CN114585920A - Kit and method for screening TORCH infection and immunoassay instrument - Google Patents
Kit and method for screening TORCH infection and immunoassay instrument Download PDFInfo
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- CN114585920A CN114585920A CN201980101478.4A CN201980101478A CN114585920A CN 114585920 A CN114585920 A CN 114585920A CN 201980101478 A CN201980101478 A CN 201980101478A CN 114585920 A CN114585920 A CN 114585920A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/76—Chemiluminescence; Bioluminescence
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- 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
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- 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
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
Abstract
A kit for screening for TORCH infection comprising a capture mixture mixed with at least two antigens selected from the group consisting of: toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, herpes simplex virus 1/2 type antigens, parvovirus Bl9 antigens, coxsackievirus antigens, and herpes zoster virus antigens; and an anti-human IgM antibody carrying a label. The kit can detect IgM antibodies caused by various different pathogenic microorganisms in a sample to be detected, and evaluate risks according to a mixed detection result. In addition, the invention also relates to an immunoassay method and an immunoassay instrument for screening the TORCH infection.
Description
The invention relates to the field of immunoassay, in particular to an analysis mode for Torch screening.
TORCH refers to an acronym for english name for a group of pathogenic microorganisms. T represents Toxoplasma gondii or Toxoplasma gondii; o represents other pathogenic microorganisms such as herpes zoster virus, parvovirus B19, coxsackie virus and the like; r represents rubella virus; c represents cytomegalovirus; and H represents herpes simplex virus type I and type II. This group of pathogens can be transmitted to the fetus via the placenta, causing perinatal infection, and there is a risk of various abnormal results resulting in abortion, stillbirth, premature birth, congenital malformation and intellectual disability, so antibody test for TORCH infection has gradually become a routine project for pregnancy test.
In the TORCH assay, a negative IgG antibody for the group of pathogens indicates that the subject is not infected or infected but does not produce antibodies; a negative IgM antibody for this group of pathogens indicates that the subject has no active infection, but does not exclude potential infections. A positive IgG antibody to a pathogen indicates that the subject has been infected with the pathogen or vaccinated with the corresponding vaccine; if the IgM antibody of a pathogen is positive, the test subject has active infection of the virus recently, and the test subject is acute infection and has higher risk.
At present, because of a plurality of detection items of TORCH, the cost of performing comprehensive examination is high, the time consumption is long, and difficulties are brought to popularization of TORCH screening.
Accordingly, there is a strong need for low-cost, high-efficiency detection of TORCH infection in the field of pregnancy screening.
Disclosure of Invention
In order to solve the problems of high cost and long time consumption of the current TORCH examination. Based on the detection characteristics of the TORCH infection, the invention provides a novel mixed detection mode through research.
In a first aspect, the present invention provides a kit comprising:
a capture mixture comprising at least two antigens selected from the group consisting of: toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, herpes simplex virus 1/2 type antigens, parvovirus B19 antigens, coxsackie virus antigens, and herpes zoster virus antigens; and
anti-human IgM antibody with a label.
The kit of the present invention coats at least two antigens required for the Torch detection on the solid phase carrier, and includes an anti-human IgM antibody with a label, thereby enabling the simultaneous mixed detection of a plurality of IgM in the Torch detection. In other words, a mixed detection result can be finally obtained by using the kit provided by the invention, and the infection risks of multiple pathogenic microorganisms in the TORCH can be simultaneously evaluated, so that the screening efficiency is improved. That is, when the test kit provided by the first aspect of the present invention is used to test a subject, a mixed test result is obtained, and if the mixed test result is negative, it indicates that the subject does not have active infection by at least two pathogenic microorganisms; if the mixed test result is positive, which indicates that the subject has active infection of at least one pathogenic microorganism recently, further screening for infection of each pathogenic microorganism individually may be suggested. Therefore, the efficiency of primary screening can be greatly improved.
In some embodiments, the at least two antigens are coated on the same solid support.
In other embodiments, the at least two antigens are coated on separate solid supports.
In a specific embodiment, the concentration of the labeled anti-human IgM antibody and the concentration of each antigen coated on the solid phase carrier are designed such that the luminescence threshold values corresponding to each antigen coated on the solid phase carrier and the internal reference (e.g., the internal reference defined according to ISO 1183-1: 2004 standard) of the anti-human IgM antibody are substantially the same when the antigen coated on the solid phase carrier and the internal reference are detected in the same reaction system.
In an exemplary embodiment, the luminescence threshold is determined by a ROC curve.
In particular embodiments, the capture mixture comprises toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, and herpes simplex virus 1/2 antigens coated on a solid support.
In particular embodiments, the capture mixture comprises toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, herpes simplex virus 1/2 type antigens, and parvovirus B19 antigens coated on a solid support.
In a specific embodiment, the capture mixture comprises parvovirus B19 antigen, coxsackievirus antigen, and herpes zoster virus antigen coated on a solid support.
In particular embodiments, the capture mixture comprises a toxoplasma antigen, a rubella virus antigen, a cytomegalovirus antigen, a herpes simplex virus 1/2 type antigen, a parvovirus B19 antigen, a coxsackievirus antigen, and a herpes zoster virus antigen coated on a solid support.
The kit of the present invention may further comprise instructions describing that when the corresponding pathogen is detected using at least two antigens on the capture mixture and the anti-human IgM antibody with a label, a positive result is determined in the case where the ratio of the mixed detection value to the luminescence threshold value is 1.1 or more.
In particular embodiments, the instructions further recite that when a positive result is determined, further testing for the pathogen to which each of the at least two antigens corresponds is recommended.
In a second aspect, the present invention provides an immunoassay method comprising the steps of:
mixing a sample to be detected with a solid phase carrier coated with at least two antigens of toxoplasma gondii antigen, rubella virus antigen, cytomegalovirus antigen, herpes simplex virus 1/2 antigen, parvovirus B19 antigen, coxsackie virus antigen and herpes zoster virus antigen, and incubating for a period of time, so that the at least two antigens coated on the solid phase carrier can be combined with IgM antibodies corresponding to the at least two antigens in the sample to be detected;
washing the mixture of the sample to be detected and the solid phase carrier to remove unbound substances;
adding a labeled anti-human IgM antibody to the washed mixture and incubating so that the labeled anti-human IgM antibody can bind to IgM antibodies corresponding to the at least two antigens bound to the solid phase carrier to form a complex;
washing the complex to remove unbound material;
and adding a luminescent substrate into the washed complex to detect a mixed detection value of the IgM antibodies corresponding to the at least two antigens in the sample to be detected.
In some embodiments, the concentration of the labeled anti-human IgM antibody and the concentration of each antigen coated on the solid support are designed such that the corresponding luminescence threshold is substantially the same when each antigen coated on the solid support and the anti-human IgM antibody are used to detect the internal reference individually in the same reaction system.
In some embodiments, the at least two antigens coated on the solid support are added to the test sample separately for mixing and incubation, or added to the test sample in a pre-mixed form for mixing and incubation.
In particular embodiments, the at least two antigens are toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, and herpes simplex virus 1/2 type antigens.
In specific embodiments, the at least two antigens are toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, herpes simplex virus 1/2-type antigens, and parvovirus B19 antigens.
In a specific embodiment, the at least two antigens are a parvovirus B19 antigen, a coxsackievirus antigen, and a herpes zoster virus antigen.
In specific embodiments, the at least two antigens are toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, herpes simplex virus 1/2-type antigens, parvovirus B19 antigens, coxsackie virus antigens, and herpes zoster virus antigens.
In specific embodiments, when a positive result is determined, the method further comprises the step of separately detecting the pathogen to which each of the at least two antigens corresponds.
In a third aspect, the present invention provides a sample analyzer for selectively detecting different types of IgM antibodies in a blood sample, comprising:
the sample device is provided with a sample storage component and a sample separate injection component, the sample storage component is used for storing a sample to be tested, and the sample separate injection component is used for sucking the sample to be tested and discharging the sample to be tested into a reaction cup to be added with sample;
the reagent device is provided with a reagent storage component and a reagent dispensing component, the reagent storage component is used for storing a reagent box, the reagent box comprises a solid phase reagent and a marking reagent, the solid phase reagent comprises solid phase components coated with at least two antigens of toxoplasma gondii antigen, rubella virus antigen, cytomegalovirus antigen, herpes simplex virus 1/2 type antigen, parvovirus B19 antigen, coxsackie virus antigen and herpes zoster virus antigen, the marking reagent comprises an anti-human IgM antibody with a marker, and the reagent dispensing component is used for sucking the solid phase components and the marking reagent in the reagent box stored on the reagent storage component and discharging the solid phase components and the marking reagent in a reaction cup to which the reagent is added;
a luminescent substrate dispensing device which is connected with a container for storing luminescent substrates and is used for injecting the luminescent substrates into a reaction cup to which the luminescent substrates are added;
a reaction device having a plurality of placement positions for placing the reaction cups and for incubating the reaction solution in the reaction cups;
the light measurement component is used for performing light measurement on the incubated reaction liquid to obtain a detection result of the sample to be detected;
a control device electrically connected to the sample device, the reagent device, the luminescent substrate dispensing device, and the photometric element, and configured to:
receiving a test instruction, wherein the test instruction comprises the type of the IgM antibody to be tested;
in response to the test instruction:
controlling the sample dispensing component to add the sample to be detected in the sample storage component into a reaction cup on the reaction device;
controlling the reagent separate injection component to add the solid phase component corresponding to the type of the IgM antibody to be detected into a reaction cup on the reaction device, so that the sample to be detected and the solid phase component are mixed in the reaction cup and incubated for a period of time, and the antigen coated on the solid phase component can be combined with the IgM antibody to be detected in the sample to be detected;
controlling the reagent dispensing component to further add a labeled reagent into the reaction cup, so that the labeled reagent is mixed with the mixture in the reaction cup and incubated for a period of time, and the labeled reagent can be combined with the IgM antibody to be detected bound on the solid phase component;
controlling the luminescent substrate dispensing device to add a luminescent substrate into the reaction cup; and
and obtaining a detection result according to the ratio of the luminous value measured in the optical measurement component to the luminous threshold value.
In some embodiments, the at least two antigens coated on the solid phase component are present in the kit in a separate aliquot or in a pre-mixed form.
In some embodiments, the kit is a kit provided by the first aspect of the invention.
In a fourth aspect, there is provided the use of the solid phase reagent and the labelled reagent of the invention in the preparation of a kit for a Torch assay.
By adopting the scheme to carry out mixed detection on a plurality of IgM in a sample to be detected, the invention realizes the evaluation of a plurality of infection risks based on one obtained detection result, thereby greatly improving the Torch detection evaluation efficiency, shortening the average detection time, reducing the detection cost and being beneficial to the popularization of Torch screening. On the other hand, the embodiment of the invention can selectively screen the items involved in the Torch detection according to the needs, thereby further improving the application range and flexibility during detection.
FIG. 1 shows a schematic diagram of an immunoassay system according to an embodiment of the present invention;
fig. 2 shows a schematic configuration diagram of a control device according to an embodiment of the present invention.
The present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that these specific embodiments and examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.
Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.
As described above, aiming at the problems of multiple items and high cost of the current Torch detection, the invention provides a multiple IgM antibody evaluation mode based on a capture mixture, which can realize the evaluation of multiple infection risks based on only one mixed detection result, and improve the screening efficiency. For example, when the test result obtained by the method of the invention is negative, the test result indicates that all pathogen IgM items detected in a mixed way are negative, and the risk is lower; if the result is positive, at least one pathogen IgM in the mixed detection is positive, and further examination is recommended. Therefore, the screening efficiency of the Torch detection is improved, the detection time is shortened, and the problems of high cost and limited popularization of the Torch detection are solved.
In embodiments of the invention, the terms "solid phase support", "solid support" and "solid support" are used interchangeably and refer to a solid surface to which an antigen or antibody can be attached. The solid phase carrier to be used in the present invention is not particularly limited, and commercially available solid phase carriers and any solid phase carrier usable for immunoassay can be used in the present invention. Exemplary solid supports may be magnetic beads (e.g., carboxyl magnetic beads), microplate, plastic plate, plastic tube, latex beads, agarose beads, glass, nitrocellulose membrane, nylon membrane, silica plate, or microchip, but the present invention is not limited thereto.
In an embodiment of the invention, the term "capture mixture" means that it comprises at least two antigens coated on a solid support and that the at least two antigens coated on a solid support are present in the kit in a mixed form.
In an embodiment of the invention, the at least two antigens may be coated on the solid support by: in one aspect, each antigen can be coated on a different solid support separately, followed by mixing the antigen-coated solid supports. For example, parvovirus B19 antigen, coxsackievirus antigen, and herpes zoster virus antigen can be coated separately on solid supports and subsequently mixed together. Alternatively, the at least two antigens may be divided into one or more groups, each group comprising one or more antigens, each group of antigens being separately coated with a different solid support, and the antigen-coated solid supports being subsequently mixed, e.g. an antigen of the herpes simplex virus type 1/2 being typically coated on the same solid support during the coating process.
Labels useful in embodiments of the invention are well known to those skilled in the art, and include, for example, enzymes such as alkaline phosphatase (ALP), oxidase, microperoxidase, horseradish peroxidase, beta-galactosidase, glucose oxidase, and glucose 6-phosphate dehydrogenase; fluorescent substances such as fluorescein isothiocyanate, tetramethylrhodamine isothiocyanate, fluorescein, rhodamine, europium and green fluorescent protein; chemiluminescent substances such as luminol, isoluminol, phenanthridinium, and acridinium esters; coenzyme such as NAD; biotin;35S、 14C、 32P、 131i and125i, etc., but the present invention is not limited thereto.
One skilled in the art will be able to select an appropriate luminescent substrate, depending on the type of label used, to generate a detectable signal. For example, when alkaline phosphatase is used as the label, 3- (2-spiroadamantane) -4-methoxy-4- (3-phosphoryloxy) -phenyl-1, 2-dioxetane is used as a luminescent substrate, which is decomposed by alkaline phosphatase to remove a phosphate group, thereby producing an unstable intermediate product, which produces a methyl-metaborate anion through intramolecular electron transfer, and produces chemiluminescence when the methyl-metaborate anion in an excited state returns from the excited state to the ground state. And measuring the number of photons generated in the reaction by a photomultiplier, wherein the amount of the generated photons is in direct proportion to the content of the detection object in the sample.
The embodiment of the invention is suitable for ELISA, chemiluminescence, electrochemiluminescence, POCT, immunochromatography, up-conversion luminescence, down-conversion luminescence and other methods, and the adopted antigen is a recombinant antigen or a natural antigen.
In the scope of the present invention, the term roc (receiver operating characteristics) curve refers to a curve obtained by dividing the diagnostic test result into several critical points, and plotting the sensitivity corresponding to each critical point as the ordinate and the specificity as the abscissa. The ROC curve is an effective tool for comprehensively and accurately evaluating a diagnostic test. Another function of the ROC curve is to determine the optimal threshold for detection. The ROC curve method determines that the critical point is the best by selecting a point on the curve as close to the upper left as possible under most conditions. In application, according to an ROC curve, the sensitivity and specificity of each tangent point are combined, and the tangent point which is as close to the upper left Youden index (Youden index) on the curve as possible is selected as the optimal critical point, so that the sensitivity and specificity of the test are high, and the misdiagnosis rate and the missed diagnosis rate are low.
The detection mode of the embodiment of the invention allows the personalized Torch screening scheme to be formulated for the individual to be tested, thereby providing a more flexible screening means. For example, when routine screening of individuals to be tested is required, solid phase carriers coated with toxoplasma gondii antigen, rubella virus antigen, cytomegalovirus antigen and herpes simplex virus 1/2 antigen can be used; for another example, when comprehensive detection is required, a solid phase carrier coated with toxoplasma gondii antigen, rubella virus antigen, cytomegalovirus antigen, herpes simplex virus 1/2 type antigen, parvovirus B19 antigen, coxsackie virus antigen and herpes zoster virus antigen; for another example, when the individual to be tested has previously received one or more tests in the Torch test, the solid phase carrier coated with the antigens corresponding to the other items can be used, so that personalized item selection can be flexibly provided for the person to be tested, and the application range in the test is widened.
When used to prepare a solid phase reagent, the antigens of the embodiments of the invention can be present, for example, in the form of multimers, recombinant antigens, antigen fragments, or antigenic peptides.
When used to prepare solid phase reagents and/or labelled reagents. The antibody according to the embodiment of the present invention may be present in the form of, for example, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a chimeric antibody, a humanized antibody, or an antigen-binding fragment of an antibody.
In the embodiments of the present invention, "mixed detection value", "mixed detection result", and "one detection result" may be used interchangeably to refer to a detection result obtained by using the kit, method, and system of the present invention. For example, when alkaline phosphatase is used as the marker, the detection result is a luminescence value.
In the embodiment of the present invention, the result is determined to be positive or negative by mixing the ratio (COI value) of the detection value to the luminescence threshold value. For example, when the ratio is 1.1 or more, the determination result is positive, indicating that the detection result of the IgM antibody corresponding to at least one pathogen is positive. When the ratio is between 0.9 and 1.1, judging that the result is a gray area and determining that the gray area is not positive or negative; when the ratio is less than 0.9, the judgment result is negative, which indicates that the IgM antibodies of the aimed items are all negative.
In the embodiment of the invention, the concentration of the anti-human IgM antibody with the marker and the concentration of each antigen coated on the solid phase carrier are designed so that the corresponding luminescence threshold values are basically the same when the internal reference substance is detected by each antigen coated on the solid phase carrier and the anti-human IgM antibody separately in the same reaction system.
In an embodiment of the invention, an "internal reference" refers to the standard and basis for the determination of the composition of the reaction system, which has the definition as in international standard ISO 18113-1:2009 and is available according to this standard. The internal reference is a sample used for verifying the product performance by a medical instrument producer, and is the most important determination standard and basis for selecting, preparing, identifying and determining raw material quality standards, determining a product production process, and reacting system compositions, reaction conditions and the like. For qualitative items, an identified sample of an internal business reference is a sample of a value or quantity that determines the limit of the presence or absence of a particular disease, condition, or measurement.
In embodiments of the invention, "substantially the same" means that the relative deviation is within ± 10%, such as within ± 5%, within ± 2%, or within ± 1%.
The present invention is not particularly limited with respect to the concentration of the labeled anti-human IgM antibody, and an exemplary concentration may be about 0.5. mu.g/mL to about 5. mu.g/mL.
In the embodiment of the present invention, the concentration of the solid phase carrier coated with a toxoplasma antigen, the solid phase carrier coated with a rubella virus antigen, the solid phase carrier coated with a cytomegalovirus antigen, the solid phase carrier coated with a herpes simplex virus 1/2-type antigen, the solid phase carrier coated with a parvovirus B19 antigen, and the solid phase carrier coated with a coxsackie virus antigen may be, for example, 0.1 to 0.3 mg/mL.
In the embodiment of the present invention, the concentration of the solid carrier coated with the herpes zoster virus antigen may be, for example, 0.1 to 0.4 mg/mL.
In an exemplary embodiment, the concentration of the anti-human IgM antibody with a label is about 1.0 μ g/mL, and the adjusted luminescence threshold is 30000, the solid-phase carrier coated with toxoplasma antigen (e.g., magnetic microsphere), the solid-phase carrier coated with rubella virus antigen, the solid-phase carrier coated with cytomegalovirus antigen, the solid-phase carrier coated with herpes simplex virus 1/2 type antigen, the solid-phase carrier coated with parvovirus B19 antigen, the solid-phase carrier coated with herpes zoster virus antigen, and the solid-phase carrier coated with coxsackie virus antigen have the following concentrations: 0.15mg/mL, 0.12mg/mL, 0.2mg/mL, 0.15mg/mL, 0.12 mg/mL.
In the present invention, the anti-human IgM antibody with a label may be derived from mouse, rabbit, goat, sheep, chicken, but the present invention is not limited thereto.
As shown in fig. 1, the present embodiment provides an immunoassay instrument that can selectively detect IgM antibody types in a blood sample. The immunoassay analyzer comprises a sample device 10, a reagent device 20, a reaction device 30, a photometric component 40 and a control device 50. The immunoassay analyzer may further include a display unit (not shown).
The sample device 10 is used for carrying a sample to be tested, and the sample is provided to the reaction device 30 after being sucked. The sample apparatus 10 includes a sample storage unit 11 and a sample dispensing unit 12. The sample storage unit 11 is used for storing a sample to be measured. In some embodiments, the Sample storage unit 11 may include a Sample Delivery Module (SDM) and a front track. In other embodiments, the sample storage unit 11 may also be a sample tray, the sample tray includes a plurality of sample sites for placing samples such as sample tubes, and the sample tray can dispatch the samples to corresponding positions by rotating the tray structure, for example, the position for the sample dispensing unit 12 to suck the samples. The sample dispensing member 12 is used to suck a sample and discharge the sample into a reaction cup to be loaded. The sample dispensing member 12 may include, for example, a sample needle that performs a two-dimensional or three-dimensional motion in space by a two-dimensional or three-dimensional driving mechanism, so that the sample needle can be moved to aspirate a sample carried by the sample storage member 11 and to a cuvette to be loaded and discharge the sample to the cuvette.
The reagent device 20 is used for carrying a reagent, and sucking the reagent and supplying the reagent to the reaction device 30. The reagent apparatus 20 includes a reagent storage unit 13 and a reagent dispensing unit 14. The reagent storage part 13 is used for storing the reagent cartridge. In some embodiments, the reagent storage component 13 may be a reagent disk, which is configured in a disk-shaped structure and has a plurality of positions for holding reagent containers, and the reagent storage component 13 can rotate and drive the reagent containers held by the reagent storage component to rotate to a specific position, for example, a position for sucking reagent by the reagent dispensing component 14. The number of the reagent storage part 13 may be one or more. The reagent dispensing unit 14 is used for sucking up a reagent in a reagent cartridge and discharging the reagent into a reaction cup to which the reagent is to be added. In some embodiments, the reagent dispensing unit 14 may include a reagent needle that performs two-dimensional or three-dimensional motion in space by a two-dimensional or three-dimensional driving mechanism, so that the reagent needle can move to aspirate a reagent carried by the reagent storage unit 13, and move to a reaction cup to which the reagent is to be added, and discharge the reagent to the reaction cup.
The reagent storage part 13 is used for storing a reagent kit, the reagent kit comprises a solid phase reagent and a marking reagent, the solid phase reagent comprises a solid phase component coated with at least two antigens of toxoplasma gondii antigen, rubella virus antigen, cytomegalovirus antigen, herpes simplex virus 1/2 antigen, parvovirus B19 antigen, coxsackie virus antigen and herpes zoster virus antigen, and the marking reagent comprises an anti-human IgM antibody with a marker.
The reaction device 30 has at least one placing position for placing the reaction cup and incubating the reaction solution in the reaction cup. For example, the reaction device 30 may be a reaction tray, which is configured in a disc-shaped structure and has one or more placing positions for placing reaction cups, and the reaction tray can rotate and drive the reaction cups in the placing positions to rotate, so as to schedule the reaction cups in the reaction tray and incubate the reaction solution in the reaction cups.
The photometric device 40 is used to perform photometric measurement on the incubated reaction solution to obtain reaction data of the sample. For example, the photometric device 40 detects the light emission intensity of the reaction solution to be measured, and calculates the concentration of the component to be measured in the sample from the calibration curve. In some embodiments, the photometric component 40 is separately disposed outside of the reaction device 30.
The immunoassay analyzer also includes a luminescent substrate dispensing device (not shown). The luminescent substrate dispensing apparatus is connected to a container storing a luminescent substrate and is used for dispensing the luminescent substrate into a reaction cuvette to which the luminescent substrate is to be added.
As shown in fig. 2, the control device 50 includes at least: a processing component 51, a RAM 52, a ROM 53, a communication interface 54, a memory 56, and an I/O interface 55, wherein the processing component 51, the RAM 52, the ROM 53, the communication interface 54, the memory 56, and the I/O interface 55 communicate over a bus 57.
The processing component may be a CPU, GPU or other chip with computing capabilities.
The memory 56 stores therein various computer programs such as an operating system and an application program to be executed by the processor unit 51, and data necessary for executing the computer programs. In addition, data stored locally during the sample testing process, if desired, may be stored in the memory 56.
The I/O interface 55 is constituted by a serial interface such as USB, IEEE1394, or RS-232C, a parallel interface such as SCSI, IDE, or IEEE1284, and an analog signal interface composed of a D/a converter and an a/D converter. The I/O interface 55 is connected to an input device including a keyboard, a mouse, a touch panel, or other control buttons, and a user can directly input data to the control apparatus 50 using the input device. In addition, a display having a display function, such as: liquid crystal screen, touch screen, LED display screen, etc., the control device 50 may output the processed data as image display data to a display for displaying, for example: analytical data, instrument operating parameters, etc.
The communication interface 54 is an interface that may be any communication protocol known today. The communication interface 54 communicates with the outside through a network. Control device 50 may communicate data with any device connected through the network via communication interface 54 using a communications protocol.
Wherein the control device 50 is configured to receive a test instruction comprising the type of IgM antibody to be tested, and in response to the test instruction to perform the following steps:
controlling the sample dispensing component 12 to add the sample to be tested in the sample storage component 11 into a reaction cup on the reaction device 30;
controlling a reagent dispensing component 14 to add a solid phase component corresponding to the type of the IgM antibody to be detected in the kit stored in a reagent storage component 13 into a reaction cup on a reaction device 30, so that the sample to be detected and the solid phase component are mixed in the reaction cup and incubated for a period of time, and the antigen coated on the solid phase component can be combined with the IgM antibody to be detected in the sample to be detected;
the control reagent dispensing component 14 further adds a labeled reagent in the kit to the reaction cup, so that the labeled reagent is mixed with the mixture in the reaction cup and is incubated for a period of time, and the labeled reagent can be combined with the IgM antibody to be detected bound on the solid phase component;
controlling a luminescent substrate dispensing device to add a luminescent substrate into the reaction cup; and
the detection result is obtained from the ratio of the light emission value measured in the light measuring section 40 to the light emission threshold value.
The immunoassay analyzer provided by the embodiment of the invention can selectively detect any one or more items in the Torch detection items in one detection, improves the flexibility of Torch detection and meets different scene requirements of users.
In some embodiments, the at least two antigens coated on the solid phase component are present in the kit in separate aliquots of the solid phase reagent. For example, the solid phase reagent comprises a toxoplasma antigen-coated solid phase component and a rubella virus antigen-coated solid phase component that are separated from each other. In this case, the user may use the immunoassay analyzer to perform preliminary screening on a plurality of items in the torrech detection items in one detection, or may use the immunoassay analyzer to perform one-by-one screening on each item of the torrech detection items, and only the user needs to input the item to be detected. The immunoassay analyzer can add a solid phase component corresponding to an item to be detected and a labeling reagent to a sample to be detected according to a user's instruction.
When the solid-phase reagent contains at least two antigens coated on the solid-phase components separately dispensed, the control device 50 is configured to control the reagent dispensing unit 14 to separately add different solid-phase components in the solid-phase reagent to the reaction cuvette.
In some embodiments, the at least two antigens coated on the solid phase component are present in the kit in a pre-mixed form in the solid phase reagent. Such a kit is for example a kit according to the invention as described above.
Experimental materials:
toxoplasma antigen, rubella virus antigen, cytomegalovirus antigen, herpes simplex virus type 1 antigen, herpes simplex virus type 2 antigen from Meridian Life Science;
alkaline phosphatase is derived from Roche pharmaceutical;
magnetic beads were from Thermo Fisher;
the antibody specifically bound by the human IgM antibody is from Jackson ImmunoResearch.
Preparation of solid-phase coating:
the antigen is first pre-treated and dialyzed to remove the protective components from its buffer matrix. The coating is carried out in a proportion of 0.5-40ug (preferably 1-30ug, more preferably 10-20ug) of antigen per mg of magnetic beads. And in the reaction process, carboxyl on the surface of the magnetic bead is coupled with amino of the antigen under the catalysis of EDC/NHS. In the embodiment of the invention, 20mg of magnetic microspheres modified with carboxyl on the surface are taken, ultrasonically dispersed in 10mM MES buffer solution, 80mg of EDC and 120mg of NHS are added, and after uniform ultrasonic mixing, the mixture is placed in a shaking table at 37 ℃ for 15 min. Then adding the antigen into the treated magnetic beads according to the proportion, mixing uniformly, and placing the mixture in a shaking table at 37 ℃ for reaction for 10-18 h. And after cleaning and sealing, preparing the magnetic microspheres coated with the antigen.
Preparation of labeling reagents：
And (3) labeling the signal marker by using the antibodies of mice, rabbits, goats, sheep, chickens and the like which are specifically combined with the human IgM antibody. In embodiments of the invention, the signal marker is alkaline phosphatase. Alkaline phosphatase was diluted with 50mM MES (2-morpholinoethanesulfonic acid) buffer pH 6.0. The concentration of the signal marker after dilution is in the range of about 0.5. mu.g/mL to about 5. mu.g/mL. In the present example, the concentration of the signal marker after dilution was about 1. mu.g/mL, and the labeling reagent was prepared.
A detection step:
in the first step, the sample and the solid phase coating are added to the reaction tube and incubated at 37 ℃ for 10 minutes so that the solid phase coating can bind to the corresponding IgM antibodies in the sample. After the incubation in the reaction tube is completed, the substance bound to the solid phase is attracted by placing it in a magnetic field, the substance bound to the solid phase of the magnetic beads is retained, and the unbound substance is washed away.
In the second step, the labeled reagent is added to the reaction tube, mixed well, incubated at 37 ℃ for 10 minutes, and combined with the conjugate formed in the first step to form a complex. After incubation in the reaction tube is complete, the complex is attracted by the magnetic field and other unbound material is washed away.
Third, AMPPD is added to the reaction tube to produce chemiluminescence. And measuring the number of photons generated by the reaction through a photomultiplier to obtain a chemiluminescence signal value of the sample.
In the embodiment of the present invention, the negative coincidence rate refers to the proportion of the number of samples determined to be negative obtained by using the test method of the embodiment of the present invention to the negative samples actually participating in the evaluation, and the positive coincidence rate refers to the proportion of the number of samples determined to be positive obtained by using the test method of the embodiment of the present invention to the positive samples actually participating in the evaluation; the true negative and positive results of the sample are from hospital diagnostic results.
Example 1 determination of threshold value for detection
Samples with definite clinical diagnosis results are selected, wherein 1153 toxoplasma IgM antibody detection samples (852 negative samples and 301 positive samples), 1123 rubella virus IgM antibody detection samples (843 negative samples and 280 positive samples), 1422 cytomegalovirus IgM antibody detection samples (1031 negative samples and 391 positive samples), 1152 herpes simplex virus 1/2 type IgM antibody detection samples (842 negative samples and 310 positive samples), 1217 parvovirus B19IgM antibody detection samples (861 negative samples and 356 positive samples), 1050 herpes zoster virus IgM antibody detection samples (801 negative samples and 249 positive samples), 1050 coxsackievirus IgM antibody detection samples (798 negative samples and 252 positive samples).
The method for preparing the solid phase coating material is adopted to respectively prepare the magnetic microspheres coated with the toxoplasma gondii antigen, the magnetic microspheres coated with the rubella virus antigen, the magnetic microspheres coated with the cytomegalovirus antigen, the magnetic microspheres coated with the herpes simplex virus 1/2 type antigen (HSV-1 and HSV-2 are mixed according to a ratio of 1:1), the magnetic microspheres coated with the parvovirus B19 antigen, the magnetic microspheres coated with the herpes zoster virus antigen and the magnetic microspheres coated with the coxsackie virus antigen, and the method for preparing the marking reagent is adopted to prepare the marking reagent, and the positive coincidence rate and the negative coincidence rate of each pathogen sample under different luminous thresholds are respectively tested according to the detection step, and the results are shown in the following table 1.
TABLE 1 determination of threshold values for various pathogens
As is clear from table 1, when the emission threshold is selected to be about 30000, the total coincidence rate is the highest, and the emission threshold of the reagent kit is selected to be 30000.
Example 2 reagent combinations formulated for different test items
In this example, reagent combinations for the experiments shown in table 2 were formulated.
TABLE 2
Wherein, the labeling reagents in experiments 1-4 are prepared according to the method in the preparation of the labeling reagents.
The preparation steps of each solid phase reagent in experiments 1-4 are as follows:
firstly, according to the preparation of a magnetic bead coating material, the magnetic bead concentrations of magnetic microspheres coated with toxoplasma antigens, magnetic microspheres coated with rubella virus antigens, magnetic microspheres coated with cytomegalovirus antigens, magnetic microspheres coated with herpes simplex virus 1 antigens and herpes simplex virus 2 antigens (1:1), magnetic microspheres coated with parvovirus B19 antigens, magnetic microspheres coated with herpes zoster virus antigens and magnetic microspheres coated with coxsackie virus antigens are respectively prepared. The results are shown in Table 3, where the magnetic microspheres were diluted with 50mM Tris pH 7.4 buffer, the concentration of the labeling reagent was maintained at about 1ug/mL, the concentration of the magnetic microsphere coating was adjusted, and the luminescence threshold was adjusted to 30000 to allow + -2% variation.
TABLE 3 determination of the concentration of the coating of each magnetic bead in experiments 1-4
As shown in table 3, the magnetic bead concentrations of the magnetic microspheres coated with toxoplasma gondii antigen, the magnetic microspheres coated with rubella virus antigen, the magnetic microspheres coated with cytomegalovirus antigen, the magnetic microspheres coated with herpes simplex virus 1/2 antigen, the magnetic microspheres coated with parvovirus B19 antigen, the magnetic microspheres coated with herpes zoster virus antigen, and the magnetic microspheres coated with coxsackie virus antigen were: 0.15mg/mL, 0.12mg/mL, 0.2mg/mL, 0.15mg/mL, 0.12 mg/mL.
According to the concentration of each bead coating determined in table 3, the solid phase reagents in experiments 1 to 4 were prepared by mixing the corresponding bead coatings according to the items aimed at in experiments 1 to 4.
Example 3 testing Using the reagent combinations in experiments 1-4
Samples with definite clinical diagnosis results were selected, 3315 in total. Of these, 1952 negative samples and 1363 positive samples were obtained. The positive samples comprise 970 positive samples of any one item of toxoplasma gondii IgM antibody, rubella virus IgM antibody, cytomegalovirus IgM antibody and herpes simplex virus 1/2 IgM antibody. 120 positive parvovirus B19IgM antibody samples, 138 positive herpes zoster virus IgM antibody samples, and 135 positive coxsackievirus IgM antibody samples.
The samples were tested using the immunoassay analyzer of the present invention as described in the "detection step" above using the reagent combinations of experiments 1-4 as prepared in example 2.
In the embodiment of the present invention, coi (Cutoff index) is a ratio of a chemiluminescence signal value (RLU) of a measurement sample to a threshold value (Cutoff value), and for a qualitative detection method, the threshold value (Cutoff value) is a cut-off value for determining whether a test result is positive or negative. In the embodiment of the present invention, whether the sample contains the detection object or not needs to compare the test result COI value of the sample with a reference value (the reference value is 1.10), and if the test result COI value is greater than or equal to 1.10, it indicates that one or more of the detection objects in the sample are positive; if less than 0.90, it indicates that all the test substances in the sample are negative. COI is between 0.90 and 1.10, the result is a gray zone (indeterminate).
The positive and negative results of the test were compared with the clinical diagnosis results and the coincidence rate was calculated, and the results are shown in table 4 below.
TABLE 4 sensitivity and specificity of the assays 1-4
As shown in table 4, the total coincidence rate of experiment 1 (detecting toxoplasma antibody IgM + rubella virus antibody IgM + cytomegalovirus antibody IgM + herpes simplex virus 1/2) was 99.49%; experiment 2 (detection of toxoplasma antibody IgM + rubella virus antibody IgM + cytomegalovirus antibody IgM + herpes simplex virus 1/2 type + parvovirus B19IgM antibody) the overall coincidence rate was 99.51%; experiment 3 (detecting parvovirus B19IgM + herpes zoster virus IgM antibody + Coxsackie virus IgM antibody) the total coincidence rate is 99.74%; the overall coincidence rate of experiment 4 (detection of toxoplasma antibody IgM + rubella virus antibody IgM + cytomegalovirus antibody IgM + herpes simplex virus type 1/2 IgM antibody + parvovirus B19IgM antibody + herpes zoster virus IgM antibody + coxsackievirus IgM antibody) was 99.52%. Thereby meeting the requirement of quickly and effectively carrying out the Torch screening.
Claims (19)
- A kit, comprising:a capture mixture mixed with at least two antigens selected from the group consisting of: toxoplasma antigen, rubella virus antigen, cytomegalovirus antigen, herpes simplex virus 1/2 type antigen, parvovirus B19 antigen, coxsackie virus antigen and herpes zoster virus antigen; andanti-human IgM antibody with a label.
- The kit of claim 1, wherein the at least two antigens are coated on the same solid support or separately coated on different solid supports.
- The kit according to claim 1 or 2, wherein the concentration of the labeled anti-human IgM antibody and the concentration of each antigen coated on the solid phase carrier are designed so that the luminescence threshold values of the internal reference substance detected by each antigen coated on the solid phase carrier and the anti-human IgM antibody alone are substantially the same in the same reaction system.
- The kit of claim 3, wherein the luminescence threshold is determined by a ROC curve.
- The kit of any one of claims 1 to 4, wherein the capture mixture comprises a toxoplasma antigen, a rubella virus antigen, a cytomegalovirus antigen and a herpes simplex virus 1/2 antigen coated on a solid support.
- The kit of any one of claims 1 to 4, wherein the capture mixture comprises toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, herpes simplex virus 1/2 antigens, and parvovirus B19 antigens coated on a solid support.
- The kit of any one of claims 1 to 4, wherein the capture mixture comprises parvovirus B19 antigen, coxsackievirus antigen, and herpes zoster virus antigen coated on a solid support.
- The kit of any one of claims 1 to 4, wherein the capture mixture comprises a toxoplasma antigen, a rubella virus antigen, a cytomegalovirus antigen, a herpes simplex virus 1/2 type antigen, a parvovirus B19 antigen, a coxsackie virus antigen, and a herpes zoster virus antigen coated on a solid support.
- The kit according to any one of claims 1 to 8, further comprising:the specification describes that when a pathogen corresponding to the capture mixture is detected using at least two antigens and the labeled anti-human IgM antibody, a positive result is determined when the ratio of the detection value of the mixture to the luminescence threshold value is 1.1 or more.
- The kit of claim 9, wherein the instructions further recite recommending further examination of the pathogen to which each of the at least two antigens corresponds when a positive result is determined.
- An immunoassay method comprising the steps of:mixing a sample to be detected with a solid phase carrier coated with at least two antigens of toxoplasma gondii antigen, rubella virus antigen, cytomegalovirus antigen, herpes simplex virus 1/2 antigen, parvovirus B19 antigen, coxsackie virus antigen and herpes zoster virus antigen, and incubating for a period of time, so that the at least two antigens coated on the solid phase carrier can be combined with IgM antibodies corresponding to the at least two antigens in the sample to be detected;washing the mixture of the sample to be detected and the solid phase carrier to remove unbound substances;adding a labeled anti-human IgM antibody to the washed mixture and incubating so that the labeled anti-human IgM antibody can be combined with IgM antibodies corresponding to the at least two antigens combined on the solid phase carrier to form a complex;washing the complex to remove unbound material;and adding a luminescent substrate into the washed complex to detect a mixed detection value of the IgM antibodies corresponding to the at least two antigens in the sample to be detected.
- The method of claim 11, wherein the concentration of the labeled anti-human IgM antibody and the concentration of each antigen coated on the solid phase carrier are designed so that the corresponding luminescence threshold values are substantially the same when the internal reference substance is detected by each antigen coated on the solid phase carrier and the anti-human IgM antibody alone in the same reaction system.
- The method according to claim 11 or 12, wherein the at least two antigens coated on the solid support are added to the sample to be tested separately for mixing and incubation, or are added to the sample to be tested in a pre-mixed form for mixing and incubation.
- The method of any one of claims 11 to 13, wherein the at least two antigens are toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, and herpes simplex virus 1/2 type antigens; orThe at least two antigens are toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, herpes simplex virus 1/2 type antigens, and parvovirus B19 antigens; or alternativelyThe at least two antigens are parvovirus B19 antigen, coxsackievirus antigen and herpes zoster virus antigen; or alternativelyThe at least two antigens are toxoplasma antigens, rubella virus antigens, cytomegalovirus antigens, herpes simplex virus 1/2 type antigens, parvovirus B19 antigens, coxsackie virus antigens and herpes zoster virus antigens.
- The method of any of claims 11-14, wherein a positive result is determined when a ratio of the mixed detection value to a threshold value is greater than or equal to 1.1.
- The method of claim 15, wherein when a positive result is determined, the method further comprises the step of separately detecting the pathogen to which each of the at least two antigens corresponds.
- An immunoassay analyzer for selectively detecting different types of IgM antibodies in a blood sample, comprising:the sample device is provided with a sample storage component and a sample separate injection component, the sample storage component is used for storing a sample to be tested, and the sample separate injection component is used for sucking the sample to be tested and discharging the sample to be tested into a reaction cup to be added with sample;the reagent device is provided with a reagent storage component and a reagent dispensing component, the reagent storage component is used for storing a reagent box, the reagent box comprises a solid phase reagent and a marking reagent, the solid phase reagent comprises solid phase components coated with at least two antigens of toxoplasma gondii antigen, rubella virus antigen, cytomegalovirus antigen, herpes simplex virus 1/2 antigen, parvovirus B19 antigen, coxsackie virus antigen and herpes zoster virus antigen, the marking reagent comprises an anti-human solid phase IgM antibody with a marker, and the reagent dispensing component is used for absorbing the anti-human solid phase reagent and the marking reagent in the reagent box stored on the reagent storage component and discharging the anti-human solid phase reagent and the marking reagent into a reaction cup to which the reagent is added;a luminescent substrate dispensing device which is connected with a container for storing luminescent substrates and is used for injecting the luminescent substrates into a reaction cup to which the luminescent substrates are added;a reaction device having a plurality of placement positions for placing the reaction cups and for incubating the reaction solution in the reaction cups;the light measurement component is used for performing light measurement on the incubated reaction liquid to obtain a detection result of the sample to be detected;a control device electrically connected to the sample device, the reagent device, the luminescent substrate dispensing device, and the photometric element, and configured to:receiving a test instruction, wherein the test instruction comprises the type of the IgM antibody to be tested;in response to the test instruction:controlling the sample dispensing component to add the sample to be detected in the sample storage component into a reaction cup on the reaction device;controlling the reagent separate injection component to add the solid phase component corresponding to the type of the IgM antibody to be detected into a reaction cup on the reaction device, so that the sample to be detected and the solid phase component are mixed in the reaction cup and incubated for a period of time, and the antigen coated on the solid phase component can be combined with the IgM antibody to be detected in the sample to be detected;controlling the reagent dispensing component to further add a labeled reagent into the reaction cup, so that the labeled reagent is mixed with the mixture in the reaction cup and incubated for a period of time, and the labeled reagent can be combined with the IgM antibody to be detected bound on the solid phase component;controlling the luminescent substrate dispensing device to add a luminescent substrate into the reaction cup; andand obtaining a detection result according to the ratio of the luminous value measured in the optical measurement component to the luminous threshold value.
- The immunoassay analyzer of claim 17, wherein the at least two antigens coated on the solid phase component are present in the kit in a separate package.
- The immunoassay analyzer of claim 17, wherein the kit is the kit according to any one of claims 1 to 10.
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| CN117230161A (en) * | 2023-11-10 | 2023-12-15 | 新羿制造科技（北京）有限公司 | Digital PCR kit for detecting TORCH pathogen |
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| US20040235189A1 (en) * | 2003-05-08 | 2004-11-25 | Lu Wei Zhao | Reversed chromatographic immunoassay |
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| CN103033612A (en) * | 2012-12-15 | 2013-04-10 | 北京金豪制药股份有限公司 | IgM antibody detection kit for five TORCH tests and preparation of IgM antibody detection kit |
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| CN108398554B (en) * | 2018-03-07 | 2020-08-07 | 深圳市伯劳特生物制品有限公司 | anti-TORCH-IgM antibody spectrum chip, preparation method thereof and TORCH detection kit |
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