CN112516325A - Stable foot-and-mouth disease vaccine composition and application thereof - Google Patents
Stable foot-and-mouth disease vaccine composition and application thereof Download PDFInfo
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- 229960005486 vaccine Drugs 0.000 title claims abstract description 68
- 241000710198 Foot-and-mouth disease virus Species 0.000 title claims abstract description 55
- 208000007212 Foot-and-Mouth Disease Diseases 0.000 title claims abstract description 51
- 239000000203 mixture Substances 0.000 title claims abstract description 39
- 239000000427 antigen Substances 0.000 claims abstract description 63
- 102000036639 antigens Human genes 0.000 claims abstract description 63
- 108091007433 antigens Proteins 0.000 claims abstract description 63
- 239000003381 stabilizer Substances 0.000 claims abstract description 38
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 27
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- 230000003053 immunization Effects 0.000 claims description 2
- 239000000654 additive Substances 0.000 description 11
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
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- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 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 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229940041984 dextran 1 Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
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- 150000007523 nucleic acids Chemical class 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/125—Picornaviridae, e.g. calicivirus
- A61K39/135—Foot- and mouth-disease virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5252—Virus inactivated (killed)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
- A61K2039/552—Veterinary vaccine
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/32011—Picornaviridae
- C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
- C12N2770/32134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Abstract
The present invention provides a stabilizer for stabilizing an antigen of foot-and-mouth disease, wherein the stabilizer comprises: DEAE dextran 0.5-2 w/V% and hydroxypropyl-beta-cyclodextrin 0.5-2 w/V% in final concentration in the vaccine composition. The stabilizer can stabilize the inactivated foot-and-mouth disease antigen in the vaccine composition for a long time, ensure the content of 146S to be stable, and simultaneously ensure the stability and consistent appearance of the vaccine composition. The invention also provides a vaccine composition containing the stabilizer.
Description
Technical Field
The invention belongs to the field of medical preparations, and particularly relates to a stable foot-and-mouth disease vaccine composition.
Background
The instability of inactivated foot and mouth disease virus antigens is one of the great challenges facing vaccine production. The foot-and-mouth disease inactivated virus antigen is mainly complete virus with sedimentation coefficient of 146S, has the size of about 30nm and has strong immunogenicity. However 146S is susceptible to disruption of particle structure during production and storage, cleaves to smaller particle 12S, less than 10nm in size, and releases viral nucleic acid, whereas cleaved 12S is almost non-immunogenic. Therefore, the yield of the active antigen complete virus 146S is critical for the production of the foot-and-mouth disease vaccine.
CN108504638A discloses a method for purifying or storing foot-and-mouth disease inactivated virus antigen, which increases the yield of active antigen by adding a multi-hydroxyl compound in the purification or storage process. From the results in the fifth page table 1 of the patent specification, it is known that among many substances generally used as general protein protectors, compounds having a polyvalent hydroxyl group such as saccharides, sugar alcohols, glycerol, and the like have an inhibitory effect on the cleavage of 146S, while amino acids, surfactants, albumins, and the like do not have a protective effect, and some of them have a cleavage accelerating effect.
"foot-and-mouth disease vaccine preservation technology research" (Li Zheng Feng, etc.) discloses a foot-and-mouth disease stabilizer, which comprises trehalose, sorbitol and PVP with the proportion of 4: 5: 1, and discloses that the stability of the vaccine is influenced by adding a stabilizer into the foot-and-mouth disease vaccine, and trehalose, sorbitol and PVP all influence the stability of the vaccine, wherein the influence of PVP is larger.
Therefore, there is a need in the art for a foot and mouth disease vaccine composition that does not affect vaccine stability, but also enhances the stability of the foot and mouth disease antigen.
Disclosure of Invention
In order to solve the above technical problems, the present invention provides a stabilizer for stabilizing an antigen of foot-and-mouth disease, wherein the stabilizer comprises: DEAE dextran 0.5-2 w/V% and hydroxypropyl-beta-cyclodextrin 0.5-2 w/V% in final concentration in the vaccine composition.
By using DEAE dextran and hydroxypropyl-beta-cyclodextrin as stabilizers, a synergistic effect is generated, the combination has a remarkable effect on the stability of the foot-and-mouth disease antigen, and the use concentrations of the DEAE dextran and the hydroxypropyl-beta-cyclodextrin can be reduced.
The final concentration of DEAE dextran in the vaccine composition may be selected from 0.5 w/V%, 0.6 w/V%, 0.7 w/V%, 0.8 w/V%, 0.9 w/V%, 1.0 w/V%, 1.1 w/V%, 1.2 w/V%, 1.3 w/V%, 1.4 w/V%, 1.5 w/V%, 1.6 w/V%, 1.7 w/V%, 1.8 w/V%, 1.9 w/V%, 2 w/V%.
The final concentration of hydroxypropyl-beta-cyclodextrin in the vaccine composition may be selected from the group consisting of 0.5 w/V%, 0.6 w/V%, 0.7 w/V%, 0.8 w/V%, 0.9 w/V%, 1.0 w/V%, 1.1 w/V%, 1.2 w/V%, 1.3 w/V%, 1.4 w/V%, 1.5 w/V%, 1.6 w/V%, 1.7 w/V%, 1.8 w/V%, 1.9 w/V%, 2 w/V%. In one embodiment of the present invention, the stabilizer for stabilizing foot-and-mouth disease antigen further comprises 0.1-0.4% w/V EDTA2 Na.
The stability was slightly improved by the addition of EDTA2 Na.
The final concentration of EDTA2Na in the vaccine composition may be selected from 0.1% w/V, 0.2% w/V, 0.3% w/V, 0.4 w/V.
In one embodiment of the present invention, the stabilizer for stabilizing a foot-and-mouth disease antigen according to the present invention comprises: (ii) 0.5 w/V% DEAE dextran, 0.5 w/V% hydroxypropyl- β -cyclodextrin in final concentration in the vaccine composition; or the stabilizer comprises: (ii) DEAE dextran 0.5 w/V%, hydroxypropyl- β -cyclodextrin 0.5 w/V%, VEDTA2Na 0.1 w/V% at final concentration in the vaccine composition; or the stabilizer comprises: 1 w/V% DEAE dextran, 1 w/V% hydroxypropyl- β -cyclodextrin, 0.2w/VEDTA2Na, in final concentration in the vaccine composition; or the stabilizer comprises: 2 w/V% DEAE dextran, 2 w/V% hydroxypropyl- β -cyclodextrin, 0.1w/VEDTA2Na, in final concentration in the vaccine composition; or the stabilizer comprises: 2 w/V% DEAE dextran, 2 w/V% hydroxypropyl-beta-cyclodextrin, 0.4w/VEDTA2Na, based on the final concentration in the vaccine composition.
In one embodiment of the present invention, the foot-and-mouth disease antigen is an inactivated foot-and-mouth disease antigen in the stabilizer for stabilizing a foot-and-mouth disease antigen according to the present invention.
In one embodiment of the present invention, the foot-and-mouth disease antigen is inactivated foot-and-mouth disease 146S antigen.
In a preferred embodiment of the present invention, the foot-and-mouth disease antigen is an inactivated O-type foot-and-mouth disease antigen in the stabilizer for stabilizing a foot-and-mouth disease antigen according to the present invention.
In a more preferred embodiment of the present invention, the foot-and-mouth disease antigen is an inactivated MYA 98/O146S antigen in the stabilizer for stabilizing a foot-and-mouth disease antigen according to the present invention.
The invention also provides a vaccine composition, wherein the vaccine composition comprises the stabilizing agent, an immunizing amount of the foot-and-mouth disease inactivated antigen and a tris buffer solution.
The addition of the stabilizer to the vaccine composition of the present invention has no effect on the stability of the vaccine and can stabilize the antigen in the vaccine for a long period of time.
In one embodiment of the present invention, in the vaccine composition of the present invention, the inactivated foot-and-mouth disease antigen is 146S.
In a preferred embodiment of the present invention, the foot-and-mouth disease antigen in the vaccine composition of the present invention is an inactivated MYA 98/O146S antigen.
As an embodiment of the invention, in the vaccine composition of the invention, the tris buffer is 0.12% w/v tris buffer and the pH is 7.5.
The invention also provides the application of the stabilizer in the aspect of stabilizing the inactivated foot-and-mouth disease antigen in a stable vaccine composition.
The invention has the advantages of
The vaccine composition of the invention has good stability and thermal stability (and vaccine appearance stability, and can realize antigen stabilization of the vaccine for a long time.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
The chemical reagents used in the examples of the present invention are all analytical reagents and purchased from the national pharmaceutical group. The experimental methods are conventional methods unless specified otherwise; the biomaterial is commercially available unless otherwise specified.
Example 1 Effect of additives on the stability of foot-and-mouth disease Virus antigens
Taking virus stock solution containing O type (MYA98/O) foot-and-mouth disease virus antigen with the concentration of 27 mug/mL, respectively adding different substances and additives with different concentrations in the table 1, storing the virus stock solution at 45 ℃ for 30min, determining the content of the residual antigen, calculating the percentage of the content of the residual antigen accounting for 0min according to a sucrose density centrifugation method, and comparing the percentage with the residual content of the antigen without any substance (blank control).
TABLE 1 residual antigen content after storing foot-and-mouth disease virus antigen with different additives and different concentrations of additives at 45 deg.C for 30min
Additive agent | Concentration of additive (w/V) | Residual antigen content |
Blank control | 23% | |
Sucrose | 5 | 76% |
Sucrose | 15 | 82% |
DEAE dextran | 1 | 22% |
DEAE dextran | 5 | 26% |
Hydroxypropyl-beta-cyclodextrin | 1 | 23% |
Hydroxypropyl-beta-cyclodextrin | 5 | 47% |
Hydroxypropyl-beta-cyclodextrin | 10 | 63% |
The test results in table 1 show that the addition of DEAE dextran at low concentration has little effect on the improvement of the stability of the foot-and-mouth disease antigen, and both hydroxypropyl-beta-cyclodextrin and sucrose require higher concentration to function as a stabilizer.
Example 2 Effect of foot-and-mouth disease antigen solution addition of stabilizers on vaccine stability
Taking the foot-and-mouth disease antigen solution added with different additives and different concentrations in the table 2 as a water phase, adding an adjuvant (206 adjuvant) to emulsify for 5 minutes at 31 ℃ according to the weight ratio of 1:1, carrying out a stability test at 25 ℃ after emulsification, and observing the appearance stability of the vaccine, wherein the test result is shown in the table 2.
TABLE 2 foot and mouth disease vaccine appearance stability at 25 ℃
Additive agent | Antigen additive and concentration (w/V) | Stability at 25 ℃ |
Blank control | —— | No obvious change in 14 days |
Sucrose | 5 | 5 days with obvious demixing |
Sucrose | 15 | Obvious demixing within 2 days |
DEAE dextran | 1 | No obvious change in 14 days |
DEAE dextran | 5 | No obvious change in 14 days |
Hydroxypropyl-beta-cyclodextrin | 1 | No obvious change in 14 days |
Hydroxypropyl-beta-cyclodextrin | 5 | No obvious change in 14 days |
Hydroxypropyl-beta-cyclodextrin | 10 | Clear delamination in 7 days |
As can be seen from the test results in table 2, sucrose has a significant effect on the stability (appearance stability) of the foot-and-mouth disease vaccine, and DEAE dextran and low-concentration hydroxypropyl- β -cyclodextrin have little effect on the stability (appearance stability) of the vaccine.
Example 3 preparation of foot-and-mouth disease vaccine and stability test
3.1 preparation of the aqueous phase
Taking 27 mu g/mL of the foot-and-mouth disease O-type antigen as an antigen stock solution, preparing a foot-and-mouth disease antigen water phase according to the additives and contents in the table 3, and taking the rest as a diluent, wherein the diluent uses 0.12% (w/v) tris alkali solution, and the final pH is 7.5. Storing the water phase at 45 deg.C for 30min, determining the residual antigen content, and calculating the percentage of the residual antigen content in 0min by sucrose density centrifugation.
TABLE 3 preparation and stability of aqueous antigen phase
The test results in Table 3 show that the DEAE dextran and the hydroxypropyl-beta-cyclodextrin are used as the stabilizing agents to generate a synergistic effect, have a remarkable effect on the stability of the foot-and-mouth disease antigen and can reduce the use concentration of the DEAE dextran and the hydroxypropyl-beta-cyclodextrin. The stability is slightly improved by adding EDTA2 Na.
In the vaccine composition, any combination of DEAE dextran with the final concentration of 0.5-2% w/V, hydroxypropyl-beta-cyclodextrin with the final concentration of 0.5-2% w/V and EDTA2Na with the final concentration of 0.1-0.4% w/V can ensure good stability of the vaccine.
3.2 preparation of vaccines
The antigen solution added with additives of different concentrations in 3.1 is taken as a water phase, and then an adjuvant (206 adjuvant) is added according to the weight ratio of 1:1, and then the mixture is emulsified for 5 minutes at 31 ℃ to prepare the vaccine.
3.3 vaccine stability test
3.2, performing stability test on the vaccine prepared in the step 2, performing stability appearance stability test at 25 ℃, performing emulsion breaking and 146S content determination on 4 ℃ stability test samples at 9 months according to a CN 102380232 method, calculating the ratio of the content to 146S determined in 0 day, and obtaining the results shown in Table 4.
TABLE 4 foot and mouth disease vaccine appearance stability at 25 deg.C
Group of | Appearance stability at 25 DEG C | Stability at 4 ℃ at 9 months |
Test example 1 vaccine preparation | No obvious change in 14 days | 88% |
Test example 2 vaccine preparation | No obvious change in 14 days | 90% |
Test example 3 preparation of vaccine | No obvious change in 14 days | 89% |
Test example 4 vaccine preparation | No obvious change in 14 days | 93% |
Test example 5 preparation of vaccine | No obvious change in 14 days | 92% |
Comparative example 1 vaccine formulation | No obvious change in 14 days | 81% |
From the results in table 4, it can be seen that the addition of the stabilizer to the vaccine composition of the present invention has no effect on the stability of the vaccine and that the stabilization of the antigen in the vaccine can be achieved for a long period of time.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (8)
1. A stabilizer for stabilizing foot and mouth disease antigen, wherein the stabilizer comprises: DEAE dextran 0.5-2 w/V% and hydroxypropyl-beta-cyclodextrin 0.5-2 w/V% in final concentration in the vaccine composition.
2. The stabilizer according to claim 1, wherein the stabilizer further comprises 0.1-0.4 w/V EDTA2 Na.
3. The stabilizer of claim 1, wherein the stabilizer comprises: (ii) 0.5 w/V% DEAE dextran, 0.5 w/V% hydroxypropyl- β -cyclodextrin in final concentration in the vaccine composition; or
The stabilizer comprises: (ii) DEAE dextran 0.5 w/V%, hydroxypropyl- β -cyclodextrin 0.5 w/V%, VEDTA2Na 0.1 w/V% at final concentration in the vaccine composition; or
The stabilizer comprises: 1 w/V% DEAE dextran, 1 w/V% hydroxypropyl- β -cyclodextrin, 0.2w/VEDTA2Na, in final concentration in the vaccine composition; or
The stabilizer comprises: 2 w/V% DEAE dextran, 2 w/V% hydroxypropyl- β -cyclodextrin, 0.1w/VEDTA2Na, in final concentration in the vaccine composition; or
The stabilizer comprises: 2 w/V% DEAE dextran, 2 w/V% hydroxypropyl-beta-cyclodextrin, 0.4w/VEDTA2Na, based on the final concentration in the vaccine composition.
4. The stabilizer of claim 1, wherein the foot-and-mouth disease antigen is an inactivated foot-and-mouth disease antigen; preferably, the foot-and-mouth disease antigen is an inactivated type O foot-and-mouth disease antigen; more preferably, the foot-and-mouth disease antigen is an inactivated MYA 98/O146S antigen.
5. A vaccine composition comprising the stabilizer of claims 1-4 and an immunizing amount of inactivated foot and mouth disease antigen, and tris buffer.
6. The vaccine composition of claim 5, wherein said inactivated foot-and-mouth disease antigen is 146S; preferably, the foot-and-mouth disease antigen is an inactivated MYA 98/O146S antigen.
7. The vaccine composition according to claim 5, wherein the tris buffer is 0.12% w/v tris buffer at a pH of 7.5.
8. Use of a stabilizer according to claims 1 to 4 for stabilizing the stability of inactivated foot and mouth disease antigen in a vaccine composition.
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CN112516325B CN112516325B (en) | 2023-12-08 |
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