CN103110943A - Novel vaccine adjuvant capable of replacing aluminum hydroxide - Google Patents
Novel vaccine adjuvant capable of replacing aluminum hydroxide Download PDFInfo
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- CN103110943A CN103110943A CN2013100778687A CN201310077868A CN103110943A CN 103110943 A CN103110943 A CN 103110943A CN 2013100778687 A CN2013100778687 A CN 2013100778687A CN 201310077868 A CN201310077868 A CN 201310077868A CN 103110943 A CN103110943 A CN 103110943A
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Abstract
The invention relates to the field of biological products, and in particular relates to a stable protective formula in a vaccine product and a novel vaccine adjuvant capable of replacing aluminum hydroxide. The novel vaccine adjuvant capable of replacing aluminum hydroxide comprises mycose, a buffer which buffers pH values, magnesium chloride, magnesium sulfate and amino acids. The novel vaccine adjuvant provided by the invention not only has the effect of a stabilizer, but also has the function of the vaccine adjuvant. The novel vaccine adjuvant can enhance the immunological competence of the vaccine and has significant social and economic benefits for popularization and application of vaccine products, so that the novel vaccine adjuvant is safe and reliable, low in cost and suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to field of biological product, especially for the stability protection formula in vaccine product and a kind of new vaccine adjuvant of alternative aluminium hydroxide.
Background technology
Vaccine product is to use the biomaterial preparations such as the tissue in the common or microorganism that obtains with biotechnology such as genetic engineering, cell engineering, protein engineering, fermentation engineerings, cell and various animal and humans source and liquid, is used for the medicine of human diseases prevention, treatment and diagnosis.Vaccine product is different from general medical drugs, and it is by stimulating body immune system, produce immune material (as antibody) and just bring into play its effect, humoral immunization, cellular immunization or cell mediated immunity occur in human body.It is the mankind to things understanding deeply and the product that brings of the progress of science and technology, be mankind's threat of resisting extraneous unfavorable factor, large sharp weapon that improve health quality.The variolation's method that is used for the prevention variola of Chinese invented during from the earliest 10th century, to the development of modern microbiology, immunology and molecular biosciences and other subjects and the inactivated vaccine that produces, attenuated live vaccine, polypeptide vaccine, monoclonal antibody etc., the mankind have stepped out major step in the vaccine product field.
Yet along with the continuous popularization of vaccine product, application limitation that its natural quality causes also constantly comes out.Most of vaccine products are under independent state, and its half-life is all shorter, and especially under the catalysis of temperature, its half-life, straight line descended along with the rising of temperature especially.Thereby most of vaccine products all need a suitable preservation condition, and to keep its stability, wherein residing liquid environment more plays a part particularly crucial to keeping of stability.And the acid-base value of liquid environment, ionic strength and some other keeping all may affect vaccine product stable period adding of stable composition (as some carbohydrate molecules, amino acid composition, esters etc.); therefore, seeking a suitable pharmaceutical formulation protects the stability of vaccine product in production, storage, transportation with popularization, very important meaning to be arranged for the application of vaccine product itself.
Simultaneously, for the biological product of vaccine, its single effective ingredient is in carrying out the process that immunity offers, be subject to the impact of various biological approaches, make it can't realize the immune effect of expecting, but therefore need some enhancing body auxiliary to the adjuvant conduct of the immunne response of vaccine antigen or change type of immune response.And the vaccine adjuvant of commonly using the most at present is aluminum hydroxide adjuvant, also has in addition lipopolysaccharide, cytokine, Alumen etc.These materials mainly by changing the physical form of antigen, extend antigen retention time in body; Stimulate mononuclear phagocyte to the ability of offering of antigen; Stimulate the lymphocyte differentiation, increase mechanism such as enlarging the immunne response ability and strengthen immunne response.
Aluminium hydroxide extensively is used to adjuvants for viral vaccines for a long time, and the application on mankind's vaccine history surpasses 70 years, but its side reaction that brings is also of common occurrence.A large amount of bibliographical information shows, in use there are a lot of vaccine safety hidden danger in aluminum hydroxide adjuvant as vaccine adjuvant: local anaphylactic reaction, the irritant reaction of local organization, cause that cutaneous lymphoid hyperplasia's disease, acute sarcoid shape are sick, cause macrophage myofascitis and confirmed fatigue, nervous system toxicity, Gulf War Syndrome dependency, infantile autism dependency, Crohn disease dependency etc.Continuous popularization along with the vaccination scope, infant becomes the object of inoculation of a lot of vaccines, and the imperfection that the infant body system is grown, certainly will increase it to the sensitivity of the side reaction of aluminum hydroxide adjuvant, to the infant cognitive development, harmful effect may be arranged especially, thereby might breed a tragedy.Therefore, the safety of vaccine adjuvant is that it uses prerequisite and the basis of promoting.(" the sick lemology magazine of learning of international popular " volume first stage February the 40th in 2013, exercise question " the hazardness progress of aluminium adjuvant in vaccine ")
At occurring in nature, there are many chemical substances vaccine product to be had the effect of stabilizing agent and adjuvant.But, the object that uses in view of vaccine product is human body, in the compatibility of selecting pharmaceutical formulation, proportioning process, not only will consider the effect of institute's adding ingredient stabilizing agent and adjuvant, to consider more whether it is poisonous to human body, be harmful to, whether can cause bad, the anaphylaxis of human body.
Therefore, seek a kind of safe, cheap, vaccine adjuvant with stabilizing agent and adjuvant function, have great Social benefit and economic benefit for the promotion and application of vaccine product.
Summary of the invention
The new vaccine adjuvant that the purpose of this invention is to provide a kind of alternative aluminium hydroxide, this adjuvant can be used as the stabilizing agent in the production of vaccine process, for the protection of the stability of the middle product of production of vaccine, semi-finished product, finished product; Function with vaccine adjuvant can strengthen again the immunocompetence of vaccine, and safe and reliable, and cheap, is applicable to large-scale industrial production.
The present invention is a kind of new vaccine adjuvant of alternative aluminium hydroxide, and this vaccine adjuvant contains trehalose, has the cushion of acid-base value buffer capacity, magnesium chloride, magnesium sulfate, aminoacid; Concrete formula constituent is that content of trehalose is the 20-200 grams per liter, and the buffer concentration with acid-base value buffer capacity is 5-40 mM/l, and content of magnesium chloride is the 1-4 grams per liter, and magnesium sulfate content is the 2-8 grams per liter, and amino acid content is the 1-20 grams per liter.
The cushion with acid-base value buffer capacity in new vaccine adjuvant of the present invention, comprise, but be not limited to phosphate-buffered thing, Tris-hydrochloride buffer thing, citric acid-sodium hydrogen phosphate cushion, ammonia-chloride buffer thing, acetic acid-sodium acetate buffer thing.
Aminoacid in new vaccine adjuvant of the present invention comprises: but be not limited to Cys, L-arginine, Pidolidone, glycine.
New vaccine adjuvant compound method of the present invention is as follows: get trehalose soluble in water, until completely dissolved, add successively buffer, magnesium chloride, magnesium sulfate, aminoacid with acid-base value buffer capacity, the regulator solution acid-base value adds the water standardize solution.
New vaccine adjuvant solution acid alkalinity of the present invention is 6.0-9.0.
New vaccine adjuvant of the present invention contains trehalose, has the cushion of acid-base value buffer capacity, magnesium chloride, magnesium sulfate, aminoacid; This vaccine adjuvant has the stability protection function, both as the stabilizing agent of vaccine, has again the function of vaccine adjuvant, can strengthen the immunocompetence of vaccine, has great Social benefit and economic benefit for the promotion and application of vaccine product.
New vaccine adjuvant of the present invention is applicable to various viral vaccines and protein vaccine.
The present invention compared with prior art has following advantages and effect: new vaccine adjuvant of the present invention contains trehalose, has the cushion of acid-base value buffer capacity, magnesium chloride, magnesium sulfate, aminoacid; It is a kind of new vaccine adjuvant of alternative aluminium hydroxide; in formula, material used is common medicine and forms with chemical substance; this vaccine adjuvant has the stability protection function; both as the stabilizing agent of vaccine; the function that has again vaccine adjuvant; can strengthen the immunocompetence of vaccine, have great Social benefit and economic benefit for the promotion and application of vaccine product, be a kind of safe and reliable and cheap, vaccine adjuvant of being applicable to large-scale industrial production.
Description of drawings
Fig. 1 be vaccine adjuvant to enterovirns type 71 (EV71) inactivated vaccine stock solution 37 ℃ of lower heat stability results.
Fig. 2 be vaccine adjuvant to enterovirns type 71 (EV71) inactivated vaccine half-finished under 56 ℃ of high temperature the heat stability result.
Fig. 3 is that enterovirns type 71 (EV71) the inactivated vaccine stock solution processed of vaccine adjuvant is in transmission electron microscope result (test group).
Fig. 4 is that enterovirns type 71 (EV71) the inactivated vaccine stock solution processed of vaccine adjuvant is at transmission electron microscope result (matched group).
Specific embodiments
Below in conjunction with embodiment, the present invention is described further, but content of the present invention is not limited to this.
Embodiment 1The stability protection of new vaccine adjuvant to enterovirns type 71 (EV71) inactivated vaccine
The preparation of A, new vaccine adjuvant
Getting trehalose 80 grams is dissolved in 700 ml waters, then add in order Tris cushion 12 grams, magnesium chloride 2 grams, magnesium sulfate 4 grams, Cys 2 grams, L-arginine 5 grams, Pidolidone 8 grams, glycine 10 gram mixings, regulate pH value to 7.2, add water and be settled to 1000 milliliters.
B, new vaccine adjuvant to enterovirns type 71 (EV71) inactivated vaccine stock solution 37 ℃ of lower heat stability protective effects
Get enterovirns type 71 (EV71) inactivated vaccine stock solution and vaccine adjuvant liquid 1:1 mixing by volume.Liquid after mixing is positioned under 37 ℃, respectively 0,1,3, the sampling in June, detect the variation of enterovirns type 71 killed vaccine antigen content with double antibody sandwich method, simultaneously with the enterovirns type 71 inactivated vaccine stock solution processed without bacterin preparation as experimental control, with the enterovirns type 71 inactivated vaccine stock solution of processing with the bacterin preparation formula that is positioned over 4 degree as positive control.
The method of double antibody sandwich method detectable antigens content is as follows: coated antibody is the polyclonal antibody of the anti-enterovirns type 71 of rabbit, and working concentration is 1.2 ug/ml, and hatch about 20 hours for 4 ℃ in 100 microlitres/hole, washes plate three times; 1% bovine serum albumin sealing 1 hour is washed plate three times; Add 37 ℃, sample to be checked to hatch 1 hour, wash plate four times; 1:1000 adds the monoclonal antibody of the anti-enterovirns type 71 of mice, washes plate four times; 1:1500 adds the enzyme labelled antibody of the goat anti-mouse immunoglobulin of horseradish peroxidase labelling, washes plate four times; Add the adjacent benzene diammonium colour developing of substrate 15 minutes, add reaction terminating liquid, microplate reader measure light absorption A
490Value.And take 2.1 times of criterion of tiring as vaccine antigen as marginal value (Cutoff) of negative control absorbance (deduction blank absorbance).(the negative control absorbance is less than 0.05
In time, calculate by 0.05, greater than 0.05 by calculated with actual values)
Vaccine adjuvant is protected results such as Fig. 1 to enterovirns type 71 (EV71) inactivated vaccine stock solution at 37 ℃ of lower heat stability.Placed 6 months under 37 ℃ with the test group that the bacterin preparation formula is processed, its antigenic content still remains unchanged; And matched group antigenic content in 3 months of not processing with the bacterin preparation formula obviously descends, and during by 6 months, antigenic content can't detect.
C, new vaccine adjuvant are to the half-finished heat stability protective effect under 56 ℃ of high temperature of enterovirns type 71 (EV71) inactivated vaccine
Get enterovirns type 71 inactivated vaccine semi-finished product and vaccine adjuvant formula liquid 1:1 mixing by volume.Liquid after mixing is positioned under 56 ℃ of high temperature, respectively sampling in 12 hours, 24 hours, 36 hours, 48 hours, 96 hours, detect the variation of enterovirns type 71 killed vaccine antigen content with double antibody sandwich method, simultaneously with the enterovirns type 71 inactivated vaccine semi-finished product processed without the bacterin preparation formula in contrast.
Vaccine adjuvant is half-finished at 56 ℃ of lower heat stability protection results such as Fig. 2 to the enterovirns type 71 inactivated vaccine.Test group still had good heat stability in 48 hours; And matched group antigenic content in the time of 36 hours begins to descend.
The performance of enterovirns type 71 inactivated vaccine stock solution under transmission electron microscope that D, vaccine adjuvant are processed
Get enterovirns type 71 inactivated vaccine stock solution and vaccine adjuvant formula liquid 1:1 mixing by volume.Liquid after mixing is positioned under 4 ℃ placed 12 months, simultaneously with the enterovirns type 71 inactivated vaccine stock solution processed without the bacterin preparation formula as experimental control.The sample of test group and matched group is passed through the phosphotungstic acid negative staining, observe under transmission electron microscope.Result shows, the enterovirns type 71 inactivated vaccine stock solution that process vaccine adjuvant formula is processed is after placing 12 months under 4 ℃, it is state such as Fig. 3 under Electronic Speculum, virion is spherical in shape, the electromicroscopic photograph background is clear, diameter is the 25-30 nanometer, and viral sub-units is high-visible, and minority virus is hollow bead.This is large-scale aggregating from highly purified pico+ribonucleic acid+virus or the lattice sample is arranged different, in vaccine adjuvant formula liquid, it is arranged evenly that virion is being dispersed in property, not large-scale aggregating, be not lattice-like yet and arrange, be conducive to the exposure in virus antigen site.Simultaneously, find out (see figure 4) from the electromicroscopic photograph of matched group, the vaccinogen liquid of process vaccine adjuvant formula liquid processing is not after placing 12 months under 4 ℃, and it does not find complete virion under Electronic Speculum, illustrates that virion has suffered to decompose, destruction.
Embodiment 2The immunological enhancement of new vaccine adjuvant to the enterovirns type 71 inactivated vaccine
The preparation of A, new vaccine adjuvant
Get trehalose 80 grams and be dissolved in 700 ml waters, then add in order the Tris buffering
Thing 12 grams, magnesium chloride 2 grams, magnesium sulfate 4 grams, Cys 2 grams, L-arginine 5 grams, Pidolidone 8 grams, glycine 10 gram mixings are regulated pH value to 7.2, add water and are settled to 1000 milliliters.
The preparation of B, enterovirns type 71 inactivated vaccine preparation
With institute preparation vaccine adjuvant and antigenic content be 1280EU/ milliliter (EU, Elisa unit) enterovirns type 71 inactivated vaccine with the ratio mixing of 1:1, being mixed with antigenic content is the enterovirns type 71 inactivated vaccine preparation of 640EU/ milliliter.
The immunity of C, enterovirns type 71 inactivated vaccine preparation
Be that the enterovirns type 71 inactivated vaccine preparation of 640EU/ milliliter is as test group with the antigenic content for preparing, take contain the aluminum hydroxide adjuvant antigenic content as the enterovirns type 71 inactivated vaccine of 640EU/ milliliter as positive controls, only to contain merely antigenic content as the enterovirns type 71 inactivated vaccine of 640EU/ milliliter negative control group the most, the BALB/c mouse of immunity cleaning level, each group is 20.Set up simultaneously the blank group of 5 mices.
Immunization protocol: be total to immunity once, 0.5 milliliter of every mouse peritoneal injection inoculation.At initial immunity after one month, by heart aorta sterile blood sampling, separation of serum.
D, Dot-ELISA detect mice serum and resist-the EV71(enterovirns type 71) IgG antibody (immunoglobulin G) level
Enterovirus 71 antigen is with coated diluted to 1 ug/ml, coated to 96 hole ELISA Plate, 100 microlitres/hole, 4 ℃ are spent the night, and wash plate three times; Add the phosphate buffer that contains 1% bovine serum albumin, 200 microlitres/hole was placed 1 hour, and was washed plate three times for 37 ℃; Serum after doubling dilution, is added on ELISA Plate, and every hole 100 microlitres are set up negative hole and blank well simultaneously, place 1 hour, and wash plate three times for 37 ℃; Add two anti-(goat anti-mouse IgG of horseradish peroxidase labelling), every hole 100 microlitres were placed 30 minutes, and were washed plate three times for 37 ℃; Add nitrite ion, every hole 100 microlitres, lucifuge was placed 20 minutes; Add stop buffer, every hole 100 microlitres; Read plate on microplate reader, measure the OD value (absorbance) in each ELISA Plate hole, carry out antibody titer with 2.1 times of threshold values as antibody titer of the average OD value of gained negative hole and calculate.
Result of the test following (seeing Table 1):
After carrying out a pin immunity, that test group is induced is anti--and EV71 IgG antibody level is 254.9; That the aluminium hydroxide positive controls is induced is anti--and EV71 IgG antibody level is 374.1; That negative control group is induced is anti--and EV71 IgG antibody level is 17.3; And that blank group is induced is anti--EV71 IgG antibody level is zero.Test group, aluminium hydroxide positive controls anti--EV71 IgG antibody average level is higher than feminine gender group (P＜0.05, t check).
Simultaneously with antibody titer more than or equal to 100 as threshold calculations mice EV71 antibody male rotary rate, test
Group antibody male rotary rate is 95%, aluminium hydroxide positive controls antibody male rotary rate is 85%, negative group antibody male rotary rate is 10%, test group, aluminium hydroxide positive controls mice EV71 antibody male rotary rate are significantly higher than negative control group (P＜0.01, X 2 test), mice EV71 antibody male rotary rate difference between test group and aluminium hydroxide positive controls is (P〉0.05, X 2 test) not significantly.Illustrate that adjuvant prescription used has the adjuvant effect that strengthens immune effect of vaccine.
Table 1 vaccine adjuvant strengthens the result that EV71 inactivated vaccine inducing mouse produces anti--EV71 IgG antibody level.
Anti--EV71 neutralizing antibody level that E, Small Volume Serum neutralisation detect mice serum
Detection method: after the accurate titration with the EV71 virus infection titer, use the MEM(cell culture fluid) be diluted to 100 TCID
50/ 0.1 milliliter of viral suspension; Serum is carried out 2 times of serial dilutions with MEM; Get the addition of different dilution factor serum and equal-volume virus, shake up, 37 ℃ of water-bath effects 1 hour, 8 ℃ of effects 24 hours.Inoculation Vero cell monolayer, each dilution factor inoculation 5 holes, every hole inoculation 100 microlitres are put 36 ℃, 5% CO2(carbon dioxide) cultivate in incubator, establish simultaneously cell contrast (replacing sample with diluent) and virus-positive and contrast.
Result is judged: when the virus-positive control wells has 75% cell typical enterovirns type 71 cytopathy (CPE) to occur, record experimental result.Calculate the serum NAT.
Criterion: neutralizing antibody has more than 4 times and 4 times to increase than negative control sera and is judged as the positive.
Result of the test following (seeing Table 2):
After carrying out a pin immunity, what test group was induced resists-the horizontal GMT(geometric mean of EV71 neutralizing antibody) be 13.32; That the aluminium hydroxide positive controls is induced is anti--and the horizontal GMT of EV71 neutralizing antibody is 20.25; That negative control group is induced is anti--and EV71 neutralizing antibody level is that GMT is 1.10.Test group, aluminium hydroxide positive controls anti--EV71 IgG antibody average level is higher than feminine gender group (P＜0.01, t check).
Neutralizing antibody is had than negative control sera increase positive calculating mice EV71 serum neutralizing antibody sun rate of rotation more than 4 times and 4 times, test group neutralizing antibody sun rate of rotation is 100%, aluminium hydroxide positive controls neutralizing antibody sun rate of rotation is 95%, negative group neutralizing antibody sun rate of rotation is for being 15%, test group, aluminium hydroxide positive controls mice EV71 antibody male rotary rate are significantly higher than negative control group (P＜0.01, X 2 test), the mice EV71 antibody male rotary rate difference between test group and aluminium hydroxide positive controls is not remarkable
(P〉0.05, X 2 test).Illustrate that adjuvant prescription used and aluminium hydroxide all have the enhancing boosting vaccine
Produce the ability of neutralizing antibody.
Table 2 vaccine adjuvant formula strengthens the result that EV71 inactivated vaccine inducing mouse produces anti--EV71 neutralizing antibody
Embodiment 3The stability protection of new vaccine adjuvant to the hepatitis A virus inactivated vaccine
The preparation of A, new vaccine adjuvant
Get trehalose 80 grams and be dissolved in 700 ml waters, then add in order Tris slow
Rush thing 12 grams, magnesium chloride 2 grams, magnesium sulfate 4 grams, Cys 2 grams, L-arginine 5 grams, Pidolidone 8 grams, glycine 10 gram mixings, regulate pH value to 7.2, add water and be settled to 1000 milliliters.
B, new vaccine adjuvant to hepatitis A virus inactivated vaccine stock solution 4 ℃ of stability inferior protective effects
Get hepatitis A virus inactivated vaccine stock solution and vaccine adjuvant formula liquid 1:1 mixing by volume.Liquid after mixing is positioned under 4 ℃, respectively sampling in 1 day, 7 days, 30 days, adopts enzyme-linked immunologic detecting kit detectable antigens changes of contents, the results are shown in Table 3.Hepatitis A virus inactivated vaccine stock solution 4 ℃ place 7 days after; the test group antigenic content is for changing; the matched group antigenic content has original 1:256 to drop to 1:128, illustrates that vaccine adjuvant used has the stability protection effect to the hepatitis A virus inactivated vaccine.
The stability protection result of table 3 vaccine adjuvant to the hepatitis A virus inactivated vaccine
。
Claims (6)
1. the new vaccine adjuvant of an alternative aluminium hydroxide, it is characterized in that cushion, magnesium chloride, magnesium sulfate, aminoacid that vaccine adjuvant contains trehalose, has the acid-base value buffer capacity, formula constituent is that content of trehalose is the 20-200 grams per liter, buffer concentration with acid-base value buffer capacity is 5-40 mM/l, content of magnesium chloride is the 1-4 grams per liter, magnesium sulfate content is the 2-8 grams per liter, and amino acid content is the 1-20 grams per liter.
2. new vaccine adjuvant according to claim 1, it is characterized in that the cushion with acid-base value buffer capacity comprises, phosphate-buffered thing, Tris-hydrochloride buffer thing, citric acid-sodium hydrogen phosphate cushion, ammonia-chloride buffer thing, acetic acid-sodium acetate buffer thing.
3. new vaccine adjuvant according to claim 1, it is characterized in that the vaccine adjuvant compound method is: get trehalose soluble in water, until completely dissolved, add successively buffer, magnesium chloride, magnesium sulfate, aminoacid with acid-base value buffer capacity, the regulator solution acid-base value adds the water standardize solution.
4. new vaccine adjuvant according to claim 3, is characterized in that solution acid alkalinity is 6.0-9.0.
5. new vaccine adjuvant according to claim 1 both is characterized in that having again the function of vaccine adjuvant as the stabilizing agent of vaccine, can strengthen the immunocompetence of vaccine.
6. new vaccine adjuvant according to claim 1, is characterized in that vaccine adjuvant is applicable to various viral vaccines and protein vaccine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108210922A (en) * | 2018-01-18 | 2018-06-29 | 浙江普康生物技术股份有限公司 | A kind of novel cellular immunity enhancing adjuvant |
| CN112618711A (en) * | 2019-09-24 | 2021-04-09 | 华南理工大学 | Pig oral vaccination nanometer composite adjuvant and preparation method and application thereof |
| CN113230396A (en) * | 2021-05-25 | 2021-08-10 | 唐水泉 | Mixed vaccine adjuvant and production method thereof |
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| CN1053747A (en) * | 1991-03-18 | 1991-08-14 | 中国医学科学院医药生物技术研究所 | Preparation technology of vaccine immunity adjuvant for hepatitis b gene engineering |
| CN101730541A (en) * | 2007-01-30 | 2010-06-09 | 圣母大学 | Extracellular matrix materials as vaccine adjuvants for diseases associated with infectious pathogens or toxins |
| CN102228687A (en) * | 2011-06-24 | 2011-11-02 | 浙江普康生物技术股份有限公司 | Freeze-dried live attenuated hepatitis A vaccine not containing gelatin or human albumin protective agent and preparation method for freeze-dried live attenuated hepatitis A vaccine |
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2013
- 2013-03-11 CN CN201310077868.7A patent/CN103110943B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1053747A (en) * | 1991-03-18 | 1991-08-14 | 中国医学科学院医药生物技术研究所 | Preparation technology of vaccine immunity adjuvant for hepatitis b gene engineering |
| CN101730541A (en) * | 2007-01-30 | 2010-06-09 | 圣母大学 | Extracellular matrix materials as vaccine adjuvants for diseases associated with infectious pathogens or toxins |
| CN102228687A (en) * | 2011-06-24 | 2011-11-02 | 浙江普康生物技术股份有限公司 | Freeze-dried live attenuated hepatitis A vaccine not containing gelatin or human albumin protective agent and preparation method for freeze-dried live attenuated hepatitis A vaccine |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108210922A (en) * | 2018-01-18 | 2018-06-29 | 浙江普康生物技术股份有限公司 | A kind of novel cellular immunity enhancing adjuvant |
| CN112618711A (en) * | 2019-09-24 | 2021-04-09 | 华南理工大学 | Pig oral vaccination nanometer composite adjuvant and preparation method and application thereof |
| CN112618711B (en) * | 2019-09-24 | 2023-09-29 | 华南理工大学 | Pig oral vaccination nano composite adjuvant and preparation method and application thereof |
| CN113230396A (en) * | 2021-05-25 | 2021-08-10 | 唐水泉 | Mixed vaccine adjuvant and production method thereof |
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