CN113933517B - Method for detecting sensitivity of T cells to inactivated vaccine - Google Patents
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- 230000035945 sensitivity Effects 0.000 title claims abstract description 22
- 210000004027 cell Anatomy 0.000 claims abstract description 18
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- 210000005259 peripheral blood Anatomy 0.000 claims description 7
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- 238000012216 screening Methods 0.000 claims description 3
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Classifications
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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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70589—CD45
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/715—Assays involving receptors, cell surface antigens or cell surface determinants for cytokines; for lymphokines; for interferons
Abstract
The invention discloses a method for detecting the sensitivity of T cells to an inactivated vaccine, which comprises the steps of detecting Tn values and Tcm values of T cells in sample cells to be detected, and then calculating the ratio Tn/Tcm of Tn to Tcm, wherein if the ratio Tn/Tcm is more than 2.4 and the ratio is larger, the sensitivity of the sample T cells to the inactivated vaccine is larger.
Description
Technical Field
The invention belongs to the technical field of medical inspection, and particularly relates to a method for detecting sensitivity of T cells to an inactivated vaccine.
Background
In the course of vaccine development, small animal replacement methods are often used to predict the susceptibility of individuals to vaccines. I.e., the serum antibody levels of the animals are detected after the animals are injected with the vaccine. Meanwhile, the serum of the immunized animal is utilized to carry out an in vitro virus neutralization method, and the effect of neutralizing the virus of the antibody is detected. In addition, animal challenge experiments are needed to detect the protective effect of the vaccine on animals and whether the ADE effect (antibody dependent enhancement) occurs. After the vaccine enters the clinical trial, the vaccinated serum antibodies, including serum total antibodies, igM, igG and serum neutralizing antibodies, were detected by chemiluminescence, ELISA (competition) methods. By detecting the antibody titer, the antibody production time and duration can reflect the sensitivity of the organism to the novel crown inactivated vaccine.
The method has the defects that: (1) ethical constraints have led to the fact that detection methods for animals, especially the toxicity attack method, are not suitable for humans. (2) The large sample clinical test can reflect the sensitivity of the organism to the vaccine on a statistical scale, but has time delay (namely, the sensitivity can not be known after inoculation and can not be predicted before inoculation), the sample number is limited, the experimental population is limited, and the like. (3) After the vaccine is formally used, the sensitivity of the vaccinated population to the vaccine can be obtained through analysis of a large amount of vaccination data. However, there is also time lag, and retrospective results can be obtained by taking serum several times over different time periods after the whole inoculation procedure is completed, and individual differences cannot be predicted before inoculation. (4) At present, most hospitals or third party detection institutions only detect the total antibodies, igM and IgG of the specific serum of the novel coronavirus, but the antibody levels cannot be completely equivalent to the neutralizing antibody levels of the novel coronavirus, and some inoculators have high IgG levels, but the neutralizing antibodies are negative; there are also vaccinators whose serum was negative for new coronavirus IgG, but whose new coronavirus neutralizing antibodies were positive. In addition, the main method for detecting the sensitivity of the organism to other virus inactivated vaccines in the prior art is also to detect serum antibodies, and the method and the defects are the same as the above.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for detecting the sensitivity of T cells to an inactivated vaccine.
In order to achieve the above purpose, the technical scheme provided by the invention is as follows:
the method for detecting the sensitivity of the T cells to the inactivated vaccine is to detect the Tn value and the Tcm value of the T cells in the sample cells to be detected, then calculate the ratio Tn/Tcm of the Tn to the Tcm, and if the Tn/Tcm is more than 2.4 and the ratio is larger, the sensitivity of the sample T cells to the inactivated vaccine is larger, namely the sample T cells are more sensitive. Wherein Tn: primary T cells; tcm: central memory T cells; tn value: initial T cell number; tcm value: central memory T cell number.
Preferably, the method is that the method is to detect the T cell surface characteristic marker molecule CD45RA with PE-CD45RA/APC-CD197 antibodies + /CD197 + Obtaining Tn value; simultaneous detection of T cell surface characteristic marker molecule CD45RA with PE-CD45RA/APC-CD197 antibodies - /CD197 + Obtaining a Tcm value; and calculating the ratio Tn/Tcm of Tn and Tcm, wherein if the ratio Tn/Tcm is more than 2.4 and the ratio is larger, the sample T cells are more sensitive to the inactivated vaccine and can generate high-level neutralizing antibodies.
More preferably, the method comprises screening the sample cells for CD4 with FITC-CD4 antibody prior to detection of the T cell surface characteristic marker molecule + T cells.
More preferably, the method is one in which the PE-CD45RA/APC-CD197 antibody is used to detect CD4 + T cell surface characteristic marker molecule CD45RA + /CD197 + Tn values were obtained. In the method, the PE-CD45RA/APC-CD197 antibody is used for detecting CD4 + T cell surface characteristic marker molecule CD45RA - /CD197 + The Tcm value is derived.
Preferably, the inactivated vaccine is a novel coronal inactivated vaccine.
More preferably, the novel coronal inactivated vaccine is BBIBP-CorV.
The invention is further described below:
the inactivated virus vaccine belongs to exogenous antigen, and is used for activating CD4+ T cells and inducing humoral immunity to generate antibodies as main immune response; and have very little effect on cd8+ T cells, failing to activate and produce an effective, sufficient amount of CTL cells. In the present invention, the primary T cells (Tn) are mature T cells which leave the thymus but have not yet been stimulated by antigen, and the surface-characteristic marker molecule is CD45RA + /CD197 + Tn comprises CD4 + Tn and CD8 + Tn. Upon antigen stimulation, a portion of Tn differentiates into central memory T cells (Tcm), characterized by the surface marker molecule CD45RA - /CD197 + . Tcm also contains CD4 + Tcm and CD8 + Tcm, which is mainly CD4 in peripheral blood + Tcm。
The method of the invention is specifically applied as follows:
currently, the conventional immunization regimen for inactivating a new coronavirus vaccine (BBIBP-CorV) is two vaccinations, with no more than 50 days apart, but with large differences in the levels of antibody production by the population. According to the prior art, part of human body generates low antibody level or does not generate antibodies, which is difficult to achieve the expected immune effect and is unfavorable for the prevention and control of new crown epidemic situation. The method can predict the capability of the organism to generate the neutralizing antibody in advance by measuring the Tn/Tcm ratio of the T cells in the cells of the inoculated individual, and is beneficial to reminding related personnel of periodically detecting the antibody level and carrying out personalized inoculation. For vaccinated populations with low Tn/Tcm ratios, little or no neutralizing antibody production after vaccination, antibody levels should be detected in time after vaccination, if necessary to boost. The method can rapidly and sensitively estimate the generation level of protective neutralizing antibodies after the subjects are inoculated with inactivated new coronavirus vaccine (BBIBP-CorV), and provides a basis for preparing a personalized inoculation scheme.
Compared with serum antibody detection, the method only needs one-time blood drawing detection after application, and the response degree of an individual to the inactivated new crown inactivated vaccine can be estimated before vaccination by calculating the Tn/Tcm ratio. Potential populations with poor responses to the vaccine can be screened in advance, personalized immunization schemes (including but not limited to increasing the number of immunizations) can be formulated, effective immunization can be ensured, and viral injury can be kept away.
Drawings
FIG. 1 is a graph showing the relationship between Tn/Tcm values and serum neocoronavirus neutralizing antibody levels in 56 subjects after two doses of BBIBP-CorV injection. P <0.05 represents significant;
FIG. 2 is an analysis of the correlation of Tn/Tcm ratios in 56 subjects with their novel coronavirus neutralizing antibody levels.
Detailed Description
Example 1
The method for detecting the sensitivity of the T cells to the inactivated vaccine comprises the following aspects:
preparation of human peripheral blood mononuclear cells
1. 5ml of the peripheral blood of the inoculator is extracted, and mononuclear cells of the peripheral blood are isolated (the specific steps are conventional in the art)
2. 5ml of PBS containing 1% BSA was added to wash the cells obtained in step 1, centrifuged at 1000rpm, and the supernatant was discarded. This washing step was repeated 2 times.
3. Cell count (the specific method is conventional in the art)
(II) incubation of detection antibody
1. Cell concentration was adjusted to 2X10 with PBS containing 1% BSA 6 Each test subject has at least two blood samples, one for each T cell ratio of the test subject and one for isotype test control antibody or blank. Cells used to detect T cell proportion, the following antibodies (table 1) were added separately:
TABLE 1
2. After addition of the antibody, incubation was performed at 4℃for 30min in the dark.
3. 5ml of PBS containing 1% BSA was added to wash the cells obtained in step 1, centrifuged at 1000rpm, and the supernatant was discarded. This washing step was repeated 2 times.
4. Cells were resuspended by addition of 500ul PBS and detected by flow cytometry.
5. Screening for CD4 with FITC-CD4 antibody + Cell and CD45RA detection by PE-CD45RA/APC-CD197 antibody + /CD197 + T cells (Tn, naive T cells) and CD45RA - /CD197 + Cell proportion of T cells (Tcm, memory T cells).
6. The larger Tn/Tcm (> 2.4) the Tn/Tcm was calculated, the higher the neutralizing antibody production level.
Example 2
The specific application of the method for detecting the sensitivity of the T cells to the inactivated vaccine is as follows:
(1) The new coronavirus inactivated vaccine (n=56) was inoculated. The subject 56 individuals injected BBIBP-CorV according to the national protocol. Among them, 11 people showed slight adverse reactions, which were manifested by low fever, hypodynamia, pain at injection site and gastrointestinal discomfort, but all disappeared after several hours to 2 days after appearance, and no persistent adverse reaction occurred later (see table 2).
TABLE 2 inoculant profile and adverse reactions
| Sex (sex) | Number of examples |
| Man's body | 36 |
| Female | 20 |
| Age of | |
| 20～30 | 20 |
| 31～40 | 26 |
| 41～55 | 10 |
| Adverse reactions | |
| Heating up | 3 |
| Debilitation | 6 |
| Gastrointestinal discomfort | 2 |
| No special reaction | 45 |
(2) The inoculum serum antibody species and antibody content were tested (table 3). Serological detection method and result judgment: collecting 5ml of peripheral blood of the investigation population, and detecting the total anti-new crown antibody, igG and IgM antibodies respectively by adopting a chemiluminescence method. The novel coronal total antibody is detected by using a Xiamen Umaike full-automatic chemiluminescence immunoassay analyzer Caris200, and a detection kit is a novel Karl-type coronavirus antibody detection kit (batch number: 20200826); igG and IgM are detected by an AutoLumo A2000plus automatic chemiluminescence immunoassay instrument in Zhengzhou Anji, and the detection kit adopts Anji biology 2019-ncovIgG and IgM kits, and the lot numbers are 201228 and 210123 respectively. The neutralizing antibody adopts an ELISA kit of Lepu biotechnology company.
TABLE 3 species and antibody content of the inoculant serum
(3) Detection of Tn/Tcm in vaccinated population
EDTA anticoagulated peripheral blood was collected 2 weeks after inoculation of the second needle for 5ml and 6 h. Cells were analyzed on a BD FACS Canto II flow cytometer using BD company FITC-CD4+, PE-CD45RA+, APC-CCR7+ labeled T lymphocytes, FITC-CD3+, PE-CD21+, percp-CD19+ labeled B lymphocytes. The relative values of Tn cells and Tcm cells were obtained for each subject, tn/Tcm was calculated and classified according to whether it produced neutralizing antibodies, and the result showed p=0.02, with statistical significance (see fig. 1).
(4) Tn/Tcm and antibody level correlation analysis
The levels of Tn/Tcm and neutralizing antibodies were positively correlated, p=0.001, as analyzed by Person correlation test, with statistical significance (see fig. 2).
In the invention, the determination of Tn/Tcm does not need animal experiments, only 5ml of peripheral blood is needed to be extracted, the materials are easy to obtain, and the method is acceptable in ethics. Before vaccine injection, the sensitivity of the organism to future injection of new crown vaccine can be determined by measuring Tn/Tcm, which belongs to advance prognosis. The existing method is to judge the sensitivity of the organism by detecting the antibody level after finishing the immunization program, belongs to retrospective judgment, and perfectly solves the time lag of the existing method.
Claims (6)
1. A method for detecting sensitivity of T cells to an inactivated vaccine is characterized by detecting Tn value and Tcm value of T cells in a sample cell to be detected, and then calculating the ratio Tn/Tcm of Tn to Tcm, wherein if Tn/Tcm is more than 2.4 and the ratio is larger, the sensitivity of the sample T cells to the inactivated vaccine is larger; the inactivated vaccine is a novel crown inactivated vaccine, the sample to be tested is a peripheral blood sample, the Tn value refers to the initial T cell number, and the Tcm value refers to the central memory T cell number; the method is used for non-diagnostic purposes.
2. The method of claim 1, wherein the method is to detect the T cell surface characteristic marker molecule CD45RA with PE-CD45RA/APC-CD197 antibodies + / CD197 + Obtaining Tn value; simultaneous detection of T cell surface characteristic marker molecule CD45RA with PE-CD45RA/APC-CD197 antibodies - / CD197 + Obtaining a Tcm value; calculating the ratio Tn/Tcm of Tn and Tcm, if Tn/Tcm is more than 2.4 and the ratio is larger, the sensitivity of the sample T cells to the inactivated vaccine is larger; the "/" indicates "sum".
3. The method for detecting sensitivity of T cells to inactivated vaccine according to claim 2, wherein the method comprises screening CD4 in sample cells with FITC-CD4 antibody before detecting the T cell surface characteristic marker molecule + T cells.
4. The method of claim 3, wherein the method is to detect CD4 with PE-CD45RA/APC-CD197 antibodies + T cell surface characteristic marker molecule CD45RA + / CD197 + Obtaining Tn value; the "/" indicates "sum".
5. The method of claim 3, wherein the method is to detect CD4 with PE-CD45RA/APC-CD197 antibodies + T cell surface characteristic marker molecule CD45RA - / CD197 + Obtaining a Tcm value; the "/" indicates "sum".
6. The method of detecting sensitivity of T cells to an inactivated vaccine according to claim 1, wherein the novel coronal inactivated vaccine is BBIBP-cov.
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| CN213800851U (en) * | 2020-11-19 | 2021-07-27 | 北京艺妙神州医药科技有限公司 | T cell activation state detection kit |
| CN113481157A (en) * | 2021-07-21 | 2021-10-08 | 上海赛傲生物技术有限公司 | Optimized preparation method of specific antiviral adoptive immune cells |
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| AU2018249493A1 (en) * | 2017-04-03 | 2019-09-19 | Oncxerna Therapeutics, Inc. | Methods for treating cancer using PS-targeting antibodies with immuno-oncology agents |
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| CN213800851U (en) * | 2020-11-19 | 2021-07-27 | 北京艺妙神州医药科技有限公司 | T cell activation state detection kit |
| CN113481157A (en) * | 2021-07-21 | 2021-10-08 | 上海赛傲生物技术有限公司 | Optimized preparation method of specific antiviral adoptive immune cells |
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