CN104623654A - Application of chitosan oligosaccharide and vaccine containing chitosan oligosaccharide - Google Patents
Application of chitosan oligosaccharide and vaccine containing chitosan oligosaccharide Download PDFInfo
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- CN104623654A CN104623654A CN201510008726.4A CN201510008726A CN104623654A CN 104623654 A CN104623654 A CN 104623654A CN 201510008726 A CN201510008726 A CN 201510008726A CN 104623654 A CN104623654 A CN 104623654A
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Abstract
The invention provides anapplication of chitosan oligosaccharide and a vaccine containing the chitosan oligosaccharide. The chitosan oligosaccharide is applied to the vaccine as an adjuvant, namely each single vaccine contains 2.5-10mg of chitosan oligosaccharide. The chitosan oligosaccharide provided by the invention is a chitosan oligosaccharidemixturewhich is formed by 2-10 glucosamines and of which the molecular weight is smaller than 3000, and is small in toxic or side effect, and is safe and reliable when being used in an immunizing dose range; antigen-specifichumoral immune responsecan be effectively induced; the induced humoral immune response effect is superior to that of a group free of an adjuvant; and the chitosan oligosaccharide is available in raw materialwhich is a commercially available product, is simple in preparation technology, low in cost, stable in performance, relatively high in biological potency, and free of a toxic or side effect, and can be add to a plurality of traditional vaccines or genetic engineering vaccines as the adjuvant.
Description
Technical field
The present invention relates to a kind of application of oligochitosan and the vaccine dose containing oligochitosan, belong to immunological technique field.
Background technology
Along with developing rapidly of deepening continuously of vaccine research, particularly Protocols in Molecular Biology, novel gene engineered vaccine purity is high, high specificity, but molecule is little, and immunogenicity is relatively poor, be difficult to produce effective immunne response, need immunological adjuvant to strengthen its immunogenicity.The adjuvant that may be used for the mankind ratified in the world at present comprises aluminum salt, MF59, AS03 and AS04.Alum adjuvant has obtained long-term practice at raising antibody horizontal and secure context and has confirmed, but can cause the shortcoming such as allergy, induction degenerative neuropathy due to it, in the urgent need to development of new vaccine adjuvant to overcome these defects, is better mankind's service.
New adjuvant is constantly being found, but most of adjuvant is high because there is cost; Poor stability; Poor stability; Not easily transport storage; Self property immunological diseases and strong toxic reaction is easily caused to comprise haemolysis, granuloma, problems such as subcutaneous nodule and can not being widely used.Thus develop active strong, can biological metabolism, have no side effect, even medicative novel adjuvant is imperative.
Oligochitosan (chtiosnaoligosaccharide, COS) refer to that the molecular weight that 2 ~ 10 glucosamine are formed by connecting by β (1-4) glycosidic bond is less than 3000 water soluble compounds, it is obtained through enzymatic degradation or chemical degradation by chitin or chitosan.COS is unique a large amount of alkaline polysaccharide existed in natural sugar, and except having the character of similar chitosan, it is low that it also has viscosity, good water solubility, molecular weight is little, and easily absorb and the advantage such as degradable, biological activity and functional character all comparatively chitosan are more extensive.Research shows that COS is very good bioactive substance, has adjustment blood pressure and blood lipoid, antioxidation, infection, strengthens the various biological such as immunity and antitumor active.COS also exists polynary to immune system, polyphenic regulating action.Research finds that COS can strengthen the expression of T cell surface IL-2 receptor, accelerates the maturation of T cell and discharges IL-2, after IL-2 and corresponding receptors bind, is the T cell of effect by the T cell differentiation and maturation accelerating tranquillization further.In addition also there are some researches show that COS significantly can impel the release of macrophage activating factor by activated T cell, and then activating macrophage, the COS of high concentration can cause Ca free in the endochylemas such as macrophage
2+the rising of concentration, thus calcium/calmodulin-dependent protein kinase (CaMK II) may be activated.The CaMK II of activation is by directly combining, and phosphorylation also activates signaling molecule TAK1 and IRF3 important in TLR signal, strengthens the activation of downstream signaling pathway, thus strengthens TLR part incite inflammation cytokine IL-2, the secretion of TNF-a and IFN-1.COS can promote T in a word, the propagation of B cell and other immunocytes and differentiation, coordinates the interaction between immunocyte, and various immunocyte can be stimulated to produce cytokine profiles, thus improves immune function, has good adjuvant researching value.
Summary of the invention
High for solving the cost that existing vaccine adjuvant exists, the problems such as toxic and side effects is strong, the invention provides a kind of safety, effectively, and preparation technology simple and the oligochitosan adjuvant that cost is low and the vaccine dose containing oligochitosan adjuvant.
The present invention is realized by following technical proposal: oligochitosan is as the application of adjuvant in vaccine.
Described oligochitosan is commercial products, and be that 2 ~ 10 glucosamine are polymerized, molecular formula is (C
6h
11nO
4)
n(n=2-10), molecular weight is less than 3000, and deacetylation is greater than 92%.Structural formula as shown in Figure 1.
The invention provides a kind of vaccine dose containing oligochitosan, it is characterized in that: the oligochitosan often containing 2.5 ~ 10mg in single part of vaccine.
Described every single part of vaccine dose is the conventional single injection reference quantity of Clinical practice.
The preferred 5mg of content of described oligochitosan.
Of the present inventionly also provide a kind of preparation method containing oligochitosan vaccine dose, it is characterized in that through following each step: add the amount of 2.5 ~ 10mg oligochitosan by every single part of vaccine dose, add with aseptic water-soluble oligochitosan in antigen-agent, add normal saline again to injecting aequum, mix homogeneously routinely, obtains the vaccine dose containing oligochitosan.
The solid-to-liquid ratio mg/ μ L of described oligochitosan and sterilized water is 2.5 ~ 10:50 ~ 120.
Described antigen-agent is the one in conventional hav antigen, hepatitis B antigen, rabies virus antigen.
The present invention compared with prior art has following advantages and effect: (1) there are some researches show that chitosan adjuvant can coordinate the effect reaching and well induce immunity of organism with vaccine; but it is large to there is molecular weight in chitosan; be insoluble in the shortcomings such as water; oligochitosan be chitosan deacetylated after product; its molecular weight is little; soluble in water, biological activity comparatively chitosan is more extensive.(2) oligochitosan belongs to low-molecular-weight polysaccharide, and safety has no side effect, and cost is low, and preparation technology is simple.(3) humoral immunoresponse(HI) of the effective inducing antigen-specific of oligochitosan adjuvant energy, and its humoral immunoresponse(HI) effect of inducing is better than without adjuvant group.(4) ability of oligochitosan elicit humoral immune response is suitable with aluminium adjuvant, has good adjuvant using value.
Accompanying drawing explanation
Fig. 1 is the molecular structural formula of oligochitosan, 2≤n≤10 in figure.
Detailed description of the invention
Below in conjunction with embodiment, set forth the present invention further.These embodiments are only not used in for illustration of the present invention and limit the scope of the invention, the experimental technique of unreceipted actual conditions in the following example, conveniently the conditioned disjunction condition of advising according to manufacturer.The use that better condition implementation method described in literary composition only presents a demonstration.
Embodiment 1
What this example provided containing the hepatitis A vaccine of oligochitosan adjuvant is: add the amount of 2.5mg oligochitosan by every single part of vaccine dose, add with the aseptic water-soluble oligochitosan of 50 μ L in hepatitis A (HAV) antigen, add normal saline to 200 μ L again, mix homogeneously routinely, obtains the hepatitis A vaccine agent containing oligochitosan.
Wherein, oligochitosan is commercial products, and be that 2 ~ 10 glucosamine are polymerized, molecular weight is less than 3000, purchased from Hubei Wei get Li chemistry Science and Technology Ltd.; The 18EU HAV antigen liquid of HAV antigen to be commercial titre be 256EU/ml, is provided by Union Medical College Institute of Health on Nutriology, Beijing of the Chinese Academy of Medical Sciences.
Embodiment 1 gained contain the immunization experiment of the hepatitis A vaccine of oligochitosan adjuvant and effect as follows:
A, immunity
By 6 ~ 8 week age, the cleaning agent ICR mice of 18 ~ 22g was divided into oligochitosan adjuvant group, aluminum hydroxide adjuvant group at random, without adjuvant group and blank group, totally four groups, often organized 8; Aluminium hydroxide used is conventional alumine hydroxide colloid adjuvant, its method for making reference " Chinese Pharmacopoeia (three) ", (Chinese Pharmacopoeia Commission. Beijing: People's Health Publisher.2005::18-119), the dosage in human body is 1.8 ~ 2.7mg.
To oligochitosan adjuvant group: the hepatitis A vaccine containing oligochitosan adjuvant of injection embodiment 1 is in Mice Body, and injected dose is every mice 200 μ l, wherein contains oligochitosan 2.5mg, hav antigen 18EU in 200 μ l.
To aluminum hydroxide adjuvant group: add normal saline to 200 μ l after being mixed with hav antigen 18EU by aluminium hydroxide 0.3mg, through abdominal cavity, subcutaneous multi-point injection is in Mice Body, injected dose is every mice 200 μ l.
To without adjuvant group: hav antigen 18EU and normal saline are mixed to 200 μ l, more subcutaneous multi-point injection is in Mice Body through abdominal cavity, injected dose is every mice 200 μ l.
To blank group: only injecting normal saline, injected dose is every mice 200 μ l.
Immunization protocol: subcutaneous multi-point injection was in Mice Body through abdominal cavity at the 0th week, and immune time is once.
B, ELISA detect serum anti-HAV IgG level
After immunity the 4th, 8,12,16 weeks, gather mouse tail vein blood, separation of serum, by KPL company general ELISA kit description operation detection mice serum IgG antibody.Data analysis.
Carrying out one factor analysis of variance to obtained experimental data with SPSS18.0 software, take P<0.05 as the difference having statistical significance.
Table 1 for after using the adjuvant immunity that provides of embodiment 1, in 16 weeks, each experimental mice serum anti-HAV IgG level (antibody titer value):
Table 1
Can be found out by data analysis, from 4th week after immunity, except blank group, each experimental group can produce anti-HAV IgG antibody, and generally reached peak value in the 8th week, wherein aluminium adjuvant group best results, within 16 weeks, antibody horizontal is all significantly higher than without Adjuvanted vaccines group, P<0.05.The antibody horizontal of oligochitosan adjuvant group is also significantly higher than without Adjuvanted vaccines group, and it is suitable with aluminium adjuvant matched group antibody horizontal in 4 ~ 12 weeks, but decreases to the 16th week its antibody horizontal.Illustrate that oligochitosan 2.5mg dosage group has humoral immunization potentiation.
Embodiment 2
What this example provided containing the hepatitis A vaccine of oligochitosan adjuvant is: add the amount of 5mg oligochitosan by every single part of vaccine dose, add with the aseptic water-soluble oligochitosan of 100 μ L in hepatitis A (HAV) antigen, add normal saline to 200 μ L again, mix homogeneously routinely, obtains the vaccine dose containing oligochitosan.Wherein, oligochitosan, HAV antigen are with embodiment 1;
This routine gained contains the immunization experiment of the hepatitis A vaccine of oligochitosan adjuvant with embodiment 1, the results are shown in Table 2.
Table 2 for after using the adjuvant that provides of embodiment 2, in 16 weeks, each experimental mice serum anti-HAV IgG antibody level:
Table 2
Can be found out by data analysis, from after immunity the 4th week, except blank group, each experimental group can produce anti-HAV IgG antibody, and generally reached peak value in the 8th week, wherein aluminium adjuvant group best results, within 16 weeks, antibody horizontal is all significantly higher than without Adjuvanted vaccines group, P<0.05.The antibody horizontal of oligochitosan adjuvant group is also significantly higher than without Adjuvanted vaccines group, and it is suitable with aluminium adjuvant matched group antibody horizontal in 4 ~ 12 weeks, but decreases to the 16th week its antibody horizontal.Illustrate that oligochitosan 5mg dosage group has humoral immunization potentiation.
Embodiment 3
What this example provided containing the hepatitis A vaccine of oligochitosan adjuvant is: add the amount of 10mg oligochitosan by every single part of vaccine dose, add with the aseptic water-soluble oligochitosan of 120 μ L in hepatitis A (HAV) antigen, add normal saline to 200 μ L again, mix homogeneously routinely, obtains the hepatitis A vaccine agent containing oligochitosan.Wherein, oligochitosan, HAV antigen are with embodiment 1;
This routine gained contains the immunization experiment of the hepatitis A vaccine of oligochitosan adjuvant with embodiment 1, the results are shown in Table 3.
Table 3 for after using the adjuvant that provides of embodiment 2, in 16 weeks, each experimental mice serum anti-HAV IgG antibody level:
Table 3
Can be found out by data analysis, from after immunity the 4th week, except blank group, each experimental group can produce anti-HAV IgG antibody, and generally reached peak value in the 8th week, wherein oligochitosan 10mg group antibody horizontal within 16 weeks is all significantly higher than without Adjuvanted vaccines group, P<0.05.4 ~ 12 weeks oligochitosan 10mg dosage group antibody horizontals are suitable with aluminium adjuvant, and are significantly higher than aluminium adjuvant matched group, P<0.05 at the 8th week.Decline to some extent to 16 weeks oligochitosan 10mg dosage group antibody horizontals but apparently higher than without adjuvant group, show that oligochitosan 10mg adjuvant group effectively can strengthen humoral immune reaction.
Embodiment 4
What this example provided containing the Hepatitis B virus vaccine of oligochitosan adjuvant is: add the amount of 5mg oligochitosan by every single part of vaccine dose, add with the aseptic water-soluble oligochitosan of 120 μ L in hepatitis B antigen, add normal saline to 200 μ L again, mix homogeneously routinely, obtain the Hepatitis B virus vaccine agent containing oligochitosan.
Wherein, oligochitosan is with embodiment 1, and hepatitis B antigen is the conventional commercial products containing hepatitis B surface antigen 1 μ g, is provided by China Medical Sciences Academy Medical Biology Institute.
This routine gained contains the immunity test of the Hepatitis B virus vaccine of oligochitosan adjuvant with embodiment 1, and effect is in table 4.
Table 4 for after using the adjuvant that provides of embodiment 3, in 16 weeks, each experimental mice serum anti-hepatitis B surface antigen IgG antibody level:
Table 4
Can be found out by data analysis, from after immunity the 4th week, except blank group, each experimental group can produce anti-hepatitis B surface antigen IgG antibody, and generally reached peak value in the 8th week, immune effect wherein acquired by aluminium adjuvant group is best, within 16 weeks, antibody horizontal is all significantly higher than without Adjuvanted vaccines group, P < 0.05, and can maintain higher level.The antibody horizontal of oligochitosan adjuvant group is also significantly higher than without adjuvant group, P<0.05.As can be seen from table 4 also, the 8th week time, the antibody horizontal of oligochitosan 5mg adjuvant group and the aluminium adjuvant group antibody horizontal of the same period close, but difference between the two does not have statistical significance (P < 0.05), show that 5mg oligochitosan adjuvant group effectively can strengthen humoral immune reaction.
Embodiment 5
Vaccine containing oligochitosan adjuvant provided by the invention is: add the amount of 5mg oligochitosan by every single part of vaccine dose, add with the aseptic water-soluble oligochitosan of 110 μ L in rabies virus antigen, add normal saline to 200 μ L again, mix homogeneously routinely, obtain the rabies vaccine agent containing oligochitosan.
Wherein, oligochitosan is with embodiment 1; Rabies virus antigen is the conventional commercial products containing rabies virus antigen 0.125IU, purchased from Dalian Hanxin Biology Pharmacy Co., Ltd.
This routine gained contains the immunity test of the rabies vaccine of oligochitosan adjuvant with embodiment 1, and effect is in table 5.
Table 5 for after using the adjuvant that provides of embodiment 4, in 16 weeks, each experimental mice serum anti-rabies virus IgG antibody level:
Table 5
Can be found out by data analysis, from after immunity the 4th week, except blank group, each experimental group can produce anti-rabies virus IgG antibody, and generally reached peak value in the 8th week, immune effect wherein acquired by aluminium adjuvant group is best, within 16 weeks, antibody horizontal is all significantly higher than without Adjuvanted vaccines group, P < 0.05, and can maintain higher level.The antibody horizontal of oligochitosan adjuvant group is also significantly higher than without adjuvant group.But as can be seen from table 5 also, the 8th week time, the antibody horizontal of oligochitosan 5mg adjuvant group and the aluminium adjuvant group antibody horizontal of the same period close, but difference between the two does not have statistical significance (P < 0.05), show that 5mg oligochitosan adjuvant group effectively can strengthen humoral immune reaction.
Claims (8)
1. oligochitosan is as the application of adjuvant in vaccine.
2. the vaccine dose containing oligochitosan, is characterized in that: the oligochitosan often containing 2.5 ~ 10mg in single part of vaccine.
3. vaccine dose according to claim 2, is characterized in that: described oligochitosan is commercial products, and be that 2 ~ 10 glucosamine are polymerized, molecular formula is (C
6h
11nO
4)
n(n=2-10), molecular weight is less than 3000, and deacetylation is greater than 92%.
4. vaccine dose according to claim 2, is characterized in that: described every single part of vaccine dose is the conventional single injection reference quantity of Clinical practice.
5. vaccine dose according to claim 2, is characterized in that: the content of described oligochitosan is 5mg.
6. the preparation method containing oligochitosan vaccine dose, it is characterized in that through following each step: add the amount of 2.5 ~ 10mg oligochitosan by every single part of vaccine dose, add with aseptic water-soluble oligochitosan in antigen-agent, add normal saline again to injecting aequum, mix homogeneously routinely, obtains the vaccine dose containing oligochitosan.
7. preparation method according to claim 6, is characterized in that: the solid-to-liquid ratio mg/ μ L of described oligochitosan and sterilized water is 2.5 ~ 10:50 ~ 120.
8. preparation method according to claim 6, is characterized in that: described antigen-agent is the one in conventional hav antigen, hepatitis B antigen, rabies virus antigen.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105396130A (en) * | 2015-11-10 | 2016-03-16 | 林海祥 | Polyriboinosinic polyribo-cytoidylic acid (PIC), ammonia and calcium adjuvant and vaccine containing same |
| CN105797153A (en) * | 2016-05-02 | 2016-07-27 | 浙江农林大学 | Veterinary vaccine immunologic adjuvant as well as preparation and application method thereof |
| CN107261136A (en) * | 2017-07-31 | 2017-10-20 | 中国医学科学院医学生物学研究所 | The application of sodium polyphosphate and the vaccine dose containing sodium polyphosphate |
| CN107648603A (en) * | 2017-09-22 | 2018-02-02 | 中国科学院过程工程研究所 | The purposes of vaccine adjuvant, vaccine combination and sulphation chitosan oligosaccharide in vaccine adjuvant and vaccine combination is prepared |
| CN113975383A (en) * | 2021-10-14 | 2022-01-28 | 广东渔跃生物技术有限公司 | Rhodococcus ruber immunopotentiator and application thereof in swine vaccine |
| WO2022226672A1 (en) * | 2021-04-30 | 2022-11-03 | 山东省药学科学院 | Chitin oligosaccharide vaccine for preventing fungal infection and preparation method therefor |
-
2015
- 2015-01-08 CN CN201510008726.4A patent/CN104623654A/en active Pending
Non-Patent Citations (1)
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| 李萍等: "壳寡糖佐剂对HAV抗原诱导小鼠体液免疫应答的影响", 《第九届全国免疫学学术大会论文集》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105396130A (en) * | 2015-11-10 | 2016-03-16 | 林海祥 | Polyriboinosinic polyribo-cytoidylic acid (PIC), ammonia and calcium adjuvant and vaccine containing same |
| CN105797153A (en) * | 2016-05-02 | 2016-07-27 | 浙江农林大学 | Veterinary vaccine immunologic adjuvant as well as preparation and application method thereof |
| CN107261136A (en) * | 2017-07-31 | 2017-10-20 | 中国医学科学院医学生物学研究所 | The application of sodium polyphosphate and the vaccine dose containing sodium polyphosphate |
| CN107261136B (en) * | 2017-07-31 | 2020-07-28 | 中国医学科学院医学生物学研究所 | Application of sodium polyphosphate and vaccine containing sodium polyphosphate |
| CN107648603A (en) * | 2017-09-22 | 2018-02-02 | 中国科学院过程工程研究所 | The purposes of vaccine adjuvant, vaccine combination and sulphation chitosan oligosaccharide in vaccine adjuvant and vaccine combination is prepared |
| WO2022226672A1 (en) * | 2021-04-30 | 2022-11-03 | 山东省药学科学院 | Chitin oligosaccharide vaccine for preventing fungal infection and preparation method therefor |
| CN113975383A (en) * | 2021-10-14 | 2022-01-28 | 广东渔跃生物技术有限公司 | Rhodococcus ruber immunopotentiator and application thereof in swine vaccine |
| CN113975383B (en) * | 2021-10-14 | 2023-10-20 | 广东渔跃生物技术有限公司 | Rhodococcus erythropolis immunopotentiator and application thereof in vaccine for pigs |
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