CN101816786A - Inactivated hepatitis A vaccine and preparation method thereof - Google Patents
Inactivated hepatitis A vaccine and preparation method thereof Download PDFInfo
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- CN101816786A CN101816786A CN201010160514A CN201010160514A CN101816786A CN 101816786 A CN101816786 A CN 101816786A CN 201010160514 A CN201010160514 A CN 201010160514A CN 201010160514 A CN201010160514 A CN 201010160514A CN 101816786 A CN101816786 A CN 101816786A
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Abstract
The invention relates to the technical field of biology, and discloses a method for preparing an inactivated hepatitis A vaccine, which comprises the following steps of: culturing human embryo lung diploid cell 2BS strains inoculated with an L-A-1 strain of hepatitis A virus to a virus multiplication peak time and normally digesting cells with pancreatin and cell lysis solution to obtain virus solution; performing PEG precipitation and chloroform extraction to remove hybrid proteins from the cells; and performing gel filtration chromatography and purification, sterilization with a filter membrane, ultrafiltration with an ultrafiltration membrane and absorption with an aluminum hydroxide adjuvant to prepare the inactivated hepatitis A vaccine. Results of potency test performed in mice in vivo show that the inactivated hepatitis A vaccine prepared by the method has mean efficacy dilution higher than that of a reference vaccine and immunogenicity superior to that of the reference vaccine. The method of the invention has the advantages of improving the security of the vaccine, simplifying a process, reducing production cost and realizing the large-scale production of the inactivated hepatitis A vaccine.
Description
Technical field
The present invention relates to biological technical field, be specifically related to a kind of preparation method of hepatitis A inactivated vaccine and the hepatitis A inactivated vaccine for preparing by described method.
Background technology
Hepatitis A is called for short hepatitis A, is the viral infectious of a class high incidence, can cause outbreak of epidemic, and China is the high popular district of hepatitis A, and the inoculation Hepatitis A Vaccine is the popular effective measures of prevention hepatitis A.
At present there are two kinds of vaccines to be used for the prevention and control of hepatitis A in the world, a kind of is Live Attenuated HAV, attenuated hepatitis A live vaccine such as L-A-1 strain nearly 20 years of large-scale production, in the outbreak of epidemic of prevention and control hepatitis A, reduce aspect the sickness rate, played huge effect, but there is the virulence reversion in attenuated live vaccine, may brings out shortcomings such as serious disease as immunodeficiency person to some individualities; Another kind is an inactivated vaccine.Antibody produces soon after the hepatitis A inactivated vaccine immunity, can be used for controlling the contingent immunization inoculation of hepatitis A outbreak of epidemic, all is better than attenuated live vaccine at aspects such as safety, effectiveness and the scopes of application.Over nearly 10 years, the application of hav inactivated vaccine shows that all it has the advantage of good, the immune back of safety antibody horizontal height, protective rate height, effect phase length, good stability.
Inactivated vaccine virulent strain preparation commonly used; the morbific danger of person that has the Infection Action in process of production; the operating process for preparing hav inactivated vaccine with attenuated strain is safer; and improve the safety of vaccine greatly; therefore be necessary that development prepares inactivated vaccine with attenuated strain, the method for preparing hav inactivated vaccine of accomplishing scale production simultaneously.
Summary of the invention
The present invention is directed to prepare in the prior art and prepare the defective that there is infection risk in hav inactivated vaccine with virulent strain; a kind of method for preparing hepatitis A inactivated vaccine with attenuated strain is provided; the required hepatitis A virus (HAV) amount of this method is few, and technology is simple, has the scale application prospect.
In order to realize the foregoing invention purpose, the present invention adopts following technical scheme:
A kind of method for preparing hepatitis A inactivated vaccine comprises the steps:
Step 1: the hepatitis A virus seed culture of viruses is inoculated in human embryonic lung diploid fibroblast 2BS strain, is cultured to the virus multiplication peak period, with the conventional peptic cell of pancreatin;
Step 2: the centrifuging and taking precipitation adds cell pyrolysis liquid, and it is fully acted on;
Step 3: add Polyethylene Glycol it is fully acted on, the centrifuging and taking precipitation suspends with the PBS buffer, adds the chloroform extracting, prepares rough hepatitis A venom;
Step 4: the rough hepatitis A venom of step 3 preparation is behind gel chromatography, through 0.2 μ m filter membrane degerming, deactivation;
Step 5: the hepatitis A venom of step 4 preparation through the ultrafilter membrane ultrafiltration, through aluminum hydroxide adjuvant absorption, is made hepatitis A inactivated vaccine.
As preferably, the described seed culture of viruses of step 1 is a hepatitis A virus L-A-1 attenuated strain, is deposited in Wuhan China typical culture collection center on the 21st in December in 1992, and deposit number is CCTCCNo.V92004.
As preferably, the described cultivation of step 1 is cultivated for utilizing multi-layered cell factory or 3L rolling bottle.
Cell factory (cell factory) is a kind of cell culture system of deft design, can utilize culture surface to greatest extent in limited space, thereby save a large amount of spaces, and can save valuable culture fluid.The more important thing is that it can guarantee the aseptic of operating effectively, thereby avoid raw material, labor service and the loss of time because of pollution brings.In the specific embodiment of the present invention, the NUNC multi-layered cell factory that adopts Denmark NUNC company to produce is the more cell factory system that uses at present, can be used for as industrial-scale production such as vaccine, monoclonal antibody or bio-pharmaceuticals, be particularly suitable for attached cell, also can be used for suspension culture.
As preferably, step 2 is specially the centrifuging and taking precipitation and adds cell pyrolysis liquid at 2-8 ℃ of effect 16-24h, and described cell pyrolysis liquid is the 0.2-0.5% deoxycholic acid sodium solution that contains mass percent 2-5% disodiumedetate.Cell pyrolysis liquid of the present invention is the cell pyrolysis liquid of inventor through a large amount of development tests, and effectively the cell of lytic virus infection fully discharges hepatitis A virus (HAV).
Through PEG precipitation, chloroform extracting, can remove the cell foreign protein substantially in the step 3.As preferably, the described molecular weight polyethylene glycol of step 3 is 6000, and final concentration is a percent by volume 8%～10%.
As preferably, the PBS buffer of the 0.01-0.02mol/L that the described PBS buffer of step 3 is pH 5.5～7.5.
As preferably, the described deactivation of step 4 is specially formalin deactivation 12-14 days that final concentration is 200-250 μ g/ml.The described gel of step 4 is preferably the propylene polydextran gel, the Sephacryl S-400HR that adopts Shanghai Suo Laibao bio tech ltd to produce in the specific embodiment.
As preferably, the molecular cut off of the described ultrafilter membrane of step 5 is 50-100KD.
The present invention also provides the hepatitis A inactivated vaccine by described method preparation.
As preferably, deactivation hepatitis A virus (HAV) concentration is 640～1280EU/ml in the described vaccine.The potency test result shows in the mice body, and when hepatitis A inactivated vaccine antigenic content of the present invention was 1280EU/ml, the effective extension rate of half was higher than the reference Seedling, and its immunogenicity is better than the reference Seedling.
The antigenicity titre of the hepatitis A virus L-A-1 attenuated strain that the present invention adopts reaches higher level, can improve virus yield effectively, and the vaccine of attenuated strain preparation is safer; Use advanced in the world cell culture apparatus multi-layered cell factory, carry out cell culture, effectively utilized the space, thereby save plant area, improve the production of vaccine ability; Through PEG precipitation, chloroform extracting, can remove the cell foreign protein substantially, through a step gel permeation chromatography purification, can obtain the higher hepatitis A virus (HAV) of high-purity again.
The method of the invention has been simplified technology, has reduced production cost, and can realize the large-scale production of hepatitis A inactivated vaccine.
The specific embodiment
The invention discloses a kind of method of hepatitis A inactivated vaccine and vaccine that is prepared by described method of preparing, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as being included in the present invention.Method of the present invention and product are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
The method for preparing hepatitis A inactivated vaccine provided by the invention comprises: step 1: the hepatitis A virus seed culture of viruses is inoculated in human embryonic lung diploid fibroblast 2BS strain, is cultured to the virus multiplication peak period, with the conventional peptic cell of pancreatin; Step 2: the centrifuging and taking precipitation adds cell pyrolysis liquid, and it is fully acted on; Step 3: add Polyethylene Glycol it is fully acted on, the centrifuging and taking precipitation suspends with the PBS buffer, adds the chloroform extracting, prepares rough hepatitis A venom; Step 4: the rough hepatitis A venom of step 3 preparation is behind gel chromatography, through 0.2 μ m filter membrane degerming, deactivation; Step 5: the hepatitis A venom of step 4 preparation through the ultrafilter membrane ultrafiltration, through aluminum hydroxide adjuvant absorption, is made hepatitis A inactivated vaccine.
According to the present invention; embodiment in the specific embodiment adopts advanced in the world cell culture apparatus cell factory or 3L rolling bottle; the human embryonic lung diploid fibroblast (2BS strain) of hepatitis A virus L-A-1 attenuated strain has been inoculated in cultivation; the cell that adopts pancreatin and cell pyrolysis liquid lytic virus to infect simultaneously; hepatitis A virus (HAV) is fully discharged, improved the production of vaccine ability effectively, can realize the large-scale production of hepatitis A inactivated vaccine; and simplified technology, reduced production cost.
Below in conjunction with embodiment, further set forth the present invention:
Embodiment 1
Get the human diploid cell (2BS strain) of the rolling bottle cultivation of covering with monolayer, through 0.25% trypsinization, be seeded to 10 layers, 40 confluent monolayer cells factories in proportion, get L-A-1 attenuated strain work seed lot seed culture of viruses simultaneously through suitably dilution, the inoculation human diploid cell, put 35 ℃ ± 0.5 ℃ static cultivation 19-26 days, change liquid 1 time every 7-10 days during this time, treat the virus multiplication peak period, discard culture fluid, washing is after trypsinization, with the centrifugal supernatant of abandoning of the cell suspension of viral infection; Centrifugation adds the 0.2-0.5% deoxycholic acid sodium solution that contains mass percent 2-5% disodiumedetate by 2-4 multiple proportions example, room temperature vibration 2h, and abundant mixing, 4 ℃ of effect 24h with abundant cell lysis, discharge virus; The adding final concentration is 8% Polyethylene Glycol (MW6000), and 4 ℃ of precipitations are spent the night, the centrifugal 1.5h of 4500r/min; Centrifugation suspends with the 0.01mol/L PBS buffer (pH 6.3) of 1/10 volume; Add the equal-volume chloroform, repeat extracting 3～5 times, make rough hepatitis A venom; Sephacryl S-400HR gel is packed in the chromatographic column, after 0.01mol/L PBS buffer (pH 6.3) balance, with sample on the rough hepatitis A venom, with 0.01mol/L PBS buffer (pH 6.3) eluting, collect the elution of virus peak, be the hepatitis A venom of purification; Again through 0.2 μ m filter membrane aseptic filtration, under aseptic condition, add final concentration and be 37 ℃ of deactivations of formaldehyde 12 days of 200 μ g/ml.The hepatitis A venom of deactivation further behind the assay approval, is done suitable dilution according to virus antigenicity titre level through the ultrafilter membrane ultrafiltration of 50KD, makes semi-finished product through aluminum hydroxide adjuvant absorption, and semi-finished product are sub-packed in the aseptic cillin bottle, makes the finished product vaccine.
The hav inactivated vaccine composition of table 1. embodiment 1 preparation
| HAV antigen | ??1280EU/ml |
| Aluminium hydroxide | ??0.5mg/ml |
| Sodium chloride | ??8.0mg/ml |
| Sodium dihydrogen phosphate | ??0.93mg/ml |
| Sodium hydrogen phosphate | ??0.32mg/ml |
The hepatitis A inactivated vaccine of the present invention preparation is through calibrating, and calibrating projects such as sterility test, abnormal toxicity test, pH value are all qualified, and aluminium hydroxide absorption back hepatitis A virus (HAV) does not have and dissociates, and external relative effectivenes reaches 1.48, and the calibrating data see Table 1.
All " Chinese pharmacopoeia appendix correlation technique carries out with reference to current edition for bacterial endotoxin inspection method and undue toxicity's inspection method; External relative effectivenes is measured with reference to " Chinese pharmacopoeia (2010 editions) appendix XS carries out.
The hav inactivated vaccine finished product verification result of table 2 embodiment 1 preparation
| The calibrating project | Criterion | Verification result |
| External relative effectivenes | ??≥0.75 | ??1.48 |
| Aluminum content | ??≤1.20mg/ml | ??0.49mg/ml |
| Free formaldehyde content | ??≤50μg/ml | ??11μg/ml |
| PH value | ??5.5～7.0 | ??6.20 |
| The chloroform residual quantity | ??≤0.006％ | ??≤0.001％ |
| Sterility test | Should be up to specification | Qualified |
| Endotoxin content | ??＜10EU/ml | ??＜10EU/ml |
| Abnormal toxicity test | Animal is all strong deposits and weight increase | Qualified |
Embodiment 2
Get the human diploid cell (2BS strain) of the rolling bottle cultivation of covering with monolayer, through 0.25% trypsinization, inoculate the 3L rolling bottle in proportion, get L-A-1 attenuated strain work seed lot seed culture of viruses simultaneously through suitably dilution, the inoculation human diploid cell, put 35 ℃ ± 0.5 ℃ rotating and culturing 19-26 days, change liquid 1 time every 7-10 days during this time, treat the virus multiplication peak period, discard culture fluid, washing is after trypsinization, with the centrifugal supernatant of abandoning of the cell suspension of viral infection; Centrifugation adds the 0.2-0.5% deoxycholic acid sodium solution (cell pyrolysis liquid) that contains mass percent 2-5% disodiumedetate by 2-4 multiple proportions example, room temperature vibration 2h, and abundant mixing, 4 ℃ of effect 24h with abundant cell lysis, discharge virus; The adding final concentration is 10% Polyethylene Glycol (MW6000), and 4 ℃ of precipitations are spent the night, the centrifugal 1.5h of 4500r/min; Centrifugation suspends with the 0.01mol/L PBS buffer (pH 6.3) of 1/10 volume; Add the equal-volume chloroform, repeat extracting 3～5 times, make rough hepatitis A venom; Sephacryl S-400HR gel is packed in the chromatographic column, after 0.01mol/L PBS buffer (pH7) balance,,, collect the elution of virus peak, be the hepatitis A venom of purification with 0.02mol/L PBS buffer (pH7) eluting with sample on the rough hepatitis A venom; Again through 0.2 μ m filter membrane aseptic filtration, under aseptic condition, add final concentration and be 37 ℃ of deactivations of formaldehyde 14 days of 250 μ g/ml.The hepatitis A venom of deactivation is through the ultrafilter membrane ultrafiltration of 100KD, further behind the assay approval, be diluted to 1280EU/ml, make semi-finished product through aluminum hydroxide adjuvant absorption according to virus antigenicity titre level, semi-finished product are sub-packed in the aseptic cillin bottle, make the finished product vaccine.Hav inactivated vaccine (1.0ml) contains following composition:
The hav inactivated vaccine composition of table 3. embodiment 2 preparations
| HAV antigen | ??1280EU/ml |
| Aluminium hydroxide | ??0.5mg/ml |
| Sodium chloride | ??8.0mg/ml |
| HAV antigen | ??1280EU/ml |
| Sodium dihydrogen phosphate | ??0.93mg/ml |
| Sodium hydrogen phosphate | ??0.32mg/ml |
The hepatitis A inactivated vaccine of the present invention preparation is through calibrating, and calibrating projects such as sterility test, abnormal toxicity test, pH value are all qualified, and aluminium hydroxide absorption back hepatitis A virus (HAV) does not have and dissociates, and external relative effectivenes reaches 1.59, and finished product calibrating data see Table 4.
All " Chinese pharmacopoeia appendix correlation technique carries out with reference to current edition for bacterial endotoxin inspection method and undue toxicity's inspection method; External relative effectivenes is measured with reference to " Chinese pharmacopoeia (2010 editions) appendix XS carries out.
The hav inactivated vaccine verification result of table 4 embodiment 2 preparations
| The calibrating project | Criterion | Verification result |
| External relative effectivenes | ??≥0.75 | ??1.59 |
| Aluminum content | ??≤1.20mg/ml | ??0.50mg/ml |
| Free formaldehyde content | ??≤50μg/ml | ??10μg/ml |
| PH value | ??5.5～7.0 | ??6.25 |
| The chloroform residual quantity | ??≤0.006％ | ??≤0.001％ |
| Sterility test | Should be up to specification | Qualified |
| Endotoxin content | ??＜10EU/ml | ??＜10EU/ml |
| Abnormal toxicity test | Animal is all strong deposits and weight increase | Qualified |
Embodiment 3
The hepatitis A inactivated vaccine that the embodiment of the invention 1, embodiment 2 are provided carries out potency test in the mice body, calculates the effective extension rate of half, observes its immunogenicity.
Get female NIH mice, body weight 16-18g, random packet.Test is divided into 4 groups, and 20 every group, negative control group: injection aluminium hydroxide thinner for vaccine; 2 groups of 1 group of test seedling and test seedlings: inject the vaccine of embodiment 1 and embodiment 2 preparations respectively, 1280EU/ml; Reference Seedling group: external hepatitis A inactivated vaccine, 1440EU/ml.With thinner for vaccine test seedling and reference Seedling are carried out 4 times of serial dilutions, totally 3 dilution factors 1: 4,1: 16 and 1; 64.Every mouse peritoneal injection 1.0ml, after immune 4 weeks, the heart blood sampling, centrifugalize serum ,-20 ℃ of preservations are standby.Adopt ELISA competition inhibition method to detect anti-HAV antibody, calculate the effective extension rate of half according to the Reed-Muench method.The results are shown in Table 5.
Table 5 hav inactivated vaccine mice of the present invention potency test result
The potency test result shows in the mice body, when the hav inactivated vaccine antigenic content of embodiment 1 and embodiment 2 preparations is 1280EU/ml, the effective extension rate of half all is higher than the reference Seedling, its immunogenicity is better than the reference Seedling, and therefore the preferred HAV antigenic content of hav inactivated vaccine provided by the invention is 1280EU/ml.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a method for preparing hepatitis A inactivated vaccine comprises the steps:
Step 1: the hepatitis A virus seed culture of viruses is inoculated in human embryonic lung diploid fibroblast 2BS strain, is cultured to the virus multiplication peak period, with the conventional peptic cell of pancreatin;
Step 2: the centrifuging and taking precipitation adds cell pyrolysis liquid, and it is fully acted on;
Step 3: add Polyethylene Glycol it is fully acted on, the centrifuging and taking precipitation suspends with the PBS buffer, adds the chloroform extracting, prepares rough hepatitis A venom;
Step 4: the rough hepatitis A venom of step 3 preparation is behind gel chromatography, through 0.2 μ m filter membrane degerming, deactivation;
Step 5: the hepatitis A venom of step 4 preparation through the ultrafilter membrane ultrafiltration, through aluminum hydroxide adjuvant absorption, is made hepatitis A inactivated vaccine.
2. method according to claim 1 is characterized in that, the described seed culture of viruses of step 1 is a hepatitis A virus L-A-1 attenuated strain, is deposited in Wuhan China typical culture collection center on the 21st in December in 1992, and deposit number is CCTCC No.V92004.
3. method according to claim 1 is characterized in that, the described cultivation of step 1 is cultivated for utilizing multi-layered cell factory or 3L rolling bottle.
4. method according to claim 1, it is characterized in that, step 2 is specially the centrifuging and taking precipitation and adds cell pyrolysis liquid at 2-8 ℃ of effect 16-24h, and described cell pyrolysis liquid is the 0.2-0.5% deoxycholic acid sodium solution that contains mass percent 2-5% disodiumedetate.
5. method according to claim 1 is characterized in that, the described molecular weight polyethylene glycol of step 3 is 6000, and final concentration is a percent by volume 8%～10%.
6. method according to claim 1 is characterized in that, the PBS buffer of the 0.01-0.02mol/L that the described PBS buffer of step 3 is pH 5.5～7.5.
7. method according to claim 1 is characterized in that, the described deactivation of step 4 is that final concentration is formalin deactivation 12-14 days of 200-250 μ g/ml.
8. method according to claim 1 is characterized in that, the molecular cut off of the described ultrafilter membrane of step 5 is 50-100KD.
9. according to the hepatitis A inactivated vaccine of each described method preparation of claim 1-8.
10. hepatitis A inactivated vaccine according to claim 9 is characterized in that, described vaccine inactivation hepatitis A virus (HAV) concentration is 640～1280EU/ml.
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| CN102058882A (en) * | 2010-12-28 | 2011-05-18 | 北京民海生物科技有限公司 | Method of preparing hepatitis A inactivated vaccine |
| CN102174477A (en) * | 2010-12-28 | 2011-09-07 | 深圳康泰生物制品股份有限公司 | Hepatitis A virus strain SH and diploid cell adaptation method thereof |
| CN102608313A (en) * | 2012-02-27 | 2012-07-25 | 中国疾病预防控制中心病毒病预防控制所 | Anti-hepatitis A virus IgM (immunoglobulin M) AlphaLISA detection kit |
| CN103525770A (en) * | 2013-10-08 | 2014-01-22 | 云南沃森生物技术股份有限公司 | Application of human fetal lung fibroblast line in preparation of hepatitis A vaccines |
| CN106754638A (en) * | 2016-12-01 | 2017-05-31 | 长春生物制品研究所有限责任公司 | Cross CO2Multi-layer cellular blake bottle human diploid cell adhere-wall culture method |
| CN110669739A (en) * | 2019-09-30 | 2020-01-10 | 长春生物制品研究所有限责任公司 | Preparation method of novel hepatitis A virus antigen |
| CN114350624A (en) * | 2021-12-28 | 2022-04-15 | 艾美康淮生物制药（江苏）有限公司 | Method for preparing hepatitis A inactivated vaccine |
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| CN102058882A (en) * | 2010-12-28 | 2011-05-18 | 北京民海生物科技有限公司 | Method of preparing hepatitis A inactivated vaccine |
| CN102174477A (en) * | 2010-12-28 | 2011-09-07 | 深圳康泰生物制品股份有限公司 | Hepatitis A virus strain SH and diploid cell adaptation method thereof |
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| CN103525770A (en) * | 2013-10-08 | 2014-01-22 | 云南沃森生物技术股份有限公司 | Application of human fetal lung fibroblast line in preparation of hepatitis A vaccines |
| CN103525770B (en) * | 2013-10-08 | 2015-08-19 | 云南沃森生物技术股份有限公司 | The application in hepatitis A vaccine is being prepared in human embryonic lung fibroblast strain |
| CN106754638A (en) * | 2016-12-01 | 2017-05-31 | 长春生物制品研究所有限责任公司 | Cross CO2Multi-layer cellular blake bottle human diploid cell adhere-wall culture method |
| CN110669739A (en) * | 2019-09-30 | 2020-01-10 | 长春生物制品研究所有限责任公司 | Preparation method of novel hepatitis A virus antigen |
| CN114350624A (en) * | 2021-12-28 | 2022-04-15 | 艾美康淮生物制药（江苏）有限公司 | Method for preparing hepatitis A inactivated vaccine |
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