CN105561293B - Immunopotentiator and its preparation method and application - Google Patents
Immunopotentiator and its preparation method and application Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
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- C12N2760/20011—Rhabdoviridae
- C12N2760/20111—Lyssavirus, e.g. rabies virus
- C12N2760/20134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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Abstract
The invention proposes immunopotentiators and its preparation method and application, wherein immunopotentiator includes: at least one of chitosan, trimethyl quaternary ammonium salt chitosan and mannatide.The immune response of immune animal can be significantly improved using the immunopotentiator, improved antibody level, to improve the immune effect of vaccine, while can be shortened immune window phase, extend protective period.
Description
Technical field
The present invention relates to field of biotechnology, and in particular to immunopotentiator and its preparation method and application.
Background technique
Rabies (Rabies) are called mad dog disease or hydrophobia, are the people as caused by hydrophobin (Rabies virus)
Beast suffers from infectious disease altogether.Rabies mainly influence central nervous system, and people once falls ill, at present still without effective clinical treatment side
Method is the acute infectious disease that the unique case fatality rate of the mankind is up to 100% so far.There are about 55000 people to die of rabies every year in the whole world,
Annual rabies death toll is more than 2000 people from after 2003 in China, although China puts into the rabic expense of prevention and control every year
More than 10,000,000,000, Meteorological occupies the first in the world, and control efficiency is that the whole world is second from the bottom, is only second to India.Rabies viruses
Propagate the public health security for having seriously affected China, it has also become a social concern very outstanding.
The existing antirabic vaccine in China is mainly inactivated vaccine, and inactivated vaccine mainly uses rolling bottle or microcarrier
Viral antigen is produced, is then concentrated, purifies, inactivation, adjuvant emulsion is added and is made, since the titre of production virus is low, reaches and exempts from
The multiple that epidemic disease efficacy requirements need to be concentrated is high, as spinner culture needs to be concentrated 30-50 times；Simultaneously as cell and Virus culture
When be added 2~10% cow's serum (serum easily causes immune side reaction as heterologous protein), cause downstream purification difficulty to add
Greatly, prepared inactivated vaccine high production cost, the selling price of existing vaccine all more than 20 yuan/parts, lead to political affairs at different levels
Mansion purchase cost is high, it is difficult to large-scale promotion.The external existing rabies vacciness for dog is using intramuscular injection
Inactivated vaccine, quality is preferable, but expensive.
The raising huge number of China dog, it is estimated that can exceed that 200,000,000, among these include a large amount of wandering dog and rural area
Dog.It needs using intramuscular injection is immune by dog Baoding, for large-scale dog and strong dog, is particularly easy to hurt carry out inoculation
Medical worker, in addition wandering dog is difficult to capture, therefore be sometimes difficult to carry out using intramuscular injection.And oral vaccine can
This problem is well solved, vaccine need to be only placed in bait by large-scale dog, strong dog and wandering dog, it is fed
It can play the role of immunoprophylaxis, it is easy to spread.
It is to carry out wild animal oral hydrophobia vaccine that successful foreign, which eliminates rabic experience, and reason is mostly
The natural reservoir (of bird flu viruses) such as wild animal such as fox, racoon that are transmitted primarily through of American-European countries's rabies viruses are propagated, and the mad dog in China
The major transmission path of virus is by the biting of dog, licks and lick, therefore prevention and control rabic primary measure in China's is exactly to cut
Disconnected propagation of the dog to human rabies poison, to the immune of 70% or more dog realization, including wandering dog and rural area dog, so that it may block
Propagation of the rabies in the mankind.
The World Health Organization thinks: carrying out oral vaccination to dog, no matter is single use or combines with injection inoculation, all
A kind of new method that dog rate of vaccination can be made to greatly improve is provided, is especially gone around everywhere, the dog of no supervision.Due to dog
Injection inoculation is carried out, is one of the main bugbear in many different regions rabies controls in the world, so WHO is in Africa, drawing
Some countries in fourth America and Asia have carried out the research of dog group and dog immunization rate.Recognize that injecting immune mode is mad in elimination dog
Limitation in terms of dog disease, WHO strengthen safer and more effective needed for research and such vaccination ways to dog oral immunity
Vaccine and bait exploitation.Its virus of the oral rabies vaccine of current all listings all derives from Evelyn-Rokitnicki-
Abelseth (ERA) strain.ERA plants be rabies street virus Street-Alabama-Dufferin (SAD) strain fixation strain.
SAD plants separate from a mad dog of U.S. Alabama in nineteen thirty-five, in mouse brain, baby hamster kidney BHK-21 cell and chicken embryo
Middle progress repeatedly after passage attenuation, obtains ERA plants.Traditional attenuated live vaccine breeds variation due to residual virulence or in vivo can
It can lead to the animal suffering from disease of inoculation, there is certain risk.Dog is immunized by way of oral at present, it was demonstrated that can induce
Dog generates Antibody against rabies virus to obtain the resistance to the virus, but existing most hydrophobin oral vaccine strain mouths
It is that immunogenicity is poor that clothes are immune, and the neutralizing antibody titers of generation are lower, it is therefore necessary to be come using certain immunopotentiator
Enhance immune effect.
Summary of the invention
The present invention is directed to solve at least some of the technical problems in related technologies.For this purpose, of the invention
One purpose is to propose immunopotentiator and its preparation method and application, can be significantly improved using the immunopotentiator immune
The immune response of animal improves antibody level, to improve the immune effect of vaccine, while can shorten immune window phase, prolong
The long protection period.
According to an aspect of the present invention, the present invention proposes a kind of immunopotentiator, includes: chitosan, trimethyl quaternary ammonium
At least one of salt chitosan and mannatide.The immune of immune animal can be significantly improved using the immunopotentiator to answer
It answers, improves antibody level, to improve the immune effect of vaccine, while immune window phase can be shortened, extended protective period.
According to a particular embodiment of the invention, in above-mentioned immunopotentiator chitosan final concentration of 2-20mg/ml, front three
The final concentration of 2-50mg/ml of based quaternary ammonium salt chitosan, the final concentration of 0.1-5.0mg/ml of mannatide.Invention human hair
It is existing, by using above-mentioned final concentration, it can be further improved the reinforcing effect of immunopotentiator, and then improve antibody level journey
Degree, to improve the immune effect of vaccine, while can shorten immune window phase, extend protective period.It is according to the present invention specific
Embodiment, above-mentioned immunopotentiator can be used for oral vaccine, specifically can be used for rabies oral vaccine, preferably oral
Live vaccine.According to a particular embodiment of the invention, the strain of rabies oral vaccine can for ERA, SAD, ERAg333 and
At least one of ERAG3M or derivatives thereof.
According to a particular embodiment of the invention, in above-mentioned immunopotentiator, it is preferable that the final concentration of 2- of the chitosan
5mg/ml, the final concentration of 4-10mg/ml of the trimethyl quaternary ammonium salt chitosan, the final concentration of 2.0- of the mannatide
5.0mg/ml.And then can be further improved the reinforcing effect of immunopotentiator, and then improve antibody level degree, to improve
The immune effect of vaccine, while immune window phase can be shortened, it extends protective period.Specifically, the purposes of the immunopotentiator can
As previously mentioned, details are not described herein.
According to a particular embodiment of the invention, in above-mentioned immunopotentiator, it is preferable that the chitosan it is final concentration of
4mg/ml, the final concentration of 10mg/ml of the trimethyl quaternary ammonium salt chitosan, the final concentration of 5.0mg/ of the mannatide
ml.And then can be further improved the reinforcing effect of immunopotentiator, and then improve antibody level degree, to improve vaccine
Immune effect, while immune window phase can be shortened, it extends protective period.Specifically, the purposes of the immunopotentiator can be as preceding
Described, details are not described herein.
According to another aspect of the present invention, the invention also provides a kind of method for preparing immunopotentiator noted earlier,
It include: to mix at least one of chitosan solution, trimethyl quaternary ammonium salt chitosan solution and mannosan peptide solution,
To obtain the immunopotentiator.There is preferable vaccine enhancing effect from there through the immunopotentiator that the above method is prepared
Fruit, and then antibody level degree is improved, to improve the immune effect of vaccine, while immune window phase can be shortened, extend and protect
The shield phase.Specifically, the purposes of the immunopotentiator can be as previously mentioned, details are not described herein.
According to a particular embodiment of the invention, the chitosan solution is prepared through the following steps: by chitosan plus
Enter into 0.8% acetic acid solution, and adjusts pH value to 7.0；And it places 20 minutes and carries out under 121 degrees Celsius and under condition of high voltage
Degerming, to obtain the chitosan solution.It can be further improved the safety of immunopotentiator by the above method.
According to a particular embodiment of the invention, the mannosan peptide solution is prepared through the following steps: by sweet dew
Glycan peptide is added in the PBS that pH value is 7.2, is mixed；And filtration sterilization, to obtain the mannosan peptide solution.It is logical
Crossing the above method can be further improved the safety of immunopotentiator.
According to a particular embodiment of the invention, the trimethyl quaternary ammonium salt chitosan solution is prepared into through the following steps
To: trimethyl quaternary ammonium salt chitosan is added in the PBS that pH value is 7.2, is mixed；And under 121 degrees Celsius and high-pressure section
Progress degerming in 20 minutes is placed under part, to obtain the trimethyl quaternary ammonium salt chitosan solution.It can be by the above method
The safety of one step raising immunopotentiator.
According to the third aspect of the invention we, the invention also provides a kind of method for improving immune animal immune response, packets
It includes: mentioned-above immunopotentiator or the immunopotentiator being prepared using method noted earlier is used to immune animal.
According to a particular embodiment of the invention, the immune animal is mouse, dog or cat.
According to the fourth aspect of the invention, the invention also provides a kind of oral vaccine, which contains front institute
The immunopotentiator stated or the immunopotentiator being prepared using method noted earlier.
According to a particular embodiment of the invention, the oral vaccine is rabies oral vaccine.It is according to the present invention specific
Embodiment, above-mentioned oral vaccine can be live oral vaccine.
According to a particular embodiment of the invention, the strain of the rabies oral vaccine be ERA, SAD, ERAg333 and
At least one of ERAG3M or derivatives thereof.According to a particular embodiment of the invention, ERA, SAD, ERAg333 and ERAG3M
Derivative can be through genetic engineering method, or be obtained by any other methods.
According to a particular embodiment of the invention, the oral vaccine is used for mouse, dog or cat.
Specific embodiment
The embodiments described below is exemplary, it is intended to is used to explain the present invention, and be should not be understood as to of the invention
Limitation.
According to an aspect of the present invention, the present invention proposes a kind of immunopotentiator, includes: chitosan, trimethyl quaternary ammonium
At least one of salt chitosan and mannatide.
Embodiment 1
The preparation of rabies live oral vaccine immunopotentiator
(1) 1g chitosan is added in 0.8% acetic acid solution of 100ml, is mixed well, with 7.5% NaHCO3Solution
Adjusting pH is value 7.0, adjusts PH that should slowly adjust in the process, prevents precipitating from generating, is settled to 100ml, 121 DEG C of high pressures later
20min, 1% chitosan solution.Chitosan solution after high pressure is mixed with virus liquid 1:1, as rabies immune increases
Strong agent 1.
(2) it weighs α-mannatide 50mg to be added in the PBS of 10ml PH7.2, mix, after completely dissolution, 0.22 μm
Filtration sterilization.α-mannosan peptide solution the 0.5ml for taking 5mg/ml, is added in 2ml virus liquid, and as rabies immune enhances
Agent 2.
(3) 100mg trimethyl quaternary ammonium salt chitosan (TMC) is added in the PBS that 10mlpH value is 7.2, is mixed, sufficiently
After dissolution, the TMC1ml after high pressure is added in the virus liquid of 1ml by 121 DEG C of high pressure 20min, and as rabies immune enhances
Agent 3.
(4) α-mannatide 50mg and 200mg trimethyl quaternary ammonium salt chitosan is weighed respectively is added to 10ml PH7.2
PBS in, mix, after completely dissolution, 0.22 μm of filtration sterilization.1ml mixed liquor is taken to be added in 4ml virus liquid, as mad dog
Sick immunopotentiator 4.
(5) α-mannatide 50mg and 200mg trimethyl quaternary ammonium salt chitosan is weighed respectively is added to 10ml PH7.2
PBS in, mix, after completely dissolution, 0.22 μm of filtration sterilization.1g chitosan is added in 0.8% acetic acid solution of 100ml,
It mixes well, with 7.5% NaHCO3It is value 7.0 that solution, which adjusts pH, adjusts PH that should slowly adjust in the process, prevents precipitating from generating,
It is settled to 100ml, 121 DEG C of high pressure 20min later.By the chitosan solution and α-mannatide, trimethyl quaternary ammonium after high pressure
Salt chitosan mixed liquor, virus liquid are mixed in the ratio of 2:1:2, as rabies immune reinforcing agent 5.
Embodiment 2
Toxicity detection of the immunopotentiator to hydrophobin
1. implementation method
It 1) is 10 by virus titer8.3TCID50The hydrophobin of/ml is dilute with 10 times of multiple proportions of DMEM culture medium containing serum
It releases, i.e., 10-1, 10-2, 10-9。
2) immunopotentiator and virus liquid are mixed into mixing with hydrophobin liquid in the ratio of 1:1, is protected in 37 DEG C of water-baths
After warming is made 1 hour, the TCID50 of mixed liquor virus is measured；It is equipped with only immunopotentiator simultaneously, virus liquid (immune increasing is not added
Strong agent is mixed with DMEM culture medium) and only compareing for immunopotentiator is not added in virus liquid.
2.TCID50Measurement result, such as table 1.
1 virus liquid TCID50 measurement result of table
| Group | lgTCID50/ml |
| Immunopotentiator 1+ virus liquid | 7.0 |
| Immunopotentiator 2+ virus liquid | 7.0 |
| Immunopotentiator 3+ virus liquid | 7.3 |
| Immunopotentiator 4+ virus liquid | 7.3 |
| Immunopotentiator 5+ virus liquid | 7.0 |
| DMEM+ virus liquid | 7.3 |
| Immunopotentiator 5 (without virus) | 0 |
Embodiment 3
The animal experiment of rabies oral vaccine immunopotentiator is verified
1. experimental animal is grouped and is immunized
4 week old SPF Balb/C mouse 70 is bought, is randomly divided into 7 groups, 10/group.Wherein it is used as negative control for one group
Group, immunologic adjuvant, one group is positive control, and the immune virus that adjuvant is not added, remaining three groups are experimental group, and details is seen below
Mice group shown in table 2 and Immunity.
2 experimental group situation of table
After 2 weeks immune first, in the same way with, etc. dosage carry out secondary immunity.After head exempts from 2 weeks, two exempt from before adopted
Blood, separation serum；Two exempt from 2 weeks after blood was collected, separation serum, in case carry out hydrophobin neutralize antibody titers measurement.
2. neutralize antibody titers measuring method
2.1 use TCID50Method measures CVS-11 titre
2.1.1 5x10 is prepared596 porocyte culture plates of/ml BHK-21 cell inoculation, 100 holes μ l/, second day grow up to cause
Close single layer.
2.1.2 CVS-11 sample 10 is serially diluted again to the dilution to be detected with the DMEM culture solution of 2% cow's serum
(50 μ l samples are added 450 μ l dilutions and are successively serially diluted for 10 times).
2.1.3 tissue culture plate is added in 100 hole μ l/ of sample diluting liquid, and every dilution does 4 multiple holes.
2.1.4 35 DEG C culture 3 days after cast out culture solution, PBS is washed twice.
2.1.5 80% acetone, 100 holes μ l/ is added, -20 DEG C of fixed 15min outwell acetone after the completion, and PBS is washed twice.
2.1.6 it is added configured fluorescence antibody (antibody 1:200 dilution), 30 holes μ l/, 37 DEG C are protected from light incubation 1h.
2.1.7 solution is outwelled after the completion of being incubated for, PBS is washed twice, dries culture plate, fluorescence microscope.
2.1.8 TCID is calculated according to Spearman/Karber method50。
2.2. fluorescence antibody virus neutralization tests (FAVN) detects serum antibody
2.2.1 blood serum sample is done 3 times with the DMEM culture solution of 2% cow's serum and is serially diluted (220 μ l serum addition, 440 μ
In l dilution, successively it is serially diluted to 1:729) for 3 times, 96 porocyte culture plates are added in 100 holes μ l/.
2.2.2 standard serum, negative serum, CVS-11 ibid do and dilute, and are added to tissue culture plate.
2.2.3 after diluting CVS-11,100TCID is added in 50 holes μ l/50Attack poison arrives cell plates (except CVS-11 control),
It sets in 37 DEG C of incubators and 1 hour.
2.2.4 5x10 is prepared5A/96 porocyte culture plates of ml BHK-21 cell inoculation, 50 holes μ l/ are cultivated 48 hours
Afterwards, fixed dyeing, observes fluorescence.
2.2.5 serum antibody titer is calculated according to Spearman/Karber method.
3. mice serum antibody titer measurement result
3 mice serum antibody determination result of table
Embodiment 4
Verification test of the rabies oral vaccine immunopotentiator to beasle dog
14 6 monthly age beasle dogs are bought, Antibody against rabies virus is detected as feminine gender, divides 7 groups, every group 2, five groups are experiment
Group takes orally trickle irrigation respectively and 2ml hydrophobin immunopotentiator 1,2,3,4,5, viral level 10 is immunized8.3TCID50, one group
For negative control group, 2ml BHK21 cell culture is immunized, one group is positive controls, and 2ml hydrophobin, virus is immunized
Content is 108.3TCID50 takes a blood sample respectively, measures antibody titer using FAVN method for 0,7,14,21,28,35 day after immune.Knot
Fruit confirms: experimental group antibody average titer is higher than positive controls by 20% or more, and wherein 4 groups of immune effects of immunopotentiator are most
It is good.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example
Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not
It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any
It can be combined in any suitable manner in a or multiple embodiment or examples.In addition, without conflicting with each other, the technology of this field
The feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by personnel
And combination.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, modifies, replacement and variant.
Claims (5)
1. a kind of oral vaccine, which is characterized in that include immunopotentiator, the immunopotentiator is gathered by trimethyl quaternary ammonium salt crust
Sugar juice and α-mannatide solution mixing system are at the oral vaccine is rabies oral vaccine, the trimethyl quaternary ammonium
The final concentration of 4mg/ml of salt chitosan, the final concentration of 1mg/ml of the α-mannatide.
2. oral vaccine according to claim 1, which is characterized in that the α-mannosan peptide solution is through the following steps
It is prepared:
α-mannatide is added in the PBS that pH value is 7.2, is mixed；And
Filtration sterilization, to obtain the α-mannosan peptide solution,
The trimethyl quaternary ammonium salt chitosan solution is prepared through the following steps:
Trimethyl quaternary ammonium salt chitosan is added in the PBS that pH value is 7.2, is mixed；And
Under 121 degrees Celsius and progress degerming in 20 minutes is placed under condition of high voltage, it is poly- to obtain the trimethyl quaternary ammonium salt crust
Sugar juice.
3. oral vaccine according to claim 1, which is characterized in that the oral vaccine is live oral vaccine.
4. oral vaccine according to claim 1, which is characterized in that the strain of the rabies oral vaccine be ERA,
At least one of SAD, ERAg333 and ERAG3M.
5. oral vaccine according to claim 1, which is characterized in that the oral vaccine is used for mouse, dog or cat.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1109783A (en) * | 1994-09-21 | 1995-10-11 | 卫生部长春生物制品研究所 | Oral hydrophobia vaccine for dog and productive process thereof |
| CN103877570A (en) * | 2014-02-19 | 2014-06-25 | 北京中联康生物科技有限公司 | Rabies live vaccine and method for preparing rabies live vaccine for oral administration |
| CN104560897A (en) * | 2015-01-20 | 2015-04-29 | 中国食品药品检定研究院 | Rabies virus attenuated strains as well as breeding method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102166356A (en) * | 2011-04-12 | 2011-08-31 | 西安交通大学 | Application of alpha-mannatide as vaccine adjuvant and vaccine preparation prepared using same |
| CN102824635A (en) * | 2012-08-20 | 2012-12-19 | 上海生物制品研究所有限责任公司 | Application of chitosan as adjuvant in preparation of influenza virus attenuated live vaccine |
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2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1109783A (en) * | 1994-09-21 | 1995-10-11 | 卫生部长春生物制品研究所 | Oral hydrophobia vaccine for dog and productive process thereof |
| CN103877570A (en) * | 2014-02-19 | 2014-06-25 | 北京中联康生物科技有限公司 | Rabies live vaccine and method for preparing rabies live vaccine for oral administration |
| CN104560897A (en) * | 2015-01-20 | 2015-04-29 | 中国食品药品检定研究院 | Rabies virus attenuated strains as well as breeding method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 口服型狂犬疫苗研究进展;刘晓志等;《白求恩军医学院学报》;20100820;第8卷(第4期);第283-284页 * |
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