CN115998853B - Attenuated live vaccine for Japanese encephalitis and protective agent thereof - Google Patents
Attenuated live vaccine for Japanese encephalitis and protective agent thereof Download PDFInfo
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- CN115998853B CN115998853B CN202310088333.3A CN202310088333A CN115998853B CN 115998853 B CN115998853 B CN 115998853B CN 202310088333 A CN202310088333 A CN 202310088333A CN 115998853 B CN115998853 B CN 115998853B
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- 230000002238 attenuated effect Effects 0.000 title claims abstract description 43
- 241000710842 Japanese encephalitis virus Species 0.000 title claims abstract description 39
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- 201000005807 Japanese encephalitis Diseases 0.000 title claims abstract description 36
- 239000003223 protective agent Substances 0.000 title claims abstract description 36
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- 238000000034 method Methods 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 10
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 7
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- 238000001035 drying Methods 0.000 claims description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
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- 238000012792 lyophilization process Methods 0.000 claims 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 206010020741 Hyperpyrexia Diseases 0.000 description 1
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- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
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- 235000013919 monopotassium glutamate Nutrition 0.000 description 1
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- HQEROMHPIOLGCB-DFWYDOINSA-M potassium;(2s)-2-aminopentanedioate;hydron Chemical compound [K+].[O-]C(=O)[C@@H](N)CCC(O)=O HQEROMHPIOLGCB-DFWYDOINSA-M 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a Japanese encephalitis attenuated live vaccine protective agent, which comprises the following components in parts by weight: sucrose: 3-5 parts of lactose: 3-5 parts of gelatin: 0.5 to 1 part of urea: 0.2-0.5 part of human serum albumin: 0.1 to 0.5 part. The protective agent can effectively protect the toxicity of the Japanese encephalitis attenuated virus, reduce titer loss in the freeze-drying process, ensure excellent freeze-drying effect, and the prepared Japanese encephalitis attenuated live vaccine freeze-dried preparation can be stored for a long time and has excellent stability.
Description
Technical Field
The invention belongs to the technical field of vaccine preparation, and particularly relates to a Japanese encephalitis attenuated live vaccine and a protective agent thereof.
Background
Epidemic encephalitis B, which is abbreviated as "Japanese encephalitis," is an acute infectious disease caused by Japanese encephalitis virus and mainly caused by damage to the central nervous system, and is transmitted by mosquitoes, popular in summer and autumn, and distributed in more Asia. The Japanese encephalitis is clinically characterized by hyperpyrexia, disturbance of consciousness, convulsion and meninges stimulation, and serious symptoms can leave nervous system sequelae with different degrees to influence the life quality of patients, and no specific treatment aiming at pathogens exists at present. However, despite the general susceptibility of the population to encephalitis, the incidence of post-infection is low and there is a persistent immunity post-infection, which makes prophylactic vaccine injection to encephalitis particularly important. At present, japanese encephalitis attenuated vaccine and freeze-dried Japanese encephalitis inactivated vaccine (Vero cells) are marketed and clinically applied in China, so that the incidence of Japanese encephalitis is greatly reduced.
The attenuated live Japanese encephalitis vaccine is a freeze-dried product, and a protective agent used during freeze-drying is a key ring for influencing the stability and efficacy of the vaccine, and can change the physicochemical environment of a biological sample during freeze-drying, reduce or prevent the damage of freeze-drying or rehydration to viruses, and keep various physiological and biochemical characteristics and biological activities (protecting virus titer) as far as possible. Therefore, to ensure the stability and efficacy of attenuated live Japanese encephalitis vaccines, it is important to provide safe and effective protective agents.
Researchers have explored the composition of the lyoprotectant of the attenuated live vaccine of Japanese encephalitis, and some reports are about the present, for example, chinese patent publication No. CN102921002B discloses a lyoprotectant of the attenuated live vaccine of Japanese encephalitis, the formulation is: 6g of sucrose, 3g of trehalose and 9g of dextran, and adding Earl's solution to 100mL; however, the freeze-dried vaccine product prepared by adding the freeze-dried protective agent has fast virus titer reduction in the storage process, and the storage stability is still to be further enhanced. For another example, chinese patent publication No. CN103301452B discloses a lyophilized vaccine for swine Japanese encephalitis, comprising the following protective agent composition: 2.5 to 3.5 percent of NZ-amine, 0.2 to 0.4 percent of monopotassium glutamate, 15 to 25 percent of sucrose, 1.5 to 2.5 percent of hydrolyzed milk protein, 4 to 6 percent of gelatin and water. The vaccine has no more than 0.2 titer loss before and after freeze-drying, and has good storage stability, but the solubility performance is not clear.
The proper freeze-drying protective agent is used, so that the loss of virus titer in the freeze-drying and storage processes is reduced while the freeze-drying effect is ensured, the solubility of the freeze-drying preparation is excellent, the re-dissolution speed is high, and the storage and the use of the encephalitis B attenuated live vaccine are convenient, so that the freeze-drying protective agent has important significance. Therefore, the novel Japanese encephalitis attenuated live vaccine lyoprotectant is still to be further researched and explored.
Disclosure of Invention
The invention aims to provide a Japanese encephalitis attenuated live vaccine and a protective agent thereof.
The invention provides a Japanese encephalitis attenuated live vaccine protective agent, which comprises the following components in parts by weight:
sucrose: 3 to 5 parts of the components in parts by weight,
lactose: 3 to 5 parts of the components in parts by weight,
gelatin: 0.5 to 1 part of the total weight of the mixture,
urea: 0.2 to 0.5 part of the total weight of the composition,
human serum albumin: 0.1 to 0.5 part.
Further, the protective agent comprises the following components in parts by weight:
sucrose: 3.5 parts of the components in parts by weight,
lactose: 3.5 parts of the components in parts by weight,
gelatin: 0.8 part of the total weight of the mixture,
urea: 0.4 part of the total weight of the mixture,
human serum albumin: 0.15 parts.
Still further, the above components further include a pH adjuster.
Further, the pH adjuster is an inorganic base or an inorganic acid, preferably sodium bicarbonate or hydrochloric acid.
Further, the pH of the aqueous solution of the above components is 6.5 to 7.0.
The invention also provides application of the protective agent in preparation of attenuated live vaccine for Japanese encephalitis.
The invention also provides a Japanese encephalitis attenuated live vaccine, which is prepared by mixing Japanese encephalitis virus and the protective agent and freeze-drying.
The invention also provides a preparation method of the encephalitis B attenuated live vaccine, which comprises the following steps:
(1) Mixing the virus stock solution with the protective agent, sterilizing and filtering to obtain a semi-finished product;
(2) Freeze drying the semi-finished product to obtain the final product.
Further, the virus stock is obtained by culturing kidney culture primary cells in a young mouse inoculated with an attenuated strain of SA14-14-2 Japanese encephalitis virus.
Further, the above procedure of freeze-drying is:
pre-freezing for 3-5 hours at-50+/-5 ℃, drying for 14-18 hours at-20+/-5 ℃, and drying for 11-15 hours at-35+/-5 ℃.
The invention has the beneficial effects that: the Japanese encephalitis attenuated live vaccine protective agent with specific composition and specific proportion disclosed by the invention can effectively protect the toxicity of Japanese encephalitis attenuated viruses, reduce titer loss in the freeze-drying process, ensure excellent freeze-drying effect, and the prepared Japanese encephalitis attenuated live vaccine freeze-dried preparation can be stored for a long time and has excellent stability.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a photograph of lyophilized form of a live attenuated Japanese encephalitis vaccine prepared in example 2 of the present invention.
Fig. 2 is a photograph of lyophilized form of encephalitis B attenuated live vaccine prepared in comparative example 1 of the present invention.
FIG. 3 is a photograph of lyophilized form of Japanese encephalitis live attenuated vaccine according to comparative example 2.
Fig. 4 is a photograph of a lyophilized form of a live attenuated Japanese encephalitis vaccine prepared in comparative example 3 according to the present invention.
Fig. 5 is a photograph of a lyophilized form of a live attenuated Japanese encephalitis vaccine prepared in comparative example 4 according to the present invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
EXAMPLE 1 preparation of the attenuated live vaccine protectant against Japanese encephalitis according to the invention
The protective agent comprises the following components: 3.5% by weight of sucrose, 3.5% by weight of lactose, 0.8% by weight of gelatin, 0.4% by weight of urea, 0.15% by weight of human serum albumin, are dissolved in water.
EXAMPLE 2 preparation of attenuated live Japanese encephalitis vaccine according to the invention
Taking kidney culture primary cells from young mice of the ground mice, inoculating SA14-14-2 encephalitis B virus attenuated strain (prepared by Chinese food and drug assay institute) to the cells, and culturing and harvesting the virus to obtain a single virus harvest liquid.
And combining a plurality of single virus harvest liquids of the same cell batch into a batch of stock solution, adding the protective agent of the example 1 into the stock solution according to a proportion, regulating the PH to 6.5-7.0 by using hydrochloric acid, and then sterilizing and filtering to obtain a semi-finished product of the Japanese encephalitis attenuated live vaccine.
And subpackaging the semi-finished product into neutral borosilicate glass tube injection bottles, and covering a butyl rubber plug. And (5) freeze-drying the subpackaged semi-finished product, and performing a freeze-drying procedure: prefreezing (-50+ -5 deg.C for 3-5 h), primary drying (-20+ -5 deg.C for 14-18 h), secondary drying (-35+ -5 deg.C for 11-15 h), capping, and labeling to obtain the final product.
Comparative example 1,
Referring to the method of example 2, only the sucrose and lactose amounts in the protective agent composition are adjusted to 7% wt, and the rest conditions are unchanged, so that the attenuated live vaccine for Japanese encephalitis is prepared.
Comparative example 2,
Referring to the method of example 2, only the gelatin dosage in the protective agent composition was adjusted to 1.6% wt, and the remaining conditions were unchanged, to prepare a live attenuated Japanese encephalitis vaccine.
Comparative example 3,
Referring to the method of example 2, only the urea dosage in the protective agent composition was adjusted to 0.8% wt, and the remaining conditions were unchanged, to prepare a live attenuated Japanese encephalitis vaccine.
Comparative example 4,
With reference to the method of example 2, only the amount of human serum albumin in the composition of the protective agent was adjusted to 0.6% by weight, and the remaining conditions were unchanged, to prepare a live attenuated Japanese encephalitis vaccine.
Comparative example 5,
Referring to the method of example 2, only the protectant set was replaced with: 5% of sucrose and 1% of gelatin, and the rest conditions are unchanged, so as to prepare the attenuated live vaccine for Japanese encephalitis.
The following experiments prove the beneficial effects of the invention.
Experimental example 1, characterization of the attenuated live vaccine for Japanese encephalitis according to the invention
The freeze-dried morphological effect, dissolution effect and osmotic pressure after reconstitution of the attenuated live vaccine of Japanese encephalitis according to the examples and comparative examples of the present invention were characterized, and the results are shown in Table 1 and FIGS. 1 to 5.
TABLE 1
Therefore, only the freeze-dried preparation of the attenuated live vaccine for Japanese encephalitis prepared by using the freeze-dried protective agent with the specific composition has stable form, excellent solubility, short re-dissolution time and optimal comprehensive performance.
Experimental example 2 characterization of viral titre of attenuated live Japanese encephalitis vaccine according to the invention
The titer of the attenuated live Japanese encephalitis vaccine (reflecting the virulence of the virus) was measured and the results are shown in Table 2. Therefore, the freeze-drying protective agent with the specific composition can effectively reduce titer loss of the Japanese encephalitis attenuated live vaccine in the freeze-drying process. The vaccine prepared by the protective agent has high storage stability, little titer drop after being placed at 37 ℃ for 7 days, long-term storage stability at 2-8 ℃ and prolonged period to 24 months.
TABLE 2
In summary, the invention provides a Japanese encephalitis attenuated live vaccine protective agent with specific composition and specific proportion, which can effectively protect the toxicity of Japanese encephalitis attenuated virus, reduce titer loss in the freeze-drying process, ensure excellent freeze-drying effect, and the prepared Japanese encephalitis attenuated live vaccine freeze-dried preparation can be stored for a long time and has excellent stability.
Claims (9)
1. The encephalitis B attenuated live vaccine protective agent is characterized by being prepared by dissolving the following components in parts by weight in water:
sucrose: 3 to 5 parts of the components in parts by weight,
lactose: 3 to 5 parts of the components in parts by weight,
gelatin: 0.5 to 1 part of the total weight of the mixture,
urea: 0.2 to 0.5 part of the total weight of the composition,
human serum albumin: 0.1 to 0.5 part; the aqueous solution of the components is adjusted to pH 6.5-7.0.
2. The protective agent as claimed in claim 1, wherein the live attenuated encephalitis B vaccine protective agent is prepared by dissolving the following components in parts by weight in water:
sucrose: 3.5 parts of the components in parts by weight,
lactose: 3.5 parts of the components in parts by weight,
gelatin: 0.8 part of the total weight of the mixture,
urea: 0.4 part of the total weight of the mixture,
human serum albumin: 0.15 parts; the aqueous solution of the components is adjusted to pH 6.5-7.0.
3. The protective agent according to claim 1 or 2, wherein the pH adjuster is an inorganic base or an inorganic acid.
4. A protective agent according to claim 3, wherein the pH adjuster is sodium bicarbonate or hydrochloric acid.
5. Use of the protective agent according to any one of claims 1 to 4 for the preparation of a live attenuated encephalitis B vaccine.
6. A live attenuated encephalitis b vaccine, which is prepared by mixing encephalitis b virus and the protective agent according to any one of claims 1-4, and freeze-drying.
7. The method for preparing the attenuated live vaccine for Japanese encephalitis according to claim 6, comprising the following steps:
(1) Mixing the virus stock with the protective agent according to any one of claims 1-4, sterilizing and filtering to obtain a semi-finished product;
(2) Freeze drying the semi-finished product to obtain the final product.
8. The method according to claim 7, wherein the virus stock is a virus stock obtained by culturing kidney-cultured primary cells from a young mouse inoculated with an attenuated strain of SA14-14-2 encephalitis B virus.
9. The method of claim 7, wherein the lyophilization process is:
pre-freezing for 3-5 hours at-50+/-5 ℃, drying for 14-18 hours at-20+/-5 ℃, and drying for 11-15 hours at-35+/-5 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310088333.3A CN115998853B (en) | 2023-01-11 | 2023-01-11 | Attenuated live vaccine for Japanese encephalitis and protective agent thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310088333.3A CN115998853B (en) | 2023-01-11 | 2023-01-11 | Attenuated live vaccine for Japanese encephalitis and protective agent thereof |
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| CN115998853B true CN115998853B (en) | 2023-11-03 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102512685A (en) * | 2010-12-21 | 2012-06-27 | 成都生物制品研究所有限责任公司 | Vaccine protection agent, and combined measles and Japanese encephalitis vaccine and preparation method thereof |
| CN114015644A (en) * | 2021-11-05 | 2022-02-08 | 成都生物制品研究所有限责任公司 | Production method of single virus harvest liquid |
-
2023
- 2023-01-11 CN CN202310088333.3A patent/CN115998853B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102512685A (en) * | 2010-12-21 | 2012-06-27 | 成都生物制品研究所有限责任公司 | Vaccine protection agent, and combined measles and Japanese encephalitis vaccine and preparation method thereof |
| CN114015644A (en) * | 2021-11-05 | 2022-02-08 | 成都生物制品研究所有限责任公司 | Production method of single virus harvest liquid |
Non-Patent Citations (3)
| Title |
|---|
| 关于病毒类减毒活疫苗去除明胶的思考及建议;刘志磊等;中国生物制品学杂志;第31卷(第11期);1286-1289 * |
| 猪瘟口服疫苗保护剂的筛选及免疫效果评价;李星;中国优秀硕士学位论文全文数据库 农业科技辑;第38页 * |
| 王鸣等.《基层免疫接种培训教程》.中山大学出版社,2019,第154页. * |
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