CN102631673A - Method for foot-and-mouth disease vaccine concentration and purification - Google Patents
Method for foot-and-mouth disease vaccine concentration and purification Download PDFInfo
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Abstract
The invention provides an effective novel method for foot-and-mouth disease viral antigen concentration and purification. The method comprises the following steps of: 1) eliminating large particle matters in the antigen by using a continuous flow centrifuge; 2) processing the antigen liquid after the step 1) by using a hollow fiber ultra-filtration system; and 3) processing the circulation liquid after the step 2) by using PEG6000 (polyethylene glycol 6000). By utilizing the method for foot-and-mouth disease vaccine concentration and purification, provided by the invention, both the concentration and purification of the foot-and-mouth disease viral antigen can be carried out; and the manufactured foot-and-mouth disease vaccine has the advantages of good immune effect and less adverse reaction.
Description
Technical field
The present invention relates to a kind of foot and mouth disease virus vaccine concentrating and purifying process, unite use, can concentrate foot-and-mouth disease antigen, can make antigen obtain purification again through continuous flow centrifuge, doughnut, PEG.
Background technology
Foot and mouth disease is by caused a kind of acute, hot, the height contagious disease artiodactylous of foot and mouth disease virus, is classified as first of the category-A infectious disease by World Organization for Animal Health (OIE).Vaccination is the main means of majority state control foot and mouth disease eqpidemic disease in the world.The vaccine manufacturing process is complicated, the selection particular importance of antigen treatment process especially, 146S antigen be the foot-and-mouth disease vaccine immunogenicity play a decisive role antigen, relatively more fragile, fragmentation or cracking easily can cause the immunogenicity forfeiture or descend.
The subject matter that the foot and mouth disease inactivated vaccine exists aspect quality is: 1. poor stability; Untoward reaction in various degree appears in animal after annotating Seedling; The lighter subtracts food or stopped eating 2～3 days or miscarry, and death takes place weight person, and reason is the non-destination protein composition height in the vaccine.Non-destination protein in the vaccine comprises: residual serum and lactoalbumin hydrolysate during cultured cell, the non-structural protein of cell protein and foot and mouth disease virus.2. vaccine immunity is renderd a service unstablely, and its performance is, immune duration is short after the vaccine injection, and its main cause is that effectively antigen (146S antigen) content is low in the vaccine.
For improving the immune efficacy of vaccine, adopt the spissated way of antigen usually, but the spissated while is often also concentrated with non-destination protein, causes untoward reaction to increase.Equally, when for reducing untoward reaction vaccine being carried out purification, the shortcoming of conventional method is that the loss of effective antigen in purge process is too big, and untoward reaction improves but the immune effect of vaccine has reduced.
Summary of the invention
The purpose of this invention is to provide the concentrated and purified new method of a kind of foot-and-mouth disease virus antigen efficiently, to solve foot and mouth disease inactivated vaccine safety and immune effect problem of unstable.
Foot-and-mouth disease vaccine concentrating and purifying process provided by the invention may further comprise the steps:
1), removes large particulate matter in the antigen with continuous flow centrifuge;
2), with antigen liquid after the Hollow Fiber Ultrafiltration system handles step 1);
3), with PEG6000 treatment step 2) the back circulation fluid.
Preferably, in the step 1), it is 3000～15000 rev/mins that (1) continuous flow centrifuge is set rotating speed, is preferably 3000～10000 rev/mins, and the light liquid after (2) collection is centrifugal discards heavy-fluid.
Preferably, step 2) in, (1) is used for foot and mouth disease virus and concentrates and use doughnut molecular weight specification to be 30K～750K; Be preferably 30K～300K, the aperture is 0.25～2.0mm, is preferably 0.5～1.0mm; (2) when the circulation fluid volume be 1/50～1/4 of stock solution volume; Be preferably at 1/20～1/10 o'clock, collect the circulation fluid of Hollow Fiber Ultrafiltration system, discard permeate.
Preferably, the quantity of doughnut is 1000～4000 a fibers/film post, and being used for foot and mouth disease virus hollow-fibre membrane post number is 1～24, is preferably 2～12.
Preferably, in the step 3), the concentration that (1) is used to handle the PEG6000 of foot-and-mouth disease virus antigen be pending liquid volume 5%～15%, be preferably 6%～10%.
Preferably, the concrete operations of step 3) are: PEG6000 is joined step 2) back circulation fluid in, centrifugal, the deposition, collecting precipitation liquid part, collecting amount is 1/2～1/2000 of a treatment fluid, is preferably 1/5～1/1000, discards light liquid, collecting precipitation liquid; Add PBS liquid.
More preferably, the PH of the PBS liquid that in precipitated liquid, adds is 7.4～8.0, adds PBS liquid, and making the final volume amount is 1.1 times～1000 times of deposition liquid measures, is preferably 2 times～100 times, promptly obtains target antigen liquid.
The present invention can also adopt with continuous flow centrifuge and remove the scheme of promptly handling with PEG6000 behind the large particulate matter in the antigen, that is, said step 1) and 3) also can accomplish concentrated and purified work continuously, the system that forms like this can use separately.The step 1) and 3 that the front limits) actual conditions here can adopt equally.
Utilize foot-and-mouth disease vaccine concentrating and purifying process provided by the invention can take into account concentrating and purification of foot-and-mouth disease antigen, the good immune effect of the foot-and-mouth disease vaccine that makes, untoward reaction is few.
The specific embodiment
Embodiment:
Embodiment 1: foot and mouth disease O type inactivated vaccine is made; Inoculate the BHK21 cell suspension cultures respectively with virus O ZK/93 strain of foot and mouth disease O type and OR/80 strain; The harvesting culture is respectively after divinyl imines (BEI) deactivation, again after following method method is handled; Add mineral oil adjuvant mixing and emulsifying and process vaccine, be used to prevent pig O type foot and mouth disease.
(1), removes large particulate matter in the antigen with continuous flow centrifuge
1. use continuous flow centrifuge, setting rotating speed is 3000 rev/mins.
2. collect the light liquid that centrifuge is discharged, discard precipitate (heavy-fluid).
(2), with antigen liquid after Hollow Fiber Ultrafiltration system handles (1) step
1. be used for foot and mouth disease virus and concentrate and to use doughnut molecular weight specification to be 50K, the aperture is 0.5mm, and quantity is 3000 a fibers/film post, and being used for the concentrated doughnut system of foot and mouth disease virus hollow-fibre membrane post number is 12.
2. when the circulation fluid volume be the stock solution volume 1/10 the time, collect the circulation fluid of Hollow Fiber Ultrafiltration system, abandoning supernatant.
(3), with circulation fluid after PEG6000 processing (2) step
1. being used to handle foot-and-mouth disease virus antigen is PEG6000, concentration be pending liquid volume 5%.
2. PEG6000 is joined after (2) step in the circulation fluid, centrifugal, deposition, collecting precipitation liquid part, collecting amount is 1/200 of a treatment fluid, abandoning supernatant stays precipitated liquid.
3. in precipitated liquid, add PH and be 7.8 PBS liquid, add PBS liquid, making the final volume amount is 100 times of deposition liquid measures, promptly obtains target antigen liquid.
Embodiment 2: foot and mouth disease O type inactivated vaccine is made; Inoculate the BHK21 cell suspension cultures respectively with virus O ZK/93 strain of foot and mouth disease O type and OR/80 strain; The harvesting culture is respectively after divinyl imines (BEI) deactivation, again after following method method is handled; Add mineral oil adjuvant mixing and emulsifying and process vaccine, be used to prevent pig O type foot and mouth disease.
(1), removes large particulate matter in the antigen with continuous flow centrifuge
1. use continuous flow centrifuge, setting rotating speed is 8000 rev/mins.
2. collect the light liquid that centrifuge is discharged, discard precipitate (heavy-fluid).
(2), with antigen liquid after Hollow Fiber Ultrafiltration system handles (1) step
1. be used for foot and mouth disease virus and concentrate and to use doughnut molecular weight specification to be 100K, the aperture is 1.5mm, and quantity is 2000 a fibers/film post, and being used for the concentrated doughnut system of foot and mouth disease virus hollow-fibre membrane post number is 4.
2. when the circulation fluid volume be the stock solution volume 1/20 the time, collect the circulation fluid of Hollow Fiber Ultrafiltration system, abandoning supernatant.
(3), with circulation fluid after PEG6000 processing (2) step
1. being used to handle foot-and-mouth disease virus antigen is PEG6000, concentration be pending liquid volume 10%.
2. PEG6000 is joined after (2) step in the circulation fluid, centrifugal, deposition, collecting precipitation liquid part, collecting amount is 1/4 of a treatment fluid, abandoning supernatant stays precipitated liquid.
3. in precipitated liquid, add PH and be 7.8 PBS liquid, add PBS liquid, making the final volume amount is 2 times of deposition liquid measures, promptly obtains target antigen liquid.
Embodiment 3: foot and mouth disease O type inactivated vaccine is made; Inoculate the BHK21 cell suspension cultures respectively with virus O ZK/93 strain of foot and mouth disease O type and OR/80 strain; The harvesting culture is respectively after divinyl imines (BEI) deactivation, again after following method method is handled; Add mineral oil adjuvant mixing and emulsifying and process vaccine, be used to prevent pig O type foot and mouth disease.
(1), removes large particulate matter in the antigen with continuous flow centrifuge
1. use continuous flow centrifuge, setting rotating speed is 5000 rev/mins.
2. collect the light liquid that centrifuge is discharged, discard precipitate (heavy-fluid).
(2), with antigen liquid after Hollow Fiber Ultrafiltration system handles (1) step
1. be used for foot and mouth disease virus and concentrate and to use doughnut molecular weight specification to be 300K, the aperture is 2.0mm, and quantity is 1500 a fibers/film post, and being used for the concentrated doughnut system of foot and mouth disease virus hollow-fibre membrane post number is 12.
2. when the circulation fluid volume be the stock solution volume 1/15 the time, collect the circulation fluid of Hollow Fiber Ultrafiltration system, abandoning supernatant.
(3), with circulation fluid after PEG6000 processing (2) step
1. being used to handle foot-and-mouth disease virus antigen is PEG6000, concentration be pending liquid volume 7%.
2. PEG6000 is joined after (2) step in the circulation fluid, centrifugal, deposition, collecting precipitation liquid part, collecting amount is 1/40 of a treatment fluid, abandoning supernatant stays precipitated liquid.
3. in precipitated liquid, add PH and be 7.9 PBS liquid, add PBS liquid, making the final volume amount is 6 times of deposition liquid measures, promptly obtains target antigen liquid.
Embodiment 4: foot and mouth disease O type inactivated vaccine is made; Inoculate the BHK21 cell suspension cultures respectively with virus O ZK/93 strain of foot and mouth disease O type and OR/80 strain; The harvesting culture is respectively after divinyl imines (BEI) deactivation, again after following method method is handled; Add mineral oil adjuvant mixing and emulsifying and process vaccine, be used to prevent pig O type foot and mouth disease.
(1), removes large particulate matter in the antigen with continuous flow centrifuge
1. use continuous flow centrifuge, setting rotating speed is 10000 rev/mins.
2. collect the light liquid that centrifuge is discharged, discard precipitate (heavy-fluid).
(2), with light liquid after PEG6000 processing (1) step
1. being used to handle foot-and-mouth disease virus antigen is PEG6000, concentration be pending liquid volume 10%.
2. PEG6000 is joined after (2) step in the circulation fluid, centrifugal, deposition, collecting precipitation liquid part, collecting amount is 1/400 of a treatment fluid, abandoning supernatant stays precipitated liquid.
3. in precipitated liquid, add PH and be 7.7 PBS liquid, add PBS liquid, making the final volume amount is 40 times of deposition liquid measures, promptly obtains target antigen liquid.
Embodiment 5: foot and mouth disease O type inactivated vaccine is made; Inoculate the BHK21 cell suspension cultures respectively with virus O ZK/93 strain of foot and mouth disease O type and OR/80 strain; The harvesting culture is respectively after divinyl imines (BEI) deactivation, again after following method method is handled; Add mineral oil adjuvant mixing and emulsifying and process vaccine, be used to prevent pig O type foot and mouth disease.
(1), removes large particulate matter in the antigen with continuous flow centrifuge
1. use continuous flow centrifuge, setting rotating speed is 4000 rev/mins.
2. collect the light liquid that centrifuge is discharged, discard precipitate (heavy-fluid).
(2), with light liquid after PEG6000 processing (1) step
1. being used to handle foot-and-mouth disease virus antigen is PEG6000, concentration be pending liquid volume 6%.
2. PEG6000 is joined after (2) step in the circulation fluid, centrifugal, deposition, collecting precipitation liquid part, collecting amount is 1/2000 of a treatment fluid, abandoning supernatant stays precipitated liquid.
3. in precipitated liquid, add PH and be 7.8 PBS liquid, add PBS liquid, making the final volume amount is 40 times of deposition liquid measures, promptly obtains target antigen liquid.
Following description effect appraisal procedure:
1, effectively antigenic content is measured, and detects foot and mouth disease 146S antigenic content with the sucrose density gradient ultraviolet light quantitative method, and the 146S content before and after detection concentrates changes through the 146S antigenic content, and the antigen response rate after concentrating does not hang down 70%.It is qualified to be evaluated as.
2, determining the protein quantity, with the total protein content before and after biuret method (pharmacopeia 2005 editions) the mensuration purification, the albumen clearance behind the purification is not less than 90% for qualified.
3, the effectiveness of vaccine is detected,, be divided into 3 groups, 10 every group with 30 of adult healthy susceptible cattle (neonatal rat NAT≤1: 4 or cell NAT≤1: 8 or ELISA antibody titer≤1: 8).Vaccine to be checked is divided into 1 part, 1/3 part, 3 dose groups of 1/9 part, and each dose groups of every type divides circle to raise respectively at 5 animals of musculi colli injection.Together with 2 of contrast cattle, the inoculation strong malicious 0.2ml of foot and mouth disease virus (containing 10000ID50).Observed 10 continuously.Control animal answers 3 above hoof pathological changes (blister or ulcer) to occur, and immune cattle only blister or ulcer occur at lingual surface, and other positions are judged to protection when not having pathological changes, are judged to when typical foot and mouth disease pathological changes (blister or ulcer) appears in arbitrary position except that lingual surface and do not protect.According to the protection number of immune cattle, calculate the PD50 of seized vaccine by the Reed-Muench method, every part vaccine should each 3 PD50 of every at least type foot and mouth disease.
4, to the antibody qualification rate of vaccine and the mensuration of holding time, with 1 dosage of every immunity of 16 cattle at 10-24 monthly age, antibody (LP-ELISA, 1: 64) qualification rate is for being not less than 60%, and immune duration was not less than 180.
5, pass through the untoward reaction of animal experiment vaccine evaluation.With 15 of the healthy susceptible piglets of 30～40 ages in days (cell NAT≤1: 8 or neonatal rat NAT≤1: 4 or liquid phase blocking-up ELISA antibody titer≤1: 8), 2 part vaccines of muscle branch injection were observed 14 day by day behind each two Herba Houttuyniae.15 of conceived milch cows, 4 part vaccines of branch injection were observed 30 day by day, the untoward reaction that causes because of vaccinate all should not occur.
Utilize above-mentioned recruitment evaluation method to detect the vaccine that above-mentioned each embodiment makes respectively, obtain following testing result:
(1) effectively antigenic content is measured
Embodiment 1: detect the 146S content before and after concentrating, concentrated preceding 2.16 μ g/ml, cycles of concentration are 20 times, are 30.7 μ g/ml after concentrating, and the antigen response rate is 71%.
Embodiment 2: detect the 146S content before and after concentrating, concentrated preceding 1.53 μ g/ml, cycles of concentration are 40 times, are 45.3 μ g/ml after concentrating, and the antigen response rate is 74%.
Embodiment 3: detect the 146S content before and after concentrating, concentrated preceding 2.03 μ g/ml, cycles of concentration are 60 times, are 86.5 μ g/ml after concentrating, and the antigen response rate is 71%.
Embodiment 4: detect the 146S content before and after concentrating, concentrated preceding 1.03 μ g/ml, cycles of concentration are 100 times, are 86.5 μ g/ml after concentrating, and the antigen response rate is 84%.
Embodiment 5: detect the 146S content before and after concentrating, concentrated preceding 3.02 μ g/ml, cycles of concentration are 50 times, are 122.3 μ g/ml after concentrating, and the antigen response rate is 81%.
(2) determining the protein quantity
Embodiment 1: detect the protein content of purification front and back, protein content is 2.6mg/ml before the purification, and cycles of concentration is 20 times, and total protein content is 1.04mg/ml behind the purification, albumen clearance 98%.
Embodiment 2: detect the protein content of purification front and back, protein content is 2.9mg/ml before the purification, and cycles of concentration is 40 times, and protein content is 1.16mg/ml behind the purification, albumen clearance 99%.
Embodiment 3: detect the protein content of purification front and back, protein content is 2.7mg/ml before the purification, and cycles of concentration is 60 times, and total protein content is 3.24mg/ml behind the purification,, albumen clearance 98%.
Embodiment 4: detect the protein content of purification front and back, protein content is 2.7mg/ml before the purification, and cycles of concentration is 100 times, and total protein content is 18.9.mg/ml behind the purification,, albumen clearance 93%.
Embodiment 5: detect the protein content of purification front and back, protein content is 2.4mg/ml before the purification, and cycles of concentration is 50 times, and total protein content is 9.6mg/ml behind the purification,, albumen clearance 92%.
(3) immune effect to vaccine detects
Embodiment 1: every part vaccine is to two counteracting toxic substances strains: the effectiveness of OZK/93 strain is 5.2PD50, and the effectiveness of OR/80 strain is 5.2PD50.
Embodiment 2: every part vaccine is to two counteracting toxic substances strains: the effectiveness of OZK/93 strain is 5.3PD50, and the effectiveness of OR/80 strain is 9.00PD50.
Embodiment 3: every part vaccine is to two counteracting toxic substances strains: the effectiveness of OZK/93 strain is 9.0PD50, and the effectiveness of OR/80 strain is 15.59PD50.
Embodiment 4: every part vaccine is to two counteracting toxic substances strains: the effectiveness of OZK/93 strain is 9.0PD50, and the effectiveness of OR/80 strain is 10.81PD50.
Embodiment 5: every part vaccine is to two counteracting toxic substances strains: the effectiveness of OZK/93 strain is 10.81PD50, and the effectiveness of OR/80 strain is 10.81PD50.
(4), estimate immune effect to the antibody of vaccine and the mensuration of holding time
Embodiment 1: with 1 dosage of every immunity of 16 cattle at 10-24 monthly age, antibody (LP-ELISA, 1: 64) qualification rate is 75%, and immune duration is 180.
Embodiment 2: with 1 dosage of every immunity of 16 cattle at 10-24 monthly age, antibody (LP-ELISA, 1: 64) qualification rate is 70%, and immune duration is 190.
Embodiment 3: with 1 dosage of every immunity of 16 cattle at 10-24 monthly age, antibody (LP-ELISA, 1: 64) qualification rate is 76%, and immune duration is 200.
Embodiment 4: with 1 dosage of every immunity of 16 cattle at 10-24 monthly age, antibody (LP-ELISA, 1: 64) qualification rate is 77%, and immune duration is 195.
Embodiment 5: with 1 dosage of every immunity of 16 cattle at 10-24 monthly age, antibody (LP-ELISA, 1: 64) qualification rate is 80%, and immune duration is 195.
(5) untoward reaction through the animal experiment vaccine evaluation
Embodiment 1: with 15 of the healthy susceptible piglets of 30～40 ages in days, 2 part vaccines of muscle branch injection were observed 14 day by day behind each two Herba Houttuyniae.15 of conceived milch cows, 4 part vaccines of branch injection were observed 30 day by day.Untoward reaction does not appear.
Embodiment 2: with 15 of the healthy susceptible piglets of 30～40 ages in days, 2 part vaccines of muscle branch injection were observed 14 day by day behind each two Herba Houttuyniae.15 of conceived milch cows, 4 part vaccines of branch injection were observed 30 day by day.Untoward reaction does not all appear.
Embodiment 3: with 15 of the healthy susceptible piglets of 30～40 ages in days, 2 part vaccines of muscle branch injection were observed 14 day by day behind each two Herba Houttuyniae.15 of conceived milch cows, 4 part vaccines of branch injection were observed 30 day by day.Untoward reaction does not all appear.
Embodiment 4: with 15 of the healthy susceptible piglets of 30～40 ages in days, 2 part vaccines of muscle branch injection were observed 14 day by day behind each two Herba Houttuyniae.15 of conceived milch cows, 4 part vaccines of branch injection were observed 30 day by day, the of short duration decline of giving milk occurred, and recovered after 3 days.Untoward reaction does not all appear.
Embodiment 5: with 15 of the healthy susceptible piglets of 30～40 ages in days, 2 part vaccines of muscle branch injection were observed 14 day by day behind each two Herba Houttuyniae.15 of conceived milch cows, 4 part vaccines of branch injection were observed 30 day by day.Untoward reaction does not all appear.
Claims (9)
1. foot-and-mouth disease vaccine concentrating and purifying process may further comprise the steps:
1), removes large particulate matter in the antigen with continuous flow centrifuge;
2), with antigen liquid after the Hollow Fiber Ultrafiltration system handles step 1);
3), with PEG6000 treatment step 2) the back circulation fluid.
2. foot-and-mouth disease vaccine concentrating and purifying process according to claim 1 is characterized in that, in the step 1), it is 3000～15000 rev/mins that (1) continuous flow centrifuge is set rotating speed, and the light liquid after (2) collection is centrifugal discards heavy-fluid.
3. foot-and-mouth disease vaccine concentrating and purifying process according to claim 1; It is characterized in that step 2) in, (1) is used for foot and mouth disease virus and concentrates and to use doughnut molecular weight specification to be 30K～750K; The aperture is 0.25～2.0mm; (2) when the circulation fluid volume be the stock solution volume 1/20～1/4 the time, collect the circulation fluid of Hollow Fiber Ultrafiltration system, discard permeate.
4. foot-and-mouth disease vaccine concentrating and purifying process according to claim 3 is characterized in that, the quantity of doughnut is 1000～4000 a fibers/film post, and being used for the spissated hollow-fibre membrane post of foot and mouth disease virus number is 1～24.
5. foot-and-mouth disease vaccine concentrating and purifying process according to claim 1 is characterized in that, in the step 3), the concentration that (1) is used to handle the PEG6000 of foot-and-mouth disease virus antigen be pending liquid volume 5%～15%.
6. foot-and-mouth disease vaccine concentrating and purifying process according to claim 1; It is characterized in that the concrete operations of step 3) are: PEG6000 is joined step 2) back circulation fluid in, centrifugal, the deposition; Collecting precipitation liquid part; Collecting amount is 1/5～1/2000 of a treatment fluid, discards light liquid, collecting precipitation liquid; Add PBS liquid.
7. foot-and-mouth disease vaccine concentrating and purifying process according to claim 6 is characterized in that, the PH of the PBS liquid that in precipitated liquid, adds is 7.4～8.0, adds PBS liquid, and making the final volume amount is 1.1 times～1000 times of deposition liquid measures, promptly obtains target antigen liquid.
8. the foot-and-mouth disease vaccine concentrating and purifying process is characterized in that, removes in the antigen with continuous flow centrifuge and promptly handles with PEG6000 behind the large particulate matter.
9. foot-and-mouth disease vaccine concentrating and purifying process according to claim 8 is characterized in that,
Remove with continuous flow centrifuge in the step of large particulate matter in the antigen, it is 3000～15000 rev/mins that (1) continuous flow centrifuge is set rotating speed, and the light liquid after (2) collection is centrifugal discards heavy-fluid;
In the PEG6000 processed steps; (1) concentration that is used to handle the PEG6000 of foot-and-mouth disease virus antigen be pending liquid volume 5%～15%, concrete operations are: PEG6000 is joined in the treatment fluid centrifugal, deposition; Collecting precipitation liquid part; Collecting amount is 1/5～1/2000 of a treatment fluid, discards light liquid, collecting precipitation liquid; Add PBS liquid.
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| CN107266537A (en) * | 2017-08-01 | 2017-10-20 | 天信和(苏州)生物科技有限公司 | Foot-and-mouth disease antigen 146S concentrating and purifying process |
| CN107384876A (en) * | 2017-07-20 | 2017-11-24 | 内蒙古必威安泰生物科技有限公司 | A kind of standard antigen for aftosa vaccine 146S content detections and its preparation method and application |
| CN110872580A (en) * | 2018-09-04 | 2020-03-10 | 无锡拓浦壹生物科技有限公司 | Foot-and-mouth disease antigen purification method |
| CN113117068A (en) * | 2021-04-21 | 2021-07-16 | 金宇保灵生物药品有限公司 | Bovine epidemic heat inactivated vaccine for livestock and large-scale production method thereof |
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| GB2572275A (en) * | 2016-12-07 | 2019-09-25 | Shanghai Shen Lian Biomedical Corp | Method for preparing Foot-and-Mouth disease vaccine |
| US11013794B2 (en) | 2016-12-07 | 2021-05-25 | Shanghai Shen Lian Biomedical Corporation | Method for preparing foot-and-mouth disease vaccines |
| GB2572275B (en) * | 2016-12-07 | 2022-03-16 | Shanghai Shen Lian Biomedical Corp | Method for preparing Foot-and-Mouth disease vaccine |
| CN107384876A (en) * | 2017-07-20 | 2017-11-24 | 内蒙古必威安泰生物科技有限公司 | A kind of standard antigen for aftosa vaccine 146S content detections and its preparation method and application |
| CN107384876B (en) * | 2017-07-20 | 2020-06-26 | 内蒙古必威安泰生物科技有限公司 | Standard antigen for detecting foot-and-mouth disease vaccine 146S content and preparation method and application thereof |
| CN107266537A (en) * | 2017-08-01 | 2017-10-20 | 天信和(苏州)生物科技有限公司 | Foot-and-mouth disease antigen 146S concentrating and purifying process |
| CN107266537B (en) * | 2017-08-01 | 2020-12-01 | 天信和(苏州)生物科技有限公司 | Foot-and-mouth disease antigen 146S concentration and purification method |
| CN110872580A (en) * | 2018-09-04 | 2020-03-10 | 无锡拓浦壹生物科技有限公司 | Foot-and-mouth disease antigen purification method |
| CN113117068A (en) * | 2021-04-21 | 2021-07-16 | 金宇保灵生物药品有限公司 | Bovine epidemic heat inactivated vaccine for livestock and large-scale production method thereof |
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