CN107537032A - A kind of tetravalence influenza virus subunit vaccine and preparation method thereof - Google Patents
A kind of tetravalence influenza virus subunit vaccine and preparation method thereof Download PDFInfo
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- CN107537032A CN107537032A CN201610459659.2A CN201610459659A CN107537032A CN 107537032 A CN107537032 A CN 107537032A CN 201610459659 A CN201610459659 A CN 201610459659A CN 107537032 A CN107537032 A CN 107537032A
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Abstract
The invention discloses a kind of tetravalence influenza virus subunit vaccine and preparation method thereof, the virus protein after cracking is further purified using decomposition agent and new purification process for the influenza vaccines, tetravalence influenza virus subunit vaccine is made, wherein every dose of type containing first 1（H1N1）, the type of first 3（H3N2）, 2 kinds of B-mode totally four kinds of influenza hemagglutinin contents more than 80%, without adjuvant, without preservatives such as thimerosals.Present invention also offers the preparation method of the influenza vaccines, comprise the following steps：Virus inoculation, virus multiplication culture, allantoic fluid harvest, clarify, be concentrated by ultrafiltration, inactivate, cracking and ultracentrifugation purifying, gel filtration chromatography（Ultrafiltration）, mixture, filtration sterilization, packing, packaging and other steps.Influenza virus subunit vaccine provided by the invention can improve the security of influenza vaccines, eliminate the adverse reaction that adjuvant is brought, eliminate toxic side effect caused by thimerosal.
Description
Technical field
The invention belongs to biological technical field, and in particular to a kind of tetravalence influenza virus subunit vaccine and its preparation side
Method.
Background technology
Influenza is that the acute respiratory that the people of extensive prevalence, poultry can be caused to suffer from altogether as caused by influenza virus is propagated
Disease.Influenza virus divides first, second, the third three types.Wherein, A type pathogenicity is most strong, infection animal and the mankind and can cause
Prevalence is even worldwide to be very popular；B-mode pathogenicity is slightly weak, can cause localized epidemics.Influenza virus often occurs anti-
Original drift and antigen transfer, escape the defence of body immune system, this is also to cause pandemic reason.Influenza virus has height
Infectiousness is spent, passes through spittle air-borne transmission.After of short duration incubation period, anxious to play high fever shiver with cold, body temperature may be up to 40 in 1 ~ 2 day
DEG C, with symptoms such as malaise, headache, myalgia, pharyngalgia, pneumonia, bronchitis, myocarditis, pericarditis etc. can be triggered concurrent
Disease, the mortality of the people at highest risk such as the elderly, weakling is caused, huge loss is brought to society.The influenza of maximum-norm
It is very popular and betides 1918 ~ 1919 years, causes 2100 ~ 40,000,000 people dead（Wherein just there are 500,000 people, only in October, 1918 in the U.S.
Just there are 19.6 ten thousand people dead）, more than the war death toll of the World War I.Therefore, the prevention of influenza is constantly subjected to generation
The great attention of various countries of boundary.Clinically still lack effective medicine to influenza, inoculation influenza vaccines are unique effectively preventions
Means.
The existing vaccine of in the market is influenza all-virus inactivated vaccine and influenza virus cracking vaccine, and traditional split vaccine purifies
Method is：The monovalent harvest liquid of clarification inactivation is through being concentrated by ultrafiltration, sucrose density zonal centrifugation purifies, ultrafiltration removes sucrose, splits
Solution, again sucrose density zonal centrifugation purify, and ultrafiltration again removes sucrose, aseptic filtration, adds thimerosal as preservative.
Complex process, complex steps, substantial amounts of manpower and materials are consumed, increase microorganism pollution risk.
Traditional influenza vaccines purity is inadequate simultaneously and contains harmful adjuvant and preservative.Although adjuvant can change
The immune response of kind vaccine, but cost is reactionogenicity increase, in addition it is very serious.For example, the elderly is inoculated with MF59 adjuvant influenza
Antibody level improves after vaccine, but the local reaction after being inoculated with is more, in the comparative study of a elderly, inoculation
The elderly containing Adjuvanted vaccines is compared with being inoculated with without the elderly of adjuvant, and pain increases by 6 times, local rubescent 2 times of increase, it is weak and
The general reactions such as courbature also increase.According to another report, the aluminium hydroxide for having used Statens serum research institute of Denmark to produce is inhaled
Attached DPT vaccine, 546 injection sites are caused the serious adverse reaction of intractable scleroma property itch occur.Wherein 77%
Adverse reaction case is confirmed as to aluminium hydroxide allergy through Skin-test.At present, state food drug administration has prohibited hydrogen
Aluminum adjuvant is used for the production of rabies vacciness.Thimerosal is used as the preservative of many vaccines always, but sulphur willow now
Mercury causes the toxic side effects such as contact dermatitis, allergic conjunctivitis, ototoxicity to have begun to the attention for causing scientific research personnel, now
Forbid using sulphur willow in pediatric vaccines in U.S. Iowa, California, Britain and other European countries
Mercury.
The content of the invention
For under above-mentioned background, present invention aims at disclose a kind of tetravalence influenza virus subunit vaccine and its preparation
Method, it is characterised in that the tetravalence influenza virus subunit vaccine uses decomposition agent and new preparation method, by chick embryo allantois
Albumen in harvest liquid after influenza virus cracking is further purified, and influenza virus subunit vaccine is made, wherein every dose contains first 1
（H1N1）, first 3（H3N2）With 2 kinds of second（B）Type totally four kinds of influenza hemagglutinin contents more than 80%.
A kind of tetravalence influenza virus subunit vaccine preparation method, it is characterised in that comprise the following steps successively：（1）Virus
Inoculation：By first 1（H1N1）, first 3（H3N2）With 2 kinds of second（B）Type influenza virus work seed is inoculated in 9 ~ 11 ages in days health respectively
In chick embryo allantoic cavity；
（2）Virus multiplication culture：Chicken embryo after inoculation is transferred to 33 ~ 35 DEG C of incubator cultures 48 ~ 72 hours, breeds influenza virus；
（3）Allantoic fluid harvests：Live chickens embryo is screened, 2 ~ 8 DEG C of cold embryos is placed and harvests allantoic fluid after 10 ~ 24 hours；
（4）Clarification：Most of impurity such as chicken embryo erythrocyte are removed with centrifugal process or filtration method；
（5）Inactivation：The formaldehyde that final concentration is not higher than 200mg/ml is added in monovalent virus harvest liquid, 40 ~ 120 are inactivated in 2 ~ 8 DEG C
Hour, this step can also be carried out after ultrafiltration concentration；
（6）It is concentrated by ultrafiltration：It is super with 300 ~ 1000kD of molecular cut off by the influenza virus allantois harvest liquid after abundant inactivation
Filter membrane is concentrated by ultrafiltration；
（7）Cracking and ultracentrifugation purifying：Liquid will be concentrated by ultrafiltration and add decomposition agent, loading is mixed, through sucrose density band centrifugation
Purifying, lysate is harvested according to certain sucrose concentration；
（8）Gel filtration chromatography or ultrafiltration：The solution that previous step sucrose density gradient centrifugation is obtained is through Gel filtration
Analysis system is further purified or ultrafiltration obtains influenza virus subunit vaccine unit price stoste；
（9）Mixture：By first 1（H1N1）, first 3（H3N2）With 2 kinds of second（B）Type influenza virus unit price stoste is according to hemagglutinin concentration 1：
1：1：1 relation carries out mixture, and various viral hemagglutinin concentration control is between 40 ~ 48mg/ml；
（10）Filtration sterilization：Virus liquid after previous step mixture is obtained into influenza virus Asia after 0.22mm membrane filtrations are degerming
Subunit vaccine semi-finished product；
（11）Packing：Vaccine semi-finished product are dispensed into pre-encapsulated injector or cillin bottle, every 0.5ml, every 1 people's agent
Measure as 0.5ml, should be in 10 ~ 20mg scopes containing each influenza virus strain hemagglutinin；
（12）Packaging：After lamp inspection is qualified, carry out labelling the packaging such as mounted box according to quality standard.
The decomposition agent is Nonoxynol-9（Nonylphenyl Polyethylene Glycol Ether）.
Described to crack the synchronous progress with ultracentrifugation purifying, more detailed way is to add decomposition agent in liquid is concentrated by ultrafiltration
In and make it well mixed, carry out loading after well mixed, cracking synchronized during sucrose density band centrifugation, with
Reach the purpose separated in cracking, lysate is harvested according to certain sucrose concentration after the completion of cracking.
Described Gel filtration analysis system is Sephadex G-25 sephadexes.
This vaccine is without adjuvants such as CpG ODN adjuvants or aluminium hydroxides.
This vaccine is without preservatives such as thimerosals.
It is 0.01 ~ 2% that agent concentration is cracked used in purifying, and preferred concentration is 0.1 ~ 1.5%.
Harvest liquid sucrose concentration is 10 ~ 40%, and preferred concentration is 15 ~ 30%
The band centrifugation time is 1 ~ 24 hour, preferably 4 ~ 16 hours.
Beneficial effects of the present invention are：The present invention uses new decomposition agent and new purification process, by the influenza after cracking
Virus protein is further purified, and it is mainly that stromatin and nucleoprotein recovery hemagglutinin obtain one kind to remove most of virus protein
The higher influenza virus subunit vaccine of purity, and adjuvant is free of in vaccine, greatly reduce red and swollen, pain caused by adjuvant
Bitterly, the serious adverse reaction such as heating.For vaccine without preservatives such as thimerosals, contact skin can be caused by eliminating introducing thimerosal
The hidden danger of the toxic side effects such as inflammation, allergic conjunctivitis, ototoxicity, in addition, Split influenza virus vaccine often uses decomposition agent in the market
For polyoxyethylene sorbitan monoleate, Triton X-100, Triton N101Deng vaccine preparation method of the invention uses new decomposition agent：Nonyl
Menthylphenoxypolyethoxy ethanol -9 is a kind of acceptable non-ionic type surfactant, and its chemical name is Nonylphenyl Polyethylene
Glycol Ether, it is Triton N101Isomer, have and Triton N101Identical lytic effect, and security
Higher than Triton N101Etc. conventional decomposition agent, the security of product is further increased.The technique of the present invention is easily achieved, and is produced
Efficiency high, it can quickly prepare the influenza virus subunit vaccine of high quality.
Brief description of the drawings
Fig. 1 is influenza virus subunit vaccine process chart.
Embodiment
With reference to embodiment, the invention will be further described.
Embodiment 1：
First 1（H1N1）Type influenza virus subunit vaccine unit price stoste production method, comprises the following steps successively：
(1) virus inoculations：By first 1（H1N1）Type influenza virus work seed is inoculated in 10 age in days health chick embryo allantoic cavities；
(2) virus multiplications culture：Chicken embryo after inoculation is transferred to 34 DEG C of incubator cultures 48 hours, breeds influenza virus；
(3) allantoic fluids harvest：Live chickens embryo is screened, 2 ~ 8 DEG C of cold embryos is placed and harvests allantoic fluid after 16 hours；
(4) is clarified：Most of impurity such as chicken embryo erythrocyte are removed with centrifugal process.
(5) is inactivated：The formaldehyde that final concentration is not higher than 200mg/ml is added in monovalent virus harvest liquid, 80 are inactivated in 2 ~ 8 DEG C
Hour；
(6) is concentrated by ultrafiltration：By the influenza virus allantois harvest liquid after abundant inactivation, with molecular cut off 1000kD milipore filter
It is concentrated by ultrafiltration；
(7) cracking and ultracentrifugation purifying：Will be concentrated by ultrafiltration liquid add 1.0% decomposition agent Nonoxynol-9, be well mixed after on
Sample, cracking 4 hours is synchronized during sucrose density band centrifugation, to reach the purpose separated in cracking, according to
Sucrose concentration, harvest the lysate between 10 ~ 20%；
(8) gel filtration chromatographies：The solution that previous step sucrose density gradient centrifugation obtains is gathered through SephadexG-25 Portugals
Sugared Gel filtration analysis system is further purified to obtain first 1（H1N1）Type influenza virus subunit vaccine unit price stoste；
Embodiment 2：
First 3（H3N2）Type influenza virus subunit vaccine unit price stoste production method, comprises the following steps successively：
(1) virus inoculations：By first 3（H3N2）Type influenza virus work seed is inoculated in 10 age in days health chick embryo allantoic cavities；
(2) virus multiplications culture：Chicken embryo after inoculation is transferred to 34 DEG C of incubator cultures 48 hours, breeds influenza virus；
(3) allantoic fluids harvest：Live chickens embryo is screened, 2 ~ 8 DEG C of cold embryos is placed and harvests allantoic fluid after 16 hours；
(4) is clarified：Most of impurity such as chicken embryo erythrocyte are removed with centrifugal process.
(5) is inactivated：The formaldehyde that final concentration is not higher than 200mg/ml is added in monovalent virus harvest liquid, in 2 ~ 8 DEG C of inactivations
100 hours；
(6) is concentrated by ultrafiltration：By the influenza virus allantois harvest liquid after abundant inactivation, entered with molecular cut off 300kD milipore filter
Row is concentrated by ultrafiltration；
(7) cracking and ultracentrifugation purifying：Will be concentrated by ultrafiltration liquid add 0.5% decomposition agent Nonoxynol-9, be well mixed after on
Sample, cracking 10 hours is synchronized during sucrose density band centrifugation, to reach the purpose separated in cracking, according to
Sucrose concentration, harvest the lysate between 15 ~ 30%；
(8) gel filtration chromatographies：The solution that previous step sucrose density gradient centrifugation obtains is gathered through SephadexG-25 Portugals
Sugared Gel filtration analysis system is further purified to obtain first 3（H3N2）Type influenza virus subunit vaccine unit price stoste.
Embodiment 3：
Second（B）Type influenza virus subunit vaccine unit price stoste production method, comprises the following steps successively：
(1) virus inoculations：By second（B）Type influenza virus work seed is inoculated in 10 age in days health chick embryo allantoic cavities；
(2) virus multiplications culture：Chicken embryo after inoculation is transferred to 34 DEG C of incubator cultures 72 hours, breeds influenza virus；
(3) allantoic fluids harvest：Live chickens embryo is screened, 2 ~ 8 DEG C of cold embryos is placed and harvests allantoic fluid after 16 hours；
(4) is clarified：Most of impurity such as chicken embryo erythrocyte are removed with centrifugal process.
(5) is inactivated：The first that final concentration is not higher than 200mg/ml is added in monovalent virus harvest liquid or in ultrafiltration concentration liquid
Aldehyde, inactivated 120 hours in 2 ~ 8 DEG C；
(6) is concentrated by ultrafiltration：By the influenza virus allantois harvest liquid after abundant inactivation, with molecular cut off 1000kD milipore filter
It is concentrated by ultrafiltration；
(7) cracking and ultracentrifugation purifying：Will be concentrated by ultrafiltration liquid add 1.5% decomposition agent Nonoxynol-9, be well mixed after on
Sample, cracking 8 hours is synchronized during sucrose density band centrifugation, to reach the purpose separated in cracking, according to
Sucrose concentration, harvest the lysate between 10 ~ 30%；
(8) gel filtration chromatographies：The solution that previous step sucrose density gradient centrifugation obtains is gathered through SephadexG-25 Portugals
Sugared Gel filtration analysis system is further purified to obtain second（B）Type influenza virus subunit vaccine unit price stoste.
(9) is concentrated by ultrafiltration：By the influenza virus allantois harvest liquid after abundant inactivation, with molecular cut off 10kD ultrafiltration
Film is concentrated by ultrafiltration；
Embodiment 4:
Vaccine finished product mixture and preparation method, comprise the following steps successively：
(1) mixtures：By first 1（H1N1）, first 3（H3N2）With 2 kinds of second（B）Type influenza virus unit price stoste is according to hemagglutinin concentration
1：1：1：1 relation carries out mixture, and various viral hemagglutinin concentration control is between 40 ~ 48mg/ml；
(2) filtration sterilizations：Virus liquid after previous step mixture is obtained into influenza virus Asia after 0.22mm membrane filtrations are degerming
Subunit vaccine semi-finished product；
(3) is dispensed：Vaccine semi-finished product are dispensed into pre-encapsulated injector or cillin bottle, every 0.5ml, every 1 people's agent
Measure as 0.5ml, should be in 10 ~ 20mg scopes containing each influenza virus strain hemagglutinin；
(4) is packed：After lamp inspection is qualified, carry out labelling the packaging such as mounted box according to quality standard.
Above-described embodiment is only the preferable embodiment of the present invention, and the present invention can not enumerate out whole embodiment party
Formula, all technical schemes using above-described embodiment, or the equivalent variations done according to above-described embodiment, protect model in the present invention
In enclosing.
Claims (10)
- A kind of 1. tetravalence influenza virus subunit vaccine and preparation method thereof, it is characterised in that the tetravalence influenza virus subunit Vaccine is cracked and separated subunit's component hemagglutinin simultaneously using one-step method, decomposition agent be new decomposition agent nonoxinol- 9, the albumen after influenza virus cracking in chick embryo allantois harvest liquid is further purified, influenza virus subunit vaccine is made, often Agent type containing first 1（H1N1）, the type of first 3（H3N2）, 2 kinds of B-mode totally four kinds of influenza hemagglutinin contents more than 80%, without adjuvant, no Containing preservatives such as thimerosals.
- 2. a kind of tetravalence influenza virus subunit vaccine preparation method, it is characterised in that comprise the following steps successively：Virus inoculation：By first 1（H1N1）, first 3（H3N2）With 2 kinds of second（B）Type influenza virus work seed is inoculated in 9 ~ 11 respectively In age in days health chick embryo allantoic cavity；Virus multiplication culture：Chicken embryo after inoculation is transferred to 33 ~ 35 DEG C of incubator cultures 48 ~ 72 hours, breeds influenza virus；Allantoic fluid harvests：Live chickens embryo is screened, 2 ~ 8 DEG C of cold embryos is placed and harvests allantoic fluid after 10 ~ 24 hours；Clarification：Most of impurity such as chicken embryo erythrocyte are removed with centrifugal process or filtration method；Inactivation：The formaldehyde that final concentration is not higher than 200mg/ml is added in monovalent virus harvest liquid, it is small in 2 ~ 8 DEG C of inactivations 40 ~ 120 When, this step can also be carried out after ultrafiltration concentration；It is concentrated by ultrafiltration：By the influenza virus allantois harvest liquid after abundant inactivation, with 300 ~ 1000kD of molecular cut off milipore filter It is concentrated by ultrafiltration；Cracking and ultracentrifugation purifying：Liquid will be concentrated by ultrafiltration and add decomposition agent, mix loading, it is pure through sucrose density band centrifugation Change, lysate is harvested according to certain sucrose concentration；Gel filtration chromatography or ultrafiltration：By the solution that previous step sucrose density gradient centrifugation obtains through gel permeation chromatography system System is further purified or ultrafiltration obtains influenza virus subunit vaccine unit price stoste；Mixture：By first 1（H1N1）, first 3（H3N2）With 2 kinds of second（B）Type influenza virus unit price stoste is according to hemagglutinin concentration 1：1： 1：1 relation carries out mixture, and various viral hemagglutinin concentration control is between 40 ~ 48mg/ml；Filtration sterilization：Virus liquid after previous step mixture is obtained into influenza virus subunit after 0.22mm membrane filtrations are degerming Vaccine semi-finished product；Packing：Vaccine semi-finished product are dispensed into pre-encapsulated injector or cillin bottle, every 0.5ml, every 1 people is with dosage 0.5ml, should be in 10 ~ 20mg scopes containing each influenza virus strain hemagglutinin；Packaging：After lamp inspection is qualified, carry out labelling the packaging such as mounted box according to quality standard.
- A kind of 3. tetravalence influenza virus subunit vaccine according to claim 1 ~ 2 and preparation method thereof, it is characterised in that The decomposition agent is Nonoxynol-9（Nonylphenyl Polyethylene Glycol Ether）.
- A kind of 4. tetravalence influenza virus subunit vaccine according to claim 2 and preparation method thereof, it is characterised in that institute Cracking synchronous progress with ultracentrifugation purifying is stated, more detailed way is to be concentrated by ultrafiltration in liquid in addition decomposition agent and making it mixed Close uniformly, carry out loading after well mixed, cracking is synchronized during sucrose density band centrifugation, to reach side cracking The purpose of side separation, lysate is harvested after the completion of cracking according to certain sucrose concentration.
- A kind of 5. tetravalence influenza virus subunit vaccine according to claim 1 and preparation method thereof, it is characterised in that institute It is Sephadex G-25 sephadexes to state Gel filtration analysis system.
- A kind of 6. tetravalence influenza virus subunit vaccine according to claim 1 and preparation method thereof, it is characterised in that institute New influenza virus subunit vaccine is stated, this vaccine is without adjuvants such as CpG ODN adjuvants or aluminium hydroxides.
- 7. new a kind of tetravalence influenza virus subunit vaccine according to claim 1 and preparation method thereof, its feature exists In the influenza virus subunit vaccine, this vaccine is without preservatives such as thimerosals.
- A kind of 8. tetravalence influenza virus subunit vaccine according to claim 4 and preparation method thereof, it is characterised in that institute It is 0.01 ~ 2% to state decomposition agent concentration, and preferred concentration is 0.1 ~ 1.5%.
- A kind of 9. tetravalence influenza virus subunit vaccine according to claim 4 and preparation method thereof, it is characterised in that institute It is 10 ~ 40% to state harvest liquid sucrose concentration, and preferred concentration is 15 ~ 30%.
- A kind of 10. tetravalence influenza virus subunit vaccine according to claim 4 and preparation method thereof, it is characterised in that institute The band centrifugation time is stated as 1 ~ 24 hour, preferably 4 ~ 16 hours.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111068048A (en) * | 2019-12-19 | 2020-04-28 | 江苏金迪克生物技术有限公司 | Preparation method of tetravalent influenza virus split vaccine |
| CN111420044A (en) * | 2020-05-11 | 2020-07-17 | 中逸安科生物技术股份有限公司 | Tetravalent influenza virus subunit vaccine and preparation method thereof |
| CN111803625A (en) * | 2020-09-09 | 2020-10-23 | 天津中逸安健生物科技有限公司 | Subunit influenza vaccine cracking agent and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104888212A (en) * | 2015-02-09 | 2015-09-09 | 天士力金纳生物技术（天津）有限公司 | Influenza virus subunit vaccine and preparation method thereof |
-
2016
- 2016-06-23 CN CN201610459659.2A patent/CN107537032A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104888212A (en) * | 2015-02-09 | 2015-09-09 | 天士力金纳生物技术（天津）有限公司 | Influenza virus subunit vaccine and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111068048A (en) * | 2019-12-19 | 2020-04-28 | 江苏金迪克生物技术有限公司 | Preparation method of tetravalent influenza virus split vaccine |
| CN111420044A (en) * | 2020-05-11 | 2020-07-17 | 中逸安科生物技术股份有限公司 | Tetravalent influenza virus subunit vaccine and preparation method thereof |
| CN111420044B (en) * | 2020-05-11 | 2021-04-09 | 中逸安科生物技术股份有限公司 | Tetravalent influenza virus subunit vaccine and preparation method thereof |
| CN111803625A (en) * | 2020-09-09 | 2020-10-23 | 天津中逸安健生物科技有限公司 | Subunit influenza vaccine cracking agent and application thereof |
| CN111803625B (en) * | 2020-09-09 | 2020-12-18 | 天津中逸安健生物科技有限公司 | Subunit influenza vaccine cracking agent and application thereof |
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