral load, who present late [18]. Anti-SARS-CoV-2 antibodies tests, served as serological testing, can detect a previously undiagnosed SARS-CoV-2 carrier among individuals for whose RT-PCR was either falsely negative or not performed [19]. And antibodies tests are beneficial for studying the epidemiological seroprevalence of COVID-19 to acquire a more accurate estimate of the circulating dynamics and virulence of SARS-CoV-2 [20], [21]. Such a lot of detection reagents for anti-SARS-CoV-2 antibodies have been developed and launched around the world [22]. However, the performance and usefulness of anti-SARS-CoV-2 antibodies tests lack a real-world study with large-scale cases in China [23].
2. Materials and methods
2.1. Study design and patient enrollment
Seven medical institutions participated in this retrospective, observational study: The 73rd Group Army Hospital of the Chinese People's Liberation Army, Xiamen Hospital of Beijing University of Traditional Chinese Medicine, Xiamen Third Hospital, The Affiliated Hospital of Putian University, Beijing Hospital, The School of Public Health of Xiamen University and The Beijing SINOVAC Biotech ltd. A total of 10776 close contacts collected from the SARS-COV-2 epidemic during September 2021 in Putian and Xiamen, Fujian of China were included for analysis. This study was approved by the Joint Prevention and Control Mechanism of the State Council.
2.2. Collection of clinical data and serum samples
All 10776 close contacts have been traced in the SARS-CoV-2 epidemic of Putian and Xiamen, Fujian, China, during September 2021. The demographic information was collected using big data, including age and gender, etc. The vaccination history was collected, including the manufacturer and date of vaccination. The date of PCR tested positive for the first time and the corresponding cycle threshold (Ct) values for both open reading frame (ORF) and nucleocapsid (N) genes were collected for the case group, and the date of PCR tested negative for the last time was collected for the control group. All blood samples from patients were collected on the date of venipuncture at 2 weeks after the onset of the disease and were stored at −20 °C before testing. A total of 7050 samples of close contacts were collected in 89 hotels for quarantine of Xiamen, and 190 samples of patients and recovered persons were collected in 2 hospitals (spot and rehabilitation); a total of 3353 samples were collected in 128 hotels for quarantine of Putian, and a designated hospital collected 183 samples of patients and recovered persons. In the end, a total of 10776 blood samples from close contacts including 373 blood samples from patients and recovered persons were collected in the 2 cities.
2.3. Chemiluminescence immunoassays (CLIA) and lateral flow immunoassays (CLIA) for anti-SARS-CoV-2 antibodies
Chemiluminescence immunoassays (CLIA) and lateral flow immunoassays (LFIA) for anti-SARS-CoV-2 antibodies were tested by Wantai Bio. (IgM, IgG, neutralizing antibody and total antibody) and Yahuilong Bio. (IgM, IgG, and neutralizing antibody); Lizhu Bio. (IgM and IgG), and Dongfang Bio. (IgM, IgG, and neutralizing antibody), according to respective instructions. For the testing of samples, The 73rd Group Army Hospital of the Chinese People's Liberation Army was responsible for the testing of 3170 serum samples, the Xiamen Hospital of Beijing University of Traditional Chinese Medicine was responsible for the testing of 2630 serum samples, the Xiamen Third Hospital was responsible for the testing of 1440 serum samples, and the Affiliated Hospital of Putian University was responsible for the completion of 1540 serum samples, Putian First Hospital was responsible for the testing of 1996 samples. Each specimen was detected with the above 4 reagents.
2.4. Pseudoviruses and euvirus neutralization assay
Pseudoviruses neutralization assay is performed to detect > 200 samples of patients and 2000 close contacts by The School of Public Health of Xiamen University as previously described [15], [24]; The Beijing SINOVAC Biotech ltd. used the euvirus neutralization assay to detect all patients and partial samples of close contacts according to its instructions. Briefly, The cultured supernatant of monoclonal hybridoma cells, gradient diluted purified antibodies (receptor-binding domain (RBD) antibody and SARS-CoV-2 S and N-proteins antibodies) or the serum of patients were mixed with diluted VSV-SARS-CoV-2-Sdel18 virus (MOI = 0.05) and incubated at 37 °C for 1 h. All samples and viruses were diluted with 10 % FBS-DMEM. The mixture was added to seeded BHK21-hACE2 cells. After 12 h of incubation, fluorescence images were obtained with Opera Phenix or Operetta CLS equipment (PerkinElmer). For quantitative determination, fluorescence images were analyzed by the Columbus system (PerkinElmer), and the numbers of GFP-positive cells for each well were counted to represent infection performance. The reduction (%) in the number of GFP-positive cells in mAb-treated wells compared with that in nontreated control wells were calculated to show the neutralizing potency.
2.5. Statistics
We calculated median and interquartile range for continuous variables and percentages for the categorical variables. The measurement agreements between different antibody tests were evaluated with nonparametric correlation analysis. The positive rate of anti-SARS-CoV-2 antibodies in different infections was analyzed by Chi-squared test, and the levels of anti-SARS-CoV-2 antibodies were tested by a Non-parametric test. The ROC curve is applied for the diagnostic analysis of antibody detection. Library (basic trendline) based on R version 3.6.3 was used to analyze the correlation between the pseudoviruses neutralization assay or euvirus neutralization assay and the several antibody detections respectively. Data were analyzed by using SPSS for Windows (v19.0). All p-values are 2-sided, and a p < 0.05 considered statistically significant.
3. Results
3.1. Anti-SARS-CoV-2 antibody response in patients with COVID-19
A total of 10776 serum samples (include373 patients) were collected from the SARS-CoV-2 epidemic in Putian and Xiamen, Fujian of China during September 2021, who were diagnosed by RT-PCR, were enrolled in this study. We used the Yahuilong Bio. Kits (YHL) to detect anti-SARS-CoV-2 IgG, IgM, and neutralizing antibodies and Wantai Bio. Kits (WT) to detect anti-SARS-CoV-2 IgG, IgM, neutralizing antibodies, and total antibodies. As shown in Fig. 1 , the patients with COVID-19 yield higher levels of anti-SARS-CoV-2 antibodies compare with uninfected patients, including IgG, IgM, total antibodies, and neutralizing antibodies. Then we analysed the correlation between RT‐PCR test results for SARS‐CoV‐2 and the results of lateral flow immunoassays (Fig. S1). We found CT values of N gene and ORF1 gene in neutralizing antibody positive patients were significantly higher than those in neutralizing antibody negative patients.
Fig. 1.
The detection of antibody level in all close contacts. (A) The level of anti-SARS-CoV-2 IgG antibody, anti-SARS-CoV-2 IgM antibody, and anti-SARS-CoV-2 neutralizing antibody by Yahuilong Bio. detection. (B) The level of anti-SARS-CoV-2 IgG antibody, anti-SARS-CoV-2 IgM antibody, anti-SARS-CoV-2 neutralizing antibody, and anti-SARS-CoV-2 total antibody by Wantai Bio. detection. P < 0.001.
3.2. The vaccinnateds elicit a higher antibody response in COVID-19
Increased studies have shown that vaccination is conducive to the production of anti-SARS-CoV-2 antibodies [25]. Then, under this epidemic, the levels of anti- SARS-CoV-2 antibodies in infections were detected by 4 antibody test kits, including Wantai Bio. (WT), Yahuilong Bio. (YHL), Dongfang Bio. (DF) and Lizhu Bio. (LZ). Among them, we found that the level of 4 types of antibodies in vaccinated all have been increased compared to unvaccinated (supplemental Tables 1 and 2). Especially in the degree of anti-SARS-CoV-2 neutralizing antibodies raised was the most significant improvement (Fig. 2 ). As pictured in Fig. 2E, the vaccinated can get the level of 4600 IU/ml and 328.38 IU/ml in unvaccinated by the detection of WT. In addition, the YHL Bio. could detect the level of 2376.36 IU/ml in vaccinated and 135.58 IU/ml in unvaccinated. Therefore, vaccination can effectively improve the patient's antibody level after SARS-CoV-2 invasion.
Fig. 2.
The detection of anti-SARS-CoV-2 antibodies levels in infections. (A) The level of anti-SARS-CoV-2 IgG antibody by chemiluminescence immunoassays. (B) The level of anti-SARS-CoV-2 IgM antibody by chemiluminescence immunoassays. (C) The level of anti-SARS-CoV-2 neutralizing antibody by chemiluminescence immunoassays. (D) The level of anti-SARS-CoV-2 total antibody by Wantai Bio. detection. (E) The level of anti-SARS-CoV-2 IgG antibody by lateral flow immunoassays. (F) The level of anti-SARS-CoV-2 IgM antibody by lateral flow immunoassays. (G) The level of anti-SARS-CoV-2 neutralizing antibody by Dongfang Bio. detection. P < 0.001.
3.3. Robust consistency in anti-SARS-CoV-2 antibody tests
In order to verify the reliability of these antibody detection methods, we evaluated the consistency of these methods. As shown in Fig. 3 , Wantai Bio. and Yahuilong Bio. chemiluminescence immunoassays showed strong consistency in the detection of anti-SARS-CoV-2 IgG and neutralizing antibodies (R was 0.964 and 0.865 respectively, P < 0.001), and the detection of anti-SARS-CoV-2 IgM antibody was ordinarily consistent (R was 0.608, P < 0.001).
Fig. 3.
The comparison of antibody testing consistency. (A) The consistency of anti-SARS-CoV-2 IgM antibody by Wantai Bio. and Yahuilong Bio. detection. (B) The consistency of anti-SARS-CoV-2 neutralizing antibody by Wantai Bio. And Yahuilong Bio. detection. (C) The consistency of anti-SARS-CoV-2 IgG antibody by Wantai bio. and Yahuilong Bio. detection. P < 0.001.
3.4. Diagnostic value of the anti-SARS-CoV-2 antibody tests
Quantitative detection of anti-SARS-CoV-2 neutralizing antibodies can be better to distinguish infected or uninfected in close contacts, which helps to identify false negatives in nucleic acid testing [26]. As shown in Fig. 4 , supplemental Tables 3 and 4, anti-SARS-CoV-2 neutralizing antibodies displayed the highest sensitivity and specificity among these antibodies tests, and the area under the curve (AUC) of the chemiluminescence immunoassays for detecting neutralizing antibodies can reach 0.939 (Wantai Bio.) and 0.916 (Yahuilong Bio.). Besides, quantitative detection of anti-SARS-CoV-2 IgM, IgG, and total antibodies and qualitative detection of anti-SARS-CoV-2 antibodies are generally capable of distinguishing between infected and non-infected people.
Fig. 4.
The ROC assay of different anti-SARS-CoV-2 antibody detections. A. Two kinds of chemiluminescence immunoassay; B. Two kinds of lateral flow immunoassays, P < 0.001.
3.5. The antibody detection substitute pseudovirus neutralization assay
To validate the effectiveness of antibodies, we randomly select 1929 (including 373 patients) serum samples for pseudovirus neutralization assay experiments. As described in Table 1 , these antibodies detection in the neutralization test of the pseudovirus has a significant correlation with the prototype strain or “Delta” strains. The IgM, IgG, total antibodies, and neutralizing antibodies detected by Wantai Bio. are strongly related to the neutralization test of the pseudovirus in prototype strains (R are 0.722, 0.854, 0.878, and 0.835, respectively). The IgM, IgG, and neutralizing antibodies detected by Yahuilong Bio. have a robust association with the neutralization test of the pseudovirus in prototype strains (R are 0.698, 0.863, and 0.874, respectively). The neutralizing antibodies and total antibodies tested by Wantai Bio. have a strong correlation with the “Delta” strain of pseudovirus neutralization test (R are 0.730 and 0.740 respectively), and other antibodies are less related to the “Delta” strain of pseudovirus neutralization test.
Table 1.
Analysis of correlation between two chemiluminescence methods and pseudovirus neutralization test.
| Wild-type |
Delta |
|||
|---|---|---|---|---|
| Antibody | rs | P | rs | P |
| WT-IgM | 0.722 | <0.001 | 0.548 | <0.001 |
| WT-IgG | 0.854 | <0.001 | 0.626 | <0.001 |
| WT-Neutralizing antibody | 0.878 | <0.001 | 0.730 | <0.001 |
| WT-Total antibody | 0.835 | <0.001 | 0.740 | <0.001 |
| YHL-IgM | 0.698 | <0.001 | 0.371 | <0.001 |
| YHL-IgG | 0.863 | <0.001 | 0.404 | <0.001 |
| YHL-Neutralizing antibody | 0.874 | <0.001 | 0.592 | <0.001 |
3.6. Antibodies neutralizing response with euvirus of SARS-CoV-2
In order to further validate the applicable potency of these 4 antibody detection methods, we took 1799 serum samples (including 373 patients) for euvirus of SARS-CoV-2 neutralization experiments. The results are described in Fig. 5 (A ∼ L), the different types of antibodies detected by these 4 antibody detection methods have significant correlations with euvirus experiments. Among them, especially in the chemiluminescence assays, the correlation between neutralizing antibody detection and euvirus tests can get the point of 0.93 (Wantai Bio.) and 0.82 (Yahuilong Bio.).
Fig. 5.
Analysis of correlation between the 4 antibody detection methods respectively and euvirus neutralization test. P < 2.2e-16. A ∼ G. The correlation between 2 kinds of chemiluminescence immunoassay respectively and euvirus neutralization test; H ∼ L. The correlation between 2 kinds of lateral flow immunoassays respectively and euvirus neutralization test.
4. Discussion
This study parallelly evaluated the performance of 4 anti-SARS-CoV-2 antibody tests in the diagnosis and severity assessment of COVID-19. We investigated the SARS-CoV-2 epidemic in Putian and Xiamen, Fujian, China during September 2021, and collected serum samples of 10776 close contacts (including 373 patients). The serum samples of this group were tested for anti-SARS-CoV-2 antibody by chemiluminescence immunoassays and lateral flow immunoassays, which are the most representative domestic antibody detection methods in China.
Though it is reported that protein chips technologies are usually used for the anti-SARS-CoV-2 antibody tests in the international epidemic, there is a huge hinder to expanding its marketing due to the cumbersome methods and high cost [5], [27]. The results showed that these 4 methods have high consistency in anti-SARS-CoV-2 antibody detection. The chemiluminescence immunoassays for detecting neutralizing antibodies have a better ability to distinguish between vaccinated and unvaccinated persons in infections. In addition, the neutralizing antibody tests have a good correlation with the pseudovirus neutralization assay, which can replace the pseudovirus neutralization test. Moreover, Further studies on the correlation between neutralizing antibody test and euvirus of SARS-CoV-2 neutralization experiments suggested that chemiluminescence immunoassays of anti-SARS-CoV-2 neutralizing antibodies can be capable of substituting euvirus neutralization experiments, and has a robust effect of resisting and destructing the SARS-CoV-2.
In this investigation, we used the ROC curve to evaluate the application potential of these 4 antibody detection methods in the diagnosis of COVID-19. Among them, though one of the lateral flow immunoassays presented modest specificity in diagnosing COVID-19, the chemiluminescence methods have shown extremely high diagnostic value in the detection of neutralizing antibodies, which can reach 0.939 (Wantai Bio.) and 0.916 (Yahuilong Bio.) respectively. The chemiluminescence method has strong diagnostic potential in the detection of anti-SARS-CoV-2 neutralizing antibodies and can be used to predict the time of vaccine injection and the number of injections.
We selected the euvirus neutralization assays as the gold standard to evaluate the detection value of these 4 antibody methods. Among them, the antibody detection reagents of Wantai Bio. and Yahuilong Bio. showed a strong correlation in the detection of neutralizing antibodies, which can reach 0.93 and 0.82 respectively. This shows that the neutralizing antibody detection of Wantai Bio. and Yahuilong Bio. have great application value and should be widely promoted and applied to the detection of COVID-19, and further to confirm the value of antibody testing in the diagnosis of COVID-19.
It is useful for antibody detection to apply for the diagnosis of COVID-19 and provides a convenient and rapid evaluation of individual vaccination effects in infections serving as the theoretical support and experimental basis.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors thank all health care workers in fighting against this epidemic for their collecting data and samples. The authors thank Wantai Bio., Lizhu Bio., Yahuilong Bio., and Dongfang Bio. for providing anti-SARS-CoV-2 antibodies testing reagents. This work was supported by the National Natural Science Foundation of China.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.cca.2022.12.017.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Data availability
The data that has been used is confidential.
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Supplementary Materials
Data Availability Statement
The data that has been used is confidential.