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EXPERIMENTAL ARTICLES
UDC 616-097.9.578 https://doi.org/10.15407/biotech12.01.058
DIAGNOSTIC CHARACTERISTICS OF THE ELISA TEST FOR THE HEPATITIS B VIRUS SURFACE ANTIGEN DETECTION
E. K. Kiseleva1 1PJSC "SPC" Diaproph-Med ", Kyiv, Ukraine
L. A. Ganova2 E. N. Chumak1
T. Yu. Trokhymchuk1 2Zabolotny Institute of Microbiology and Virology
V. G. Serdyuk1 of the National Academy of Sciences of Ukraine, Kyiv
N. Ya. Spivak1, 2
E-mail: ekiselova26@ukr.net
Received 23.09.2018 Revised 18.12.2018 Accepted 14.01.2019
The aim of the work was to define the diagnostic ability of the enzyme immunoassay test system DIA-HBsAg (PJSC "SPC "Diaprof-Med""), in which the principle of analysis is based on biotin-streptavidin amplification of a specific signal.
The assay performance was studied on WHO Second International Standard for HBsAg, subtype adw2, genotype A (NIBSC code: 00/588) in concentration 0.006 IU/ml; on Capricorn HBsAg standard subtypes ad and ay in concentration 0.006 ng/ml and 0.004 ng/ml respectively. All 14 members of the HBsAg Low Titer Performance Panel PHA 106 (BBI, USA) were detected in DIA-HBsAg with high OD/ CO ratio 11.9-40.7.
The DIA-HBsAg sensitivity were similar to the sensitivity of Roche COBAS and Murex HBsAg 3.0 when tested on the HBsAg Mixed Titer Performance Panel PHA 206 (BBI, USA) which consisted of sera with various HBsAg concentrations.
The DIA-HBsAg has correctly detected low reactive members of the HBsAg Verification Panel VHA 601 (BBI, USA) with OD/CO ratio 21.0-40.7 whereas the negative member OD/CO was 0.4.
In the evaluation of 174 cross-reactive serum specimens one false positive result was obtained out of 8 sera reactive for IgM to HSV-1/2. The DIA-HBsAg specificity on 1 177 blood donors' specimens was 99.9%.
Key words: ELISA, diagnostics, hepatitis B, analytical and diagnostic sensitivity, specificity.
Hepatitis B is an infectious liver disease with various clinical manifestations [1]. The infection is characterized by severity, high lethality, chronic forms with the development of cirrhosis and liver carcinoma [2]. The infectious agent is a DNA virus (HBV- hepatitis B virus), which is widely distributed because of its incredible resistance to various physical and chemical factors [3]. The HBV virus has infected approximately 350 million people worldwide, including 1.5 million in Ukraine [4]. Creating new highly sensitive tests for
the HBV diagnosis will significantly reduce the spread of the infection.
The surface HBV antigen, HBsAg is a main serological marker in hepatitis diagnostics. Only a small amount of HBsAg takes part in virion formation while the rest persists in the infected organism [5]. In acute hepatitis B, the antigen is found in blood one-two weeks after the infection occurred and disappears one-two months later. If it circulates in the body for more than six months, the illness has become chronic [6, 7]. Since it appears before the clinical symptoms
of the disease and the increase in the activity of aminotransferases, the diagnosis of HBV includes an obligatory blood test for HBsAg [8, 9]. However, most ELISA kits for HBsAg determination can only detect it in concentrations of 0.1-0.05 IU/ml [10, 11]. At lower concentrations of the antigen, for example during early stages of the disease, the analysis can give false negative results before HBsAg is eliminated in the blood or in the cases of concurrent infections.
The aim of our research was to study qualitative parameters of the ELISA kit DIA-HBsAg with sensitivity level of 0.01 IU/ ml for the diagnostics of HBsAg HBV. The kit is manufactured by SPC Diaproph-Med (Ukraine).
Materials and Methods
ELISA kits
ELISA kit DIA-HBsAg was constructed as a two-stage sandwich. The immunosorbent and biotinylated conjugate included mouse monoclonal antibodies to various immunodominant HBsAg sites. The specific signal is amplified at the next stage of the reaction, when biotinylated antibodies to HBsAg bind to the streptavidin conjugate labeled with high polymer horseradish peroxidase. To detect the reaction we used mono-component TMB/substrate (3, 3', 5, 5'-tetramethylbenzidine in citrate buffer with hydrogen peroxide). The reaction was terminated using 0.5 M HCl solution. Analysis of the results is carried out by measuring the optical density of the liquid in the wells in a two-wave mode at 450/620 nm, it's proportional to the HBsAg concentration in the serum/plasma. Immunoassay was performed using thermoshaker according to the Instruction for the DIA-HBsAg kit. Results of ELISA were considered at ratio of optical density (OD) to the cut off value (CO). Serum was considered positive at OD/CO >1,0 or negative at OD/CO < 1,0.
To confirm of HBsAg in test sera of the patients with hepatitis B we used ELISA kits — Immunite HBsAg (Diagnostic Products Corporation, USA), flC-I^A-HBsAg-0,01 (RPS Diagnostic systems, Russia), BeKTopren B-HBs-aHTnreH (RPS Vector-Best, Russia). The assays were carried out according to the instructions for use.
HBsAg standards
Second International standard HBsAg subtype adw2, genotype A (NIBSC, code
00/588) was diluted with blood serum from healthy donors which was previously tested for the absence of HBsAg, to concentrations of 0.02 IU/ml, 0.01 IU/ml, 0.006 IU/ml and 0.004 IU/ml.
Commercial standard flC-CO-HBsAg (Russia) was diluted by the manufacturer relative to the Second International standard HBsAg (NIBSC) to 20 IU/ml. The antigen was used in concentrations of 0.02 IU/ml, 0.01 IU/ ml, 0.006 IU/ml and 0.004 IU/ml.
Standard HBsAg Capricorn, subtypes ad and ay (USA) were diluted by blood serum without HBsAg to concentrations of 0.01 ng/ ml, 0.006 ng/ml and 0.004 ng/ml.
Test blood sera
The diagnostic sensitivity of DIA-HBsAg kit was determined using:
- standard serum panel HBsAg Low Titer Performance Panel (Modified) PHA 106 M (BBI), consisting of 15 samples, 14 of which with low concentrations of HBsAg and 1 (sample No. 7) was negative;
- standard serum panel HBsAg Mixed Titer Performance Panel PHA 206 (BBI) including of 25 samples, 23 of which with different HBsAg concentrations and 2 (No.1 and 25) negative;
- standard HBsAg Verification Panel VHA 601 (BBI), in which 5 sera were weakly positive for HBsAg and 1 (sample No.6) was negative;
- 22 blood sera patients with hepatitis B, 8 of which were additionally diluted by blood sera of healthy donors.
The specificity parameter of the test kit was studied using:
- 174 blood sera with cross-reactive components which can lead to false positives in analysis for hepatitis B, including:
30 samples with IgM/IgG to HCV;
32 samples with IgG to HSV1/2;
8 samples with IgM to HSV1/2;
16 samples with IgM/IgG to HSV1/2, IgM/ IgG to CMV;
16 samples with IgG to CMV;
24 samples with IgG to CMV, IgG to HSV1/2;
8 samples with IgM to CMV;
8 samples with IgM/ IgG to CMV, IgG to HSV1/2;
8 samples with IgM/IgG to CMV;
24 samples from pregnant women, and 1177 blood sera of nonselective donors.
The test kit specificity was calculated according to the following formula:
Specificity =
TN
-x!00%.
(1)
TN+FP
where TN is the amount of true negative results; FP is the amount of false positive results.
In the tables and pictures the results of typical experiment are presented.
Results and Discussion
The investigation in the DIA-HBsAg kit different commercial standards of the surface antigen of hepatitis B virus established that it detects Second International standard HBsAg (NIBSC) and Russian standard flC-CO-HBsAg, diluted by it, in concentration
0.006 IU/ml (Table 1). Test kit was able to detect the standard HBsAg Capricorn subtype ad at 0.006 ng/ml and the subtype ay at 0.004 ng/ml.
To determine diagnostic sensitivity of the DIA-HBsAg kit, we tested samples from serum panel PHA 106 M (BBI) with low concentrations of HBsAg (Figure).
Analysis results in commercial test kits were taken from the passport on the panel. The DIA-HBsAg kit identified all 14 sera with
Table 1. Performance of DIA-HBsAg kit in tests on various HBsAg standards
HBsAg standards HBsAg concentration ELISA results OD/CO
Second International standard HBsAg (NIBSC, code 00/588) 0.02 IU/ml 3.4
0.01 IU/ml 1.8
0.006 IU/ml 1.1
0.004 IU/ml 0.7
flC-CO-HBsAg 0.02 IU/ml 3.7
0.01 IU/ml 1.9
0.006 IU/ml 1.2
0.004 IU/ml 0.8
Standard HBsAg Capricorn (USA):
Subtype ad 0.01 ng/ml 1.7
0.006 ng/ml 1.0
0.004 ng/ml 0.7
Subtype ay 0.01 ng/ml 3.0
0.006 ng/ml 1.9
0.004 ng/ml 1.2
£0 45 40 35 30
O
y 35 □
o
20
r \
—•—Abbott Architect ■ BioRad Momofisa Murex HBsAg 3.0 Roche COBAS
11 A A-A
1 2 3 4 5 6 7 > 9 ti It 12 13 14 15 No. serum
Comparative analysis results HBsAg Low Titer Performance Panel (Modified) PHA 106 M (BBI) in different
ELISA kits (P < 0.05)
HBsAg as positive with high OD/CO ratio (11.9-40.7), and the one without HBsAg as negative. The data showed the ability of the DIA-HBsAg kit to identify low concentration of HBsAg to be significantly higher than in test kits comparing leading foreign manufacturers (Abbott Architect, BioRad Monolisa Plus, Murex HBsAg 3.0, Roche COBAS).
Table 2 presents the results for PHA 206 (BBI) serum panel with 25 samples containing various ratios of HBV DNA and HBsAg (23 samples) or negative for HBV (No.1 and
25) according to the panel passport. The data on commercial kits were taken from the panel's passport. The DIA-HBsAg kit revealed the HBV surface antigen in all positive samples not inferior in its diagnostic ability to commercial analogues. A false-negative result was obtained in the analysis of serum No. 22 in the Roche COBAS kit, while Murex HBsAg 3.0 and DIA-HBsAg identified this sample positive with OD/CO ratio of 1.9 and 8.9 respectively.
The qualitative parameters of industrially-manufactured ELISA kits
Table 2. Results of identification of the antigen in samples of HBsAg Mixed Titer Performance Panel PHA 206 (BBI) using various test systems
Sample № Test system
HBV DNA PCR Roche Amplicor Monitor Roche COBAS Murex HBsAg 3.0 DIA-HBsAg
results
copies/ml OD/CO
1 <300 0.1 0.4 0.3
2 >2xl05 59.0 >max 40.9
3 >2xl05 47.4 35.9 42.5
4 >2xl05 74.5 >max 42.0
б >2xl05 74.5 >max 42.3
6 >2xl05 74.5 >max 41.1
7 2xl05 44.6 31.9 41.9
8 lxl05 25.3 26.1 46.4
9 2xl05 32.8 30.9 46.2
10 4xl04 10.8 11.5 39.5
11 7xl04 9.8 11.1 38.1
12 2xl05 16.0 15.3 38.7
13 lxl05 10.6 13.2 40.6
14 5xl03 7.8 7.4 42.4
15 5xl04 3.6 5.6 35.6
16 4xl03 4.9 4.8 36.7
17 <300 1.2 2.0 7.4
18 2xl04 2.2 3.6 43.2
19 6xl04 2.7 4.1 34.2
20 2xl04 4.6 5.2 40.0
21 2xl05 5.7 4.7 42.0
22 <300 0.5 1.9 8.9
23 5xl03 2.1 2.3 25.6
24 9xl02 1.2 1.6 16.6
25 <300 0.2 0.5 0.3
Table 3. Serum panel test results for HBsAg Verification Panel VHA 601 (BBI)
using DIA-HBsAg test kit
№ HBsAg analysis (from the panel passport) IEA results for DIA-HBsAg kit, OD/CO
1 Weakly positive 45.0
2 Weakly positive 43.5
3 Weakly positive 37.1
4 Weakly positive 35.4
5 Weakly positive 21.0
6 Negative 0.4
designed for diagnostics of various infections are determined using the special commercial verification serum panels. They allow to determine the ability of the ELISA kits to distinguish weakly positive samples from negative ones.
In our study, the diagnostic ability of the DIA-HBsAg kit was tested on the commercial serum verification panel VHA 601 (BBI). The panel included 6 samples of which 5 had low concentration of HBsAg and one was negative for HBV. DIA-HBsAg kit identified the surface antigen of HBV in all weakly positive blood sera with OD/CO 21.0-45.0 (Table 3). Sample No.6, without HBsAg, was identified as negative with OD/CO 0.4.
The high diagnostic capability of DIA-HBsAg for standard serological samples, including the ones with low HBsAg content, was further corroborated by testing clinical material obtained from hepatitis B patients (Table 4). We used 22 blood sera, pre-checked for HBsAg using commercial kits. To lower HBsAg content, 8 samples were diluted with sera of healthy donors after which the HBsAg in them was confirmed again.
In investigating of undiluted sera from hepatitis B patients OD/CO was 35.3-51.2. The value OD/OC barely changed (48.1-39.7) for sample No.1 and secondary samples obtained by its dilution 10 and 1000 times. In the analysis of weakly positive samples obtained after dilution of serum No. 13 in 150-1600 times, the ratio of OD/CO was in the range of 1.2-18.1.
Thus, research of diagnostic sensitivity of the DIA-HBsAg kit on standard serum panels and blood serum samples from patients with hepatitis B patients with different virus surface antigen titers showed the kit's ability to detect HBsAg in low concentrations common for the early stages of the disease.
The diagnostic specificity of the DIA-HBsAg kit was tested on 1177 sera of nonselective donors. The ability of the test kit to correctly analyze sera without HBsAg but with various cross-reactive reagents that can cause false positive results was established by testing the sera with specific antibodies to HCV, HSV1/2, CMV, and sera of blood of pregnant women (Table 5).
One sample was determined positive when investigated in DIA-HBsAg 1177 sera from nonselective donors from various units of the Ukrainian Blood Service. At the same time, flC-I^A-HBsAg-0,01 and BeKTopren B-HBs-aHTHreH identified it as negative. The kit's specificity, calculated according to formula 1, was 99.9%.
In the investigating of 174 sera with potential cross-reactivity in DIA-HBsAg kit was obtained single false positive result for 1 serum out of 8 studied with antibodies of class M to the herpes simplex virus. The specificity parameter in thise experiment was 99.4%.
Therefore, the DIA-HBsAg kit for detecting the main serological marker of hepatitis B — HBsAg, which appears early in the acute stage and persists in the chronic form, has a sufficiently high analytical and diagnostic ability. The ELISA kit employs amplificatory method of boosting a specific signal combined with high-polymer enzyme label. This construction allows to detect low HBsAg concentration - International standard HBsAg (NIBSC) in concentration 0.006 IU/ml, standard HBsAg Capricorn subtypes ad and ay in concentration 0.006 ng/ml and 0.004 ng/ml, respectively. Comparative research showed that DIA-HBsAg kit was able to detect small HBsAg concentrations more reliably than its leading foreign analogues produced by Abbott Architect, BioRad Monolisa Plus,
Table 4. Results of testing DIA-HBsAg kit against blood sera of hepatitis B patients
with varying HBsAg content
№ Serum (and dilution) Test kit IEA results in the DIA-HBsAg kit (OD/CO)
1 1 48.1
2 1 (1/10) 47.3
3 1 (1/100) 47.5
4 1 (1/1000) 39.7
5 2 45.2
6 3 Immulite HBsAg 48.5
7 4 46.0
8 5 45.5
9 6 47.6
10 7 43.4
11 8 35.3
12 9 37.8
13 10 48.7
14 11 ДС-IФА-HBsAg-0,01 39.1
15 12 48.2
16 13 38.3
17 13 (1/150) 18.1
18 13 (1/200) Векторгеп В- 12.7
19 13 (1/400) HBs-антиген, ДС-ИФА-HBsAg 3.9
20 13 (1/800) 1.9
21 13 (1/1600) 1.2
22 14 51.2
Table 5. Specificity values for DIA-HBsAg kit obtained analyzing sera with interferent components
from nonselective donors
Samples Number of samples Number of positive results Number of negative results Specificity
Interfering components in blood sera:
IgM/IgG to HCV 30 0 30
IgG to HSV1/2 32 0 32
IgM to HSV1/2 8 1 7
IgM/ IgG to HSV1/2 IgM/IgG to CMV 16 0 16
IgG to CMV 16 0 16
IgG to CMV IgG to HSV1/2 24 0 24
IgM to CMV 8 0 8
IgM/ IgG to CMV IgG to HSV1/2 8 0 8 99.4%
IgM/ IgG to CMV 8 0 8
Pregnant women's blood sera 24 0 24
Total: 174 1 173
Nonselective donors' blood sera 1177 1 1176 99.9%
Murex HBsAg 3.0, Roche COBAS. The high diagnostic ability of the kit was confirmed also by the results obtained for hepatitis B patients. The kit correctly distinguishes weakly positive sera of from negative ones. Testing 1177 sera of nonselective donors
established the DIA-HBsAg kit specificity to be 99.9%. The qualitative parameters of the kit allow it to be widely used in specific diagnostics of hepatitis B and to detect both early and chronic stages of the disease, making donated blood safer.
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Д1АГНОСТИЧНА ХАРАКТЕРИСТИКА
ELISA ТЕСТ-СИСТЕМИ ДЛЯ ВИЗНАЧЕННЯ ПОВЕРХНЕВОГО АНТИГЕНУ В1РУСУ ГЕПАТИТУ В
O. К. Киселъова1, Л. А. Ганова2, O. М. Чумак1, Т. Ю. Трохимчук1, В. Г. Сердюк1, М. Я. Ствак1 2
1ПрАТ «НВК «^апроф-Мед»», Кшв, Украша 21нститут мiкробiологiï i вiрусологiï iM. Д. К. Заболотного НАН Украши, Киïв
E-mail: ekiselova26@ukr.net
Метою роботи було визначити дiагностич-ну здатшсть iмуноензимноï тест-системи DIA-HBsAg (НВК «^апроф-Мед»), в якш принцип аналiзу засновано на б^тинстрептавщиновш амплiфiкацiï специфiчного сигналу. Дiагности-кум виявляе 2-й Мiжнародний стандарт HBsAg, субтип adw2, генотип A (NIBSC, code: 00/588) в концентраций 0,006 МО/мл, стандарт HBsAg Capricorn субтипу ad та ay (USA) — 0,006 нг/мл i 0,004 нг/мл ввдповвдно.
Шд час дослщження панелi сироваток PHA 106 M (BBI), 14 зразшв якоï мiстять низьк концентрацiï HBsAg, тест-система виявила його у вих позитивних сироватках з високим сшввщношенням ОГ/cut off —11,9-40,7.
За результатами аналiзу панелi сироваток PHA 206 (BBI) з рiзними концентрацiями HBsAg дiагностична здатнiсть тест-системи не поступалася ïï закордонним аналогам — Roche COBAS i Murex HBsAg 3.0.
Дiагностикум коректно розд^яв слабопо-зитивнi зразки верифiкацiйноï панелi VHA 601 (BBI) — ОГ/cut off 21,0-40,7 вщ негативного (ОГ/cut off — 0,4).
У процем дослщження 174 сироваток кров1 з кросреактивними компонентами на гепатит В отримано один хибнопозитивний результат тд час аналiзу 1 зразка з 8 дослщжених, якi метили IgM до HSV1/2. Специфiчнiсть тест-системи за результатами аналiзу 1177 донорiв станови-ла 99,9%.
Ключовi слова: iмуноензивна тест-система, дiагностика, гепатит В, аналогична i дiагнос-тична чутлив^ть, специфiчнiсть.
ДИАГНОСТИЧЕСКАЯ ХАРАКТЕРИСТИКА ELISA ТЕСТ-СИСТЕМЫ ДЛЯ
ОПРЕДЕЛЕНИЯ ПОВЕРХНОСТНОГО АНТИГЕНА ВИРУСА ГЕПАТИТА В
Е. К. Киселева1, Л. А. Ганова2, Е. Н. Чумак1, Т. Ю. Трохимчук1, В. Г. Сердюк1, Н. Я. Спивак1, 2
1ЧАО «НПК «Диапроф-Мед»», Киев, Украина 2Институт микробиологии и вирусологии им. Д. К. Заболотного НАН Украины, Киев
E-mail: ekiselova26@ukr.net
Целью работы было определение диагностической способности иммуноэнзимной тест-системы DIA-HBsAg (НПК «Диапроф-Мед»), в которой принцип анализа основан на биотинстрептавидиновой амплификации специфического сигнала. Диагностикум выявляет 2-й Международный стандарт HBsAg, субтип adw2, генотип A (NIBSC, code: 00/588) в концентрации 0,006 МЕ/мл, стандарт HBsAg Capricorn (USA) субтипы ad и ay — 0,006 нг/мл и 0,004 нг/мл соответственно.
При исследовании панели сывороток PHA 106 M (BBI), 14 образцов которой содержат низкие концентрации HBsAg, тест-система выявила его во всех положительных сыворотках с высоким соотношением ОП/cut off — 11,9-40,7.
По результатам анализа панели сывороток PHA 206 (BBI) с различными концентрациями HBsAg диагностическая способность тест-системы не уступала ее зарубежным аналогам — Roche COBAS и Murex HBsAg 3.0.
Диагностикум корректно разделял слабоположительные образцы верификационной панели VHA 601 (BBI) — ОП/cut off 21,0-40,7 от отрицательного (ОП/cut off — 0,4).
При исследовании 174 сывороток крови с кросс-реактивными компонентами на гепатит В получен один ложноположительный результат при анализе 1 образца из 8 исследованных, которые содержали IgM к HSV1/2. Специфичность тест-системы по результатам анализа 1177 доноров составила 99,9%.
Ключевые слова: иммуноэнзимная тест-система, диагностика, гепатит В, аналитическая и диагностическая чувствительность, специфичность.
