CN108210922A - A kind of novel cellular immunity enhancing adjuvant - Google Patents
A kind of novel cellular immunity enhancing adjuvant Download PDFInfo
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- CN108210922A CN108210922A CN201810049632.5A CN201810049632A CN108210922A CN 108210922 A CN108210922 A CN 108210922A CN 201810049632 A CN201810049632 A CN 201810049632A CN 108210922 A CN108210922 A CN 108210922A
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
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- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
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Abstract
The present invention relates to field of biological product, particularly enhance adjuvant for a kind of novel cellular immunity of therapeutic vaccine.Novel cellular immunity enhancing adjuvant contains ginsenoside Rb1, trehalose, absolute ethyl alcohol, polysorbas20, amino acid, the cushion with acid-base value buffer capacity；Formulated, mixing adjusts solution acid alkalinity, adds water constant volume, then filter filtration sterilization.Cellular immunity enhancing adjuvant can effectively improve the specific cellular immunity effect of therapeutic vaccine, it is simple for process, convenient for preparation and degerming, stablize at 28 degree and preserve, be conducive to conventional cold chain transportation, it is a kind of safe and stable, effective, suitable for the therapeutic vaccine adjuvant of large-scale industrial production.
Description
Technical field
The present invention relates to field of biological product, particularly a kind of novel cell Immune-enhancing effect for therapeutic vaccine is helped
Agent.
Background technology
Therapeutic vaccine refers in the biology of pathogenic infection or in suffering from the body of certain diseases, special by the way that body is induced to generate
The opposite sex or nonspecific immune response, with the biological products for reaching treatment or preventing disease progression.Used in therapeutic vaccine
Immunogene generally select and can cause neutralizing antibody and can induce killer T cell（CTL）The antigen of immune response.It is but single
Only antigen can not often induce body to obtain effective immune response level, so that the big discounting of the therapeutic effect of vaccine
Button.Therefore, a kind of vaccine adjuvant effectively, safe is selected to enhance the immune response of therapeutic vaccine level, is had important
Meaning.The vaccine adjuvant clinically having been widely used has aluminium hydroxide, MF59, AS40 etc., these adjuvants are mainly used for improving pre-
The Humoral of anti-property vaccine.At present, CpG adjuvants are a kind of adjuvants of effective enhancing Cellular Immunity, but because of it
Safety is also there are certain dispute, it is therefore provided that the time of its listing is undecided.Therefore, it is necessary to find it is a kind of safety,
Effectively, novel adjuvant enhances the Study On Cellular Immune of therapeutic vaccine.
One of the principle active component of ginsenoside as ginseng is a steroidal compounds, has more than 40 kinds of people at present
It is isolated to join saponin monomer.It is existing research shows that, many ginsenoside monomers all have the function of to adjust immune collaboration.Example
Enhancing senile rat spleen lymphocyte proliferation ability and Bai Jie that can be selective in being tested in vivo and in vitro such as ginsenoside Rg1
The generation and release of element -2；Ginsenoside Rh 1 can directly facilitate spleen lymphocyte proliferation, hence it is evident that it is thin to improve mouse peritoneal macrophage
The phagocytic activity of born of the same parents promotes the release of NO；Ginsenoside Ro can remarkably promote the proliferation of mouse spleen lymphocyte, and ConA is promoted to lure
The generation of mouse spleen lymphocyte proleulzin and interferon-γ led.These results of study disclose ginsenoside in body
Immune response in can play crucial adjustment effect.But there is also some problems for ginsenoside monomer.Some ginseng soaps
Glycosides is not soluble in water, is dissolved only in organic solvent, it should so that the mathematical chance of its clinical practice；Meanwhile some ginsenosides dissolve
Rear stability is bad, greatly limits its use scope.Therefore, a kind of suitable ginsenoside monomer is selected, by rational
It prepares so that it can be used as safe and stable, effective therapeutic vaccine adjuvant, have great Social benefit and economic benefit.
Invention content
The object of the present invention is to provide a kind of novel cellular immunities to enhance adjuvant, which can be used as therapeutic vaccine
Enhance adjuvant, for improving the immune effect of therapeutic vaccine, and it is safe and stable, suitable for large-scale industrial production.
The novel cellular immunity enhancing adjuvant of the present invention contains ginsenoside Rb1, trehalose, absolute ethyl alcohol, polysorbas20, ammonia
Base acid, the cushion with acid-base value buffer capacity；Formulated, mixing adjusts solution acid alkalinity, adds water constant volume, then filter mistake
Filter out bacterium.Cellular immunity enhancing adjuvant can effectively improve the specific cellular immunity effect of therapeutic vaccine, simple for process, just
In preparation and degerming, stablize in 2-8 degree and preserve, be conducive to conventional cold chain transportation, be a kind of safe and stable, effective, be suitable for
The therapeutic vaccine adjuvant of large-scale industrial production.
The novel cellular immunity enhancing adjuvant of the present invention, the vaccine adjuvant contain ginsenoside Rb1, trehalose, have acid
Cushion, absolute ethyl alcohol, polysorbas20, the amino acid of basicity buffer capacity；Specific formula component is content of ginsenoside Rb1 contents
It it is 0.4-0.8 g/l, content of trehalose is 40-80 g/l, and the buffer concentration with acid-base value buffer capacity is 5-40 millis
Mol/L, 5 ml l of absolute ethyl alcohol, polysorbas20 content are 4-8 g/l, and amino acid content is 5-10 g/l；It is specific to prepare
Method is as follows：
Take the buffer solution with acid-base value buffer capacity, trehalose, absolute ethyl alcohol, amino acid, polysorbas20 soluble in water successively, then
The ginsenoside Rb1 for being dissolved in water in advance is added in, solution acid alkalinity is adjusted after mixing to 6.5-8.5, adds water constant volume, then with 0.22
Zut filter degerming to get.
The cushion with acid-base value buffer capacity in the novel cellular immunity enhancing adjuvant of the present invention, including, but not
It is confined to, phosphate-buffered object, trishydroxymethylaminomethane-hydrochloride buffer object, citric acid-disodium hydrogen phosphate cushion, ammonia-chlorine
Change ammonium cushion, Acetic acid-sodium acetate cushion.
Amino acid in the novel cellular immunity enhancing adjuvant of the present invention includes but is not limited to L-cysteine.
The novel cellular immunity enhancing adjuvant of the present invention is stablized in 2-8 degree to be preserved, and is conducive to the transport of conventional cold chain.
The present invention relates to novel cellular immunities to enhance adjuvant, suitable for various therapeutic vaccines, including but not limited to
Therapeutic recombinant proteins vaccine and therapeutic recombinant adenoviral vector vaccine.
The present invention has following advantages and effect compared with prior art：The novel cellular immunity enhancing adjuvant of the present invention contains
There are ginsenoside Rb1, trehalose, absolute ethyl alcohol, cushion, polysorbas20, the amino acid with acid-base value buffer capacity；In formula
Substance used is made of common pharmacologic chemical substances, which has the Study On Cellular Immune of raising therapeutic vaccine
Function to the vaccine prepared, can be stablized in 2-8 degree and preserve, be conducive to conventional cold chain transportation, for therapeutic vaccine product
Promotion and application have great Social benefit and economic benefit, are a kind of safe and stable, effective, suitable for large-scale industry
The therapeutic vaccine adjuvant of metaplasia production.
Description of the drawings
The enzyme-linked Dot-ELISA detection adjuvants of Fig. 1 are to the immunological enhancement of protein vaccine
Fig. 2 mouse tumor models detect immunological enhancement of the adjuvant to protein vaccine
The enzyme-linked Dot-ELISA detection adjuvants of Fig. 3 are to the immunological enhancement of recombination adenovirus carrier vaccine
Fig. 4 mouse tumor models detect immunological enhancement of the adjuvant to recombination adenovirus carrier vaccine
The stability study of cellular immunity enhancing adjuvant novel Fig. 5.
Specific embodiment
The present embodiment is used to be the present invention further proof, but be not limited to the present invention.
The preparation of the novel cellular immunity enhancing adjuvant of embodiment 1
（1）Solution A is prepared：5 grams of trehalose is taken to be dissolved in 60 milliliters of water, then adds in trishydroxymethylaminomethane buffering in order
1.2 grams of object, 0.5 milliliter of absolute ethyl alcohol, 0.5 gram of polysorbas20,0.2 gram of L-cysteine, mixing.
（2）Solution B is prepared：0.05 gram of ginsenoside Rb1 is taken to be dissolved in 20 milliliters of water, mixing.
（3）By solution A and solution B mixing, pH value is adjusted to 7.01, water is added to be settled to 100 milliliters, is placed in the preservation of 2-8 degree.
The novel cellular immunity enhancing adjuvant of embodiment 2 can enhance treatment human papilloma virus recombinant protein vaccine
Specific cellular immunity is horizontal
Experimental animal is divided into three groups：Vaccine group, vaccine and adjuvant co-immunization group and adjuvant group, every group sets three C57/BL
Mouse.Dosage of inoculation is as follows：The treatment that vaccine group is inoculated with 100 microlitres of a concentration of 500 mcg/mls is recombinated with human papilloma virus
Protein vaccine, vaccine and adjuvant co-immunization group are inoculated with 100 microlitres of treatments human papilloma virus recombinant protein vaccine and adjuvants
Mixture（1：1 mixing）, adjuvant group is inoculated with the mixture of 100 microlitres of vaccine compatibility liquid and adjuvant（1：1 mixing）；Vaccine program
For：The booster shot in two days of every mouse interval is inoculated with three times altogether.
It puts to death mouse within the 14th day after initial immunity, spleen is taken gently to roll under aseptic condition, obtain spleen cell suspension.
Gained spleen cell suspension acts on the acid buffer that phosphorates after five minutes with erythrocyte cracked liquid（PBS）Neutralize, 1000 revs/min from
The heart abandons supernatant, then is washed twice with serum-free RPMI-1640 culture mediums, and cell precipitation finally is resuspended in 5% serum RPMI-
In 1640 culture mediums, mouse spleen lymphocyte suspension is obtained.
Mouse spleen lymphocyte suspension is diluted to 5.5 × 106A cells/ml is examined according to enzyme-linked spot immune
Specification is surveyed to be operated.
As a result it shows：Individual adjuvant itself will not cause mouse to generate specific interferon expression, independent epidemic disease
Seedling can cause mouse to generate specific interferon expression, and adjuvant is done with mouse specificity γ caused by vaccine combined immunization
The expression for disturbing element is higher than the immune effect of independent vaccine（See Fig. 1）.
The novel cellular immunity enhancing adjuvant of embodiment 3 can enhance treatment human papilloma virus recombinant protein vaccine
Antineoplastic immune effect
(1) foundation of mouse tumor model
By TC-1 tumor model cells with 1:4 passages, when cell length to about 90% degree of merging, with 0.25% pancreas of 37 DEG C of preheatings
Enzymic digestion 20 seconds, after 1640 culture mediums containing 10% newborn bovine serum neutralize, 1000 revs/min centrifuge 5 minutes, abandon supernatant, are resuspended
In sterile isotonic phosphate buffer, after centrifugation removes supernatant and is resuspended in PBS again, it is dense to count cell with ox Boydii tally
Degree.Gained cell is diluted to 3.2 × 10 with phosphate buffer5A/milliliter, the then left inboard leg abdomen to experiment mice C57/BL
At butt crack inoculate 100 microlitres of tumour cell/only.
(2) in mouse model inoculated tumour cell two days later, egg is recombinated with adjuvant, treatment human papilloma virus respectively
Mouse tumor model, each experimental group set 10 tumor model mouse, exempt from for white vaccine and vaccine and adjuvant mixture inoculation
Epidemic disease dosage is as follows：Vaccine group is inoculated with the treatment human papilloma virus recombinant protein epidemic disease of 100 microlitres of a concentration of 500 mcg/mls
Seedling, vaccine and adjuvant co-immunization group are inoculated with the mixing of 100 microlitres for the treatment of human papilloma virus recombinant protein vaccines and adjuvant
Object（1：1 mixing）, adjuvant group is inoculated with the mixture of 100 microlitres of vaccine compatibility liquid and adjuvant（1：1 mixing）；Vaccine program is：Often
Mouse interval booster shot in two days, inoculation is three times altogether.
(3) periodically each mouse is observed and recorded into knurl situation.
(4) result is shown：Independent vaccine on mouse tumor model has inhibiting effect, and adjuvant is drawn with vaccine combined immunization
The mouse tumor model inhibiting effect risen is better than the immune effect of independent vaccine（See Fig. 2）.
The novel cellular immunity enhancing adjuvant of embodiment 4 can enhance treatment human papilloma virus recombinant adenoviral vector
The specific cellular immunity of vaccine is horizontal
Experimental animal is divided into three groups：Vaccine group, vaccine and adjuvant co-immunization group and adjuvant group, every group sets three C57/BL
Mouse.Dosage of inoculation is as follows：Vaccine group is inoculated with 100 microlitres a concentration of 1 × 108The treatment of VP human papilloma virus recombinant adenovirus
Poisonous carrier vaccine, vaccine and adjuvant co-immunization group are inoculated with 100 microlitres for the treatment of human papilloma virus recombinant adenoviral vector epidemic diseases
The mixture of seedling and adjuvant（1：1 mixing）, adjuvant group is inoculated with the mixture of 100 microlitres of vaccine compatibility liquid and adjuvant（1：1 mixing）；
Vaccine program is：The booster shot in two days of every mouse interval is inoculated with three times altogether.
It puts to death mouse within the 14th day after initial immunity, spleen is taken gently to roll under aseptic condition, obtain spleen cell suspension.
Gained spleen cell suspension erythrocyte cracked liquid acts on after five minutes plus PBS is neutralized, and 1000 revs/min of centrifugations abandon supernatant, then use
Serum-free RPMI-1640 culture mediums wash twice, and finally cell precipitation is resuspended in 5% serum RPMI-1640 culture mediums, is obtained
Obtain mouse spleen lymphocyte suspension.
Mouse spleen lymphocyte suspension is diluted to 5.5 × 106A cells/ml is said according to the detection of enzyme-linked spot immune
Bright book is operated.
As a result it shows：Individual adjuvant itself will not cause mouse to generate specific interferon expression, independent epidemic disease
Seedling can cause mouse to generate specific interferon expression, and adjuvant is done with mouse specificity γ caused by vaccine combined immunization
The expression for disturbing element is higher than the immune effect of independent vaccine（See Fig. 3）.
The novel cellular immunity enhancing adjuvant of embodiment 5 can enhance treatment human papilloma virus recombinant adenoviral vector
The antineoplastic immune effect of vaccine
(1) foundation of mouse tumor model
By TC-1 tumor model cells with 1:4 passages, when cell length to about 90% degree of merging, with 0.25% pancreas of 37 DEG C of preheatings
Enzymic digestion 20 seconds, after 1640 culture mediums containing 10% newborn bovine serum neutralize, 1000 revs/min centrifuge 5 minutes, abandon supernatant, are resuspended
In sterile isotonic phosphate buffer, after centrifugation removes supernatant and is resuspended in PBS again, it is dense to count cell with ox Boydii tally
Degree.Gained cell is diluted to 3.2 × 10 with phosphate buffer5A/milliliter, the then left inboard leg abdomen to experiment mice C57/BL
At butt crack inoculate 100 microlitres of tumour cell/only.
(2) after mouse model inoculated tumour cell three days, gland is recombinated with adjuvant, treatment human papilloma virus respectively
Vector-viral vaccine and vaccine and adjuvant mixture are inoculated with mouse tumor model, and it is small that each experimental group sets 10 tumor models
Mouse, immunizing dose are as follows：Vaccine group is inoculated with 100 microlitres a concentration of 1 × 108The treatment of VP human papilloma virus recombined adhenovirus
Carrier bacterin, vaccine and adjuvant co-immunization group are inoculated with 100 microlitres for the treatment of human papilloma virus recombinant adenoviral vector vaccines
With the mixture of adjuvant（1：1 mixing）, adjuvant group is inoculated with the mixture of 100 microlitres of vaccine compatibility liquid and adjuvant（1：1 mixing）；It connects
Planting program is：Every mouse is inoculated with once altogether.
(3) periodically each mouse is observed and recorded into knurl situation.
(4) result is shown：Independent vaccine on mouse tumor model has inhibiting effect, and adjuvant is drawn with vaccine combined immunization
The mouse tumor model inhibiting effect risen is better than the immune effect of independent vaccine（See Fig. 4）.
The stability study of the novel cellular immunity enhancing adjuvant of embodiment 6
Novel cellular immunity is taken to enhance adjuvant to be placed in 2-8 DEG C simultaneously with individual ginsenoside Rb1's aqueous solution, place 30 days
Afterwards, respectively with treatment with human papilloma virus recombinant protein vaccine co-immunization C57/BL mouse, every group to set three C57/BL small
Mouse, while compared with vaccine group.Immunizing dose is as follows：Vaccine group is inoculated with the treatment of 100 microlitres of a concentration of 500 mcg/mls
With human papilloma virus recombinant protein vaccine, vaccine and adjuvant co-immunization group are inoculated with 100 microlitres for the treatment of human papilloma virus
The mixture of recombinant protein vaccine and adjuvant（1：1 mixing）, adjuvant group is inoculated with the mixture of 100 microlitres of vaccine compatibility liquid and adjuvant
（1：1 mixing）；Vaccine program is：The booster shot in two days of every mouse interval is inoculated with three times altogether.
It puts to death mouse within the 14th day after initial immunity, spleen is taken gently to roll under aseptic condition, obtain spleen cell suspension.
Gained spleen cell suspension erythrocyte cracked liquid acts on after five minutes plus PBS is neutralized, and 1000 revs/min of centrifugations abandon supernatant, then use
Serum-free RPMI-1640 culture mediums wash twice, and finally cell precipitation is resuspended in 5% serum RPMI-1640 culture mediums, is obtained
Obtain mouse spleen lymphocyte suspension.
Mouse spleen lymphocyte suspension is diluted to 5.0 × 106A cells/ml is said according to the detection of enzyme-linked spot immune
Bright book is operated.
As a result it shows：Caused mouse generates specific interferon expression after 2-8 DEG C of vaccine adjuvant is placed 30 days
It is higher than independent vaccine group, and caused mouse generates specificity γ after individually 2-8 DEG C of ginsenoside Rb1 aqueous solutions are placed 30 days
Interferon expression level and individual vaccine group difference is not notable.（See Fig. 5）.
Claims (7)
1. a kind of novel cellular immunity enhancing adjuvant, it is characterised in that vaccine adjuvant contains ginsenoside Rb1, trehalose, tool
There are cushion, absolute ethyl alcohol, polysorbas20, the amino acid of acid-base value buffer capacity；Specific formula component is content of ginsenoside Rb1
Content is 0.4-0.8 g/l, and content of trehalose is 40-80 g/l, and the buffer concentration with acid-base value buffer capacity is 5-
40 mM/ls, 5 ml l of absolute ethyl alcohol, polysorbas20 content is 4-8 g/l, and amino acid content is 5-10 g/l.
2. cellular immunity according to claim 1 enhances adjuvant, it is characterised in that in novel cellular immunity enhancing adjuvant
The cushion with acid-base value buffer capacity include, phosphate-buffered object, trishydroxymethylaminomethane-hydrochloride buffer object, Chinese holly
Rafter acid-disodium hydrogen phosphate cushion, ammonia-chloride buffer object, Acetic acid-sodium acetate cushion.
3. cellular immunity according to claim 1 enhances adjuvant, it is characterised in that in novel cellular immunity enhancing adjuvant
Amino acid include, L-cysteine.
4. cellular immunity according to claim 1 enhances adjuvant, it is characterised in that novel cellular immunity enhancing adjuvant is matched
Method processed is as follows：The buffer solution with acid-base value buffer capacity, trehalose, absolute ethyl alcohol, amino acid, polysorbas20 is taken to be dissolved in successively
In water, the ginsenoside Rb1 for being dissolved in water in advance is added, solution acid alkalinity is adjusted after mixing, adds water constant volume, it is then micro- with 0.22
Rice filter filtration sterilization to get.
5. cellular immunity according to claim 1 enhances adjuvant, it is characterised in that novel cellular immunity enhancing adjuvant is molten
Liquid acid-base value is 6.5-8.5.
6. cellular immunity according to claim 1 enhances adjuvant, it is characterised in that novel cellular immunity enhancing adjuvant can
Stablize in 2-8 degree and preserve, be conducive to conventional cold chain transportation.
7. cellular immunity according to claim 1 enhances adjuvant, it is characterised in that novel cellular immunity enhancing adjuvant is fitted
For various therapeutic vaccines, including but not limited to therapeutic recombinant proteins vaccine.
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| CN201810049632.5A CN108210922A (en) | 2018-01-18 | 2018-01-18 | A kind of novel cellular immunity enhancing adjuvant |
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| CN201810049632.5A CN108210922A (en) | 2018-01-18 | 2018-01-18 | A kind of novel cellular immunity enhancing adjuvant |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109568575A (en) * | 2018-12-02 | 2019-04-05 | 河南师范大学 | It is a kind of enhance Aeromonas hydrophila OmpA vaccine inoculation effect small molecule metabolites adjuvant and its application |
| CN112294955A (en) * | 2020-10-28 | 2021-02-02 | 国药中生生物技术研究院有限公司 | Compound immunologic adjuvant and application thereof |
| CN113016967A (en) * | 2021-04-15 | 2021-06-25 | 深圳仙草生物科技股份有限公司 | Specific immunity-inducing composition and specific immunity-inducing beverage |
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| CN103110943A (en) * | 2013-03-11 | 2013-05-22 | 浙江普康生物技术股份有限公司 | Novel vaccine adjuvant capable of replacing aluminum hydroxide |
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| CN103110943A (en) * | 2013-03-11 | 2013-05-22 | 浙江普康生物技术股份有限公司 | Novel vaccine adjuvant capable of replacing aluminum hydroxide |
| CN104383534A (en) * | 2014-10-24 | 2015-03-04 | 威海芝恩药业股份有限公司 | Immunological adjuvant containing fucosan sulfate and application of immunological adjuvant |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109568575A (en) * | 2018-12-02 | 2019-04-05 | 河南师范大学 | It is a kind of enhance Aeromonas hydrophila OmpA vaccine inoculation effect small molecule metabolites adjuvant and its application |
| CN112294955A (en) * | 2020-10-28 | 2021-02-02 | 国药中生生物技术研究院有限公司 | Compound immunologic adjuvant and application thereof |
| CN113016967A (en) * | 2021-04-15 | 2021-06-25 | 深圳仙草生物科技股份有限公司 | Specific immunity-inducing composition and specific immunity-inducing beverage |
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Application publication date: 20180629 |