WO2012128658A1 - Procédé de fabrication d'un panel de sérums avec hbsag de sous-types ad et ay à des fins de contrôle de qualité du diagnostic de l'hépatite b - Google Patents

Procédé de fabrication d'un panel de sérums avec hbsag de sous-types ad et ay à des fins de contrôle de qualité du diagnostic de l'hépatite b Download PDF

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Publication number
WO2012128658A1
WO2012128658A1 PCT/RU2011/000317 RU2011000317W WO2012128658A1 WO 2012128658 A1 WO2012128658 A1 WO 2012128658A1 RU 2011000317 W RU2011000317 W RU 2011000317W WO 2012128658 A1 WO2012128658 A1 WO 2012128658A1
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WIPO (PCT)
Prior art keywords
hbsag
subtypes
samples
panel
sera
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PCT/RU2011/000317
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English (en)
Russian (ru)
Inventor
Александр Николаевич KAHEB
Талгат Сальманович БАКИРОВ
Наталья Сангиреевна ЧЕРЕПАНОВА
Ирина Викторовна ЮДИНА
Михаил Викторович ЛОСЕВ
Ольга Николаевна НАДТОЧИЙ
Original Assignee
Федеральное Бюджетное Учреждение Науки "Государственный Научный Центр Вирусологии И Биотехнологии "Beктop"
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Application filed by Федеральное Бюджетное Учреждение Науки "Государственный Научный Центр Вирусологии И Биотехнологии "Beктop" filed Critical Федеральное Бюджетное Учреждение Науки "Государственный Научный Центр Вирусологии И Биотехнологии "Beктop"
Publication of WO2012128658A1 publication Critical patent/WO2012128658A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/576—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis
    • G01N33/5761—Hepatitis B
    • G01N33/5764—Hepatitis B surface antigen
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the invention relates to a manufacturing technology for reference panels of serums containing antigens of the most dangerous viral infections, in particular hepatitis B virus (HBV) and can be used in medicine and biotechnology.
  • HBV hepatitis B virus
  • hepatitis B carriers with a very low concentration of HBsAg can be detected, in particular among individuals who are carriers of anti-HBc antibodies.
  • HBsAg subtypes in reference drugs in everyday work will expand the range of diagnosable markers and use these materials to detect HBsAg in blood products intended for transfusion or processing.
  • the closest technical solution is a method for preparing serum panels HBV DNA Genotype Performance Panel, developed in the laboratory of Boston Biomedical Inc. (USA) - BBI. This panel includes 10 samples with A-D genotypes (BBI Product catalog).
  • Samples 5 panels represent HBV DNA serum diluted in a pool of donor sera that do not contain markers of dangerous viral infections.
  • the technical result of the claimed invention is the creation of such a method of manufacturing a panel of sera to control the quality of diagnosis of hepatitis B, which provides samples
  • the specified technical result is achieved by the fact that a method of manufacturing a panel of serums with extremely low concentrations
  • 25 HBsAg AD and AY subtypes for quality control of the diagnosis of hepatitis B includes testing of donor sera by polymerase chain reaction for the presence of hepatitis B virus DNA, anti-HIV, anti-HCV and anti-HBs antibodies of non-specific binding of HBsAg, selection of donor serums that do not contain specific antibodies to the main markers of viral infections by the values of the effect of suppressing HBsAg (spike / recovery test) and having a negative result in an enzyme-linked immunosorbent assay, the manufacture of dilution solutions based on selected sera, certification monoprep subtypes of HBsAg AD and AY subtypes by enzyme-linked immunosorbent assay, titration in a diluting solution of samples
  • HBsAg plasma 100% antigens containing AD and AY subtypes of HBsAg are used.
  • the prepared samples of the serum panel with extremely low concentrations of HBsAg AD and AY subtypes are lyophilized to a residual moisture content of less than 2.0 mass. %
  • Samples of the serum panel with extremely low concentrations of HBsAg AD and AY subtypes are examined using a thermal degradation test to determine their shelf life.
  • Alignment of standard samples to the required concentration of HBsAg is carried out using dilution factors of the initial AY & AD subtypes calculated according to the equations of the calibration curves of AY & AD of HBsAg preparations in a diluting stabilized solution to the required concentration of HBsAg (0.1 IU / ml, 0.05 IU / ml and 0.01 IU / ml).
  • preparations with a content of HBsAg of up to 100% for the desired protein are used.
  • the following is a manufacturing chart for a serum panel with extremely low concentrations of HBsAg AY & AD subtypes. 1. Testing of samples of donor sera using the laboratory standard HBsAg to study the amount of suppression of the analytical signal by the components of the tested plasma. A dilution solution (PP) is prepared from donor serums with a minimum level of suppression for the manufacture of samples of a panel of serums with extremely low concentrations (PN) of HBsAg.
  • PP dilution solution
  • PP diluting solution
  • the HBsAg AD and AY subtypes include 8 samples: 2 samples of donor sera, 3 samples of AY subtype of HBsAg and 3 samples of AD subtype of HBsAg prepared by diluting samples in a stabilized pool of donor serums (PP) to a concentration of 0.1 IU / ml, 0.05 IU / ml and 0.01 IU / ml antigen.
  • PP donor serums
  • Concentrated preparations of AD and AY subtypes of HBsAg, but not native serums, are used to make samples of the serum panel.
  • the sera are treated with trypsin, filtered through 0.45 ⁇ m and 0.22 ⁇ m filters, high-speed centrifugation and concentration.
  • the resulting product called "purified plasma HBs antigen,” is certified for protein content and activity with anti-HBs antibodies.
  • the content of the desired HBsAg protein in such preparations exceeds 95%.
  • Proline has a powerful disintegrating potential that prevents the process of association of HBsAg monoparticles.
  • proline as a primary amino acid, does not introduce foreign ingredients into solutions (Voshn R., Woodtli K., Bartschi M. Et al. L-proline reduces IgG dimmer content and enhances the stability of intravenous immunoglobulin solutions // Biologicals 38 (2010), 150-157) [6].
  • Benzoic acid is a classic antioxidant used to stabilize medications and foods, exhibits antimicrobial and antifungal effects, and inhibits mold, yeast and certain types of bacteria.
  • the low viscosity of the stabilizer solution for a standard preparation is a critical parameter for the detection of HBsAg in practice, because many manufacturers of test systems are trying to reduce analysis time. Under these conditions, a decrease in diffusion inhibition of the MCA + HBsAg interaction process is of great importance, due primarily to a decrease in the solution viscosity (Kanev AN, Bakirov TS, Yudina IV and Zaitsev BN Simulation of interaction of particles HBsAg with antibodies immobilized on a surface of the microplate well at ELISA // Biotechnology, 2005, 6, 74-82) [7].
  • the panel serum certification procedure includes three stages, the results of which are independent and allow reliable identification of the concentration of various subtypes of HBs Ag.
  • HBsAg PNA serum panels prepared in accordance with the claimed method with analog panels of the same purpose showed that a combination of essential features that is different from the prototype provides a new previously unknown property: the possibility of manufacturing HBsAg panels in a dry (lyophilic) form with an extremely low certified the concentration of the main subtypes of HBsAg, which allows us to evaluate the sensitivity of the test systems at the level of 0.01 IU / ml and specificity to various subtypes of HBsAg, to control the level of professional asterstva employees clinical diagnostic laboratories and control the quantity of hepatitis B vaccine
  • FIG. 1 shows the weighted average AY & AD titration curves of HBsAg samples and the standard deviation curves ⁇ ⁇ ⁇ , where:
  • Yep is the average value of Ln OD
  • the total mean square error at the selected level is calculated (table 2) as the square root of the sum of the squares of the intra-group and inter-group errors. For example, for sample ⁇ ° 1, the in-group errors associated with titration errors in various laboratories are 4.25% (VB) and 9.22% (DS).
  • Example of a method for manufacturing a panel of serums with extremely low concentrations of HBsAg AY and AD subtypes Preparation of a dilution solution.
  • RR for the preparation of positive panel samples with a certain concentration of HBsAg, donor sera that do not contain markers of viral infections are used.
  • Serum is prepared immediately after blood sampling. Whole blood is centrifuged at a speed of 2800-3200 * rpm at a temperature of 10 - 12 ° C for 15 minutes and the supernatant is decanted. Store until use at a temperature of + (2 - 4) ° C.
  • samples of 20 amber-colored sera are taken, which are transparent in the light. A total of 9 high-quality sera were selected.
  • the stabilizer (stabilizing additive) according to the following recipe.
  • To 1 l of the pool of donor serums add 250 mm L- proline and 0.07% benzoic acid to you as an antioxidant.
  • the pool is adjusted to a pH of 6.8-7.1 with 0.1 M NaCl.
  • As a bactericidal additive merthiolate is introduced in an amount of 0.01% and gentamicin - 0.2% by weight of the solution.
  • PP is poured into containers of 250 cm 3 and used immediately or stored at a temperature of (2-8) ° C for no more than 1 month.
  • Table 2 shows the weighted average titration curves of the AD sample of HBsAg (Fig. 1)
  • test system "DS-IFA-HBsAg" (DS)
  • the drug was diluted in PP with 0.05 M FSB during titration.
  • HBsAg preparations of each subtype must be introduced into PP so that the final antigen concentration is 0.1 IU / ml, 0.05 IU / ml and 0.01 IU / ml. Findings. Based on the measurements, the concentration of the ad-subtype of HBsAg in a 100% preparation in ME is approximately 6 ME.
  • HBsAg subtype AD preparation (Genelab Diagnostics, Singapore) is used.
  • AY HBsAg samples are prepared from the HBsAg AY subtype preparation (NPK Preparation, NN) with a concentration of 0.1 IU / ml 0.05 IU / ml and 0.01 IU / ml. Adjustment of standards is performed using test systems.
  • HBsAg - ELISA - Best - 0.01 and "DS - ELISA - HBsAg - 0.01" by the addition of either HBsAg or PP.
  • the total standard error of the AY preparations at the selected level is calculated in the same way as the square root of the sum of the intragroup and intergroup variances.
  • the intragroup dispersions associated with the titration error in various laboratories are 4.95% and 5.03%.
  • the standard error of the selected level ⁇ ( ⁇ ) 0.1 ME is
  • Filtered HBsAg PNA samples are poured in a 0.5 ml laminar cabinet into 2 ml vials, closed with rubber stoppers and placed in metal cassettes for freezing.
  • the drug in bottles is frozen at a counter temperature of 50-60 ° C for 10-12 hours.
  • Frozen samples in bottles are transferred to the sublimation chamber of the TG-50 lyophilic unit, the shelves of which are cooled to minus 32 ° C.
  • the temperature of the drug at the stage of sublimation dehydration maintain below its glass transition temperature (-30 ° C).
  • the compressor of the installation for cooling the desublimator and the shelves of the drying chamber is turned on. On each of the five shelves placed on a cassette with bottles, one of which is frozen in a sensor for measuring the temperature of the material.
  • the set temperature on everything 5 during the drying is supported automatically with an accuracy of 1-3 degrees.
  • the temperature values of each shelf, the temperature of the material on each shelf, as well as the temperature of the sublimator are constantly recorded by the KP-35 recorder.
  • the temperature of the material at the time of switching on the vacuum pump must not exceed minus 30 ° C.
  • the average heating rate of the material at the second stage of drying is 6 ° ⁇ / min, thermostating time at 27 ° ⁇ is 10 hours.
  • the bottles with the preparation are capped under vacuum. Monitoring the end of the drying process is carried out according to the readings of the residual pressure sensor. Freeze-dried preparation has a residual water content of about 1.0 - 1.5 wt.%. The determination is carried out according to the method
  • thermogravimetry The total average drying time is 32 hours
  • a pooled sample of lyophilized candidates for AY & AD subtypes was investigated in an accelerated thermal degradation test.
  • the samples were thermostatically controlled under conditions of controlled temperature at -20 ° C, + 4 ° C + 37 ° C and + 50 ° C; they were removed at regular intervals,
  • the predicted loss of activity per month is approximately 4.4% at 37 ° C.
  • Table 4 shows the forecast activity of samples of HBsAg PNA for the proposed method based on accelerated tests at elevated storage temperatures.
  • Subtype HBsAg AY & AD is used as a prognostic marker of hepatitis B. It circulates in the blood of infected people 2-3 weeks earlier than antibodies appear. The earlier detection of HBsAg with increased sensitivity of test systems helps to reduce the time needed to diagnose infected patients. Earlier medical care and controlled by the number and subtypes of HBsAg are socially significant cost-effectiveness associated with reducing the time of treatment of people. The introduction of the Russian panel of serum PNA HBsAg, obtained by the claimed method, will significantly reduce the costs of the control organizations of health care for the purchase of expensive foreign analogues.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Cell Biology (AREA)
  • Genetics & Genomics (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne la biotechnologie. Le procédé de fabrication d'un panel de sérums à concentration basses attestées de sous-types AD et AX de l'antigène HBs destiné à contrôler la qualité du diagnostic de l'hépatite B comprend la sélection de sérums de donneur ne comportant pas d'anticorps spécifiques aux marqueurs principaux d'infections virales sur la base de détermination de l'effet de suppression HBsAg et l'essai immuno-enzymatique, la production de solutions de dilution sur la base des sérums sélectionnés, l'attestation des monopréparations HBsAg de sous-types AD et AY au moyen de l'essai immuno-enzymatique, le titrage des solutions de dilution des échantillons des monopréparations indiquées dans l'intervalle de 0,01 et 0,5 ME/ml par rapport aux normes internationales et leur analyse statistique avec une détermination subséquente du nombre de monopréparations HBsAg de chaque sous-type qui est nécessaire à l'obtention d'une concentration finale désirée de l'antigène et la fabrication d'un panel de sérums par la dilutions dans les solutions de dilution des monopréparations HBsAg de sous-types AD et AY jusqu'aux concentrations finales 0,1; 0,05 et 0,01 ME/ml selon les données des courbes d'échantillonnage.
PCT/RU2011/000317 2011-03-22 2011-05-10 Procédé de fabrication d'un panel de sérums avec hbsag de sous-types ad et ay à des fins de contrôle de qualité du diagnostic de l'hépatite b WO2012128658A1 (fr)

Applications Claiming Priority (2)

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RU2011110828/10A RU2463610C1 (ru) 2011-03-22 2011-03-22 СПОСОБ ИЗГОТОВЛЕНИЯ ПАНЕЛИ СЫВОРОТОК С HBsAg AD- И AY-СУБТИПОВ ДЛЯ КОНТРОЛЯ КАЧЕСТВА ДИАГНОСТИКИ ГЕПАТИТА В
RU2011110828 2011-03-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020176620A1 (fr) * 2019-02-26 2020-09-03 Tempus Systèmes et procédés d'utilisation de données de séquençage pour la détection de pathogènes
CN112146955A (zh) * 2020-09-23 2020-12-29 深圳市亚辉龙生物科技股份有限公司 血清的制备方法
CN114200139A (zh) * 2021-12-01 2022-03-18 首都医科大学附属北京朝阳医院 一种癌胚抗原参考物质准确赋值的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2265028C2 (ru) * 2003-11-06 2005-11-27 Государственный научный центр вирусологии и биотехнологии "Вектор" СПОСОБ ИЗГОТОВЛЕНИЯ КОНТРОЛЬНОЙ ПАНЕЛИ СЫВОРОТОК AY ЭНД AD СУБТИПОВ HBsAg ДЛЯ КОНТРОЛЯ КАЧЕСТВА ДИАГНОСТИКИ ГЕПАТИТА B
KR20090059772A (ko) * 2007-12-07 2009-06-11 주식회사 제이에스마루 혈장크린접착제 및 이의 제조방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
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RU2265028C2 (ru) * 2003-11-06 2005-11-27 Государственный научный центр вирусологии и биотехнологии "Вектор" СПОСОБ ИЗГОТОВЛЕНИЯ КОНТРОЛЬНОЙ ПАНЕЛИ СЫВОРОТОК AY ЭНД AD СУБТИПОВ HBsAg ДЛЯ КОНТРОЛЯ КАЧЕСТВА ДИАГНОСТИКИ ГЕПАТИТА B
KR20090059772A (ko) * 2007-12-07 2009-06-11 주식회사 제이에스마루 혈장크린접착제 및 이의 제조방법

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Title
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REINHARD BOLLI ET AL.: "L-Proline reduces IgG dimer content and enhances the stability of intravenous immunoglobin (IVIG) solutions", BIOLOGICALS, vol. 38, 2010, pages 150 - 157 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020176620A1 (fr) * 2019-02-26 2020-09-03 Tempus Systèmes et procédés d'utilisation de données de séquençage pour la détection de pathogènes
US11043304B2 (en) 2019-02-26 2021-06-22 Tempus Labs, Inc. Systems and methods for using sequencing data for pathogen detection
CN112146955A (zh) * 2020-09-23 2020-12-29 深圳市亚辉龙生物科技股份有限公司 血清的制备方法
CN114200139A (zh) * 2021-12-01 2022-03-18 首都医科大学附属北京朝阳医院 一种癌胚抗原参考物质准确赋值的方法

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