CN104096229B - Zinc glycinate adjuvant and the vaccine containing zinc glycinate adjuvant - Google Patents
Zinc glycinate adjuvant and the vaccine containing zinc glycinate adjuvant Download PDFInfo
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- CN104096229B CN104096229B CN201410313922.8A CN201410313922A CN104096229B CN 104096229 B CN104096229 B CN 104096229B CN 201410313922 A CN201410313922 A CN 201410313922A CN 104096229 B CN104096229 B CN 104096229B
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Abstract
The present invention provides a kind of zinc glycinate adjuvant and the vaccine containing zinc glycinate adjuvant, contains the zinc glycinate adjuvant of 0.1 ~ 1mg of the PBS dissolving of useful pH=6 ~ 8 in the most single part of vaccine dose.The zinc glycinate adjuvant that the present invention provides is pharmaceutic adjuvant, it it is nourishment intensifying agent with zinc, toxic and side effects is little, it is safe and reliable for using in the range of immunizing dose, can the humoral immunoresponse(HI) of effective inducing antigen-specific, and the humoral immunoresponse(HI) effect induced is better than without adjuvant group, zinc glycinate adjuvant raw material is easy to get, for commercially available prod, preparation technology is simple, low cost, stable performance, biological value is higher, nonhazardous effect, can make an addition in multiple traditional vaccine and recombinant vaccine as vaccine adjuvant.
Description
Technical field
The present invention relates to a kind of zinc glycinate adjuvant and the vaccine containing this adjuvant, belong to immunological technique field.
Background technology
In recent years, along with developing rapidly of deepening continuously of vaccine research, particularly molecular biotechnology, that develops is new
Type recombinant vaccine purity is high, high specificity, but molecule is little, and immunogenicity is relatively weak, it is difficult to producing effective immunity should
Answer.Therefore apply adjuvant to strengthen its immunogenicity to be just particularly important.
At present, authentication application is very the fewest in the adjuvant of the mankind, and Alum adjuvant is exactly one of them.Alum adjuvant exists
Improve antibody horizontal and secure context has obtained long-term practice and confirmed, but owing to it can cause allergy, induction degenerative neurological
The shortcomings such as pathological changes, in the urgent need to exploitation new vaccine adjuvant to overcome these defects, preferably service for the mankind.
Zinc glycinate (Glycine zinc) is microelements aminophenol chelated, and zinc-amino acid chelate is that a class is with bivalence
The amino nitrogen atom giving electronics in zinc ion and aminoacid forms coordinate bond, again with to the carbonylic oxygen atom of electronics formed five yuan or
Hexatomic ring complex.It integrates aminoacid and zinc element, is absorpting form and biological function shape in a kind of similar animal body
The zinc source additive of formula, has good palatability, biological value height, good stability and can improve the features such as immunity of organisms.
Zinc is one of growth of animal and biogenic trace element, plays important life in animal body
Reason biochemical function, it is constituent or the activator of internal multiple enzyme, have accelerate human body growth promoter, improve the sense of taste,
Improve intelligence, sexual function improving, regulation immunity of organism, prevention infection and promote the effects such as wound healing.Zinc is as directly participating in
The important biological element of immunologic function, is trophic factors necessary to immune organ growth promoter and immunne response.Zinc can strengthen
Synthesis capability and the cell of liver to viral sensitivity and participate in removing toxic substances, thus improve the defence capability of body.Zinc participates in mending
Precursor reactant, it can promote the Cascaded amplification of complement, play the effect of the defence capability of subsidy and reinforcement phagocyte and antibody.
Glycine is the aminoacid that molecular weight is minimum, and it reacts, with trace element, the aminoacid that the sequestration thing generated also is molecular weight minimum
Trace element sequestration thing, preferably can be absorbed by human body, utilize.Owing to aminoacid and zinc all have certain bactericidal action, again
Having suitable Nutrition, both have good compatibility.And the chelate structure of aminoacid and zinc makes zinc glycinate have well
Chemical stability and heat stability, there is antagonism that is anti-interference and that alleviate between mineral, enter that blood is fast, bioavailability
High remarkable advantage, by country's relevant health detection Department certification, and confirms as food enrichment.Relevant document table
Bright certain density zinc glycinate human peripheral blood lymphocyte nucleic acid synthesizes in obvious activation, and zinc-amino acid chelate has increasing
Strong antibacterial ability, raising immune response, promotion zooblast and effect of humoral immunity, it is mainly by improving animal
The main humoral immune material content of primary immune response and secondary immune response improves animal immune reaction, thus can speculate
Zinc glycinate has immunological enhancement, can be applied to multiple vaccine as vaccine adjuvant.
Summary of the invention
For solving toxic and side effects, the problem such as expensive that existing vaccine adjuvant exists, the present invention provide one safely, have
Effect, stable, economic zinc glycinate adjuvant and the vaccine containing zinc glycinate adjuvant.
The zinc glycinate of the present invention application in preparing vaccine adjuvant.
Described zinc glycinate is commercial curable product, and for amino-acid chelate, molecular formula is, point
Son amount is 213.5, and Zn content is 29.0～30.6wt%, and structural formula is as shown in Figure 1.
The vaccine containing zinc glycinate that the present invention provides, it is characterised in that sweet containing 0.1 ~ 1mg in the most single part of vaccine dose
Propylhomoserin zinc.
Described zinc glycinate is the zinc glycinate dissolved with the PBS of pH=6 ~ 8.
Described zinc glycinate adjuvant recommended dose in human body is: in every 200 μ L vaccine liquid, zinc glycinate consumption is less than
1mg。
The vaccine containing zinc glycinate adjuvant that the present invention provides is prepared through following method:
Add the amount of 0.1 ~ 1mg zinc glycinate by the most single part of vaccine dose, add in vaccine dose and dissolve with the PBS of pH=6 ~ 8
Zinc glycinate, then add normal saline to 200 μ L, routinely mix homogeneously, obtain the vaccine containing zinc glycinate adjuvant.
Described every single part of vaccine dose is clinical or the conventional single injection reference quantity of use in zoopery.
Described vaccine is the one in conventional hav antigen, hepatitis B antigen, rabies virus antigen.
Zinc glycinate adjuvant can be obviously enhanced the humoral immune reaction of antigenic specificity.
The present invention compared with prior art has following advantages and effect: (1) zinc glycinate adjuvant is pharmaceutic adjuvant, is zinc
Nutrition enhancer, toxic and side effects is little, and it is safe and reliable for using in the range of immunizing dose；(2) zinc glycinate adjuvant can have
The humoral immunoresponse(HI) of inducing antigen-specific of effect, and its humoral immunoresponse(HI) effect induced is better than without adjuvant group；(3)
Zinc glycinate adjuvant raw material is easy to get, and for commercially available prod, preparation technology is simple, low cost, stable performance, biological value is higher,
Nonhazardous effect, can make an addition in multiple traditional vaccine and recombinant vaccine as vaccine adjuvant；(4) zinc glycinate adjuvant with
Vaccine use in conjunction can effectively strengthen vaccine humoral immunoresponse(HI), and immune effect is better than the vaccine without adjuvant.
Accompanying drawing explanation
Fig. 1 is zinc glycinate molecular structural formula.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is expanded on further.These embodiments are merely to illustrate the present invention rather than limit
The scope of the present invention processed, the experimental technique of unreceipted actual conditions in the following example, all according to normal condition or according to manufacture
Condition proposed by manufacturer.Preferable condition implementation described in literary composition only presents a demonstration and is used.
Embodiment 1
The hepatitis A vaccine containing zinc glycinate adjuvant that this example provides is: 0.1mg zinc glycinate is dissolved in the PBS of pH=6.5
In, then mix homogeneously routinely with the most single part of HAV antigen (bolus doses that i.e. zoopery uses), glycine must be contained
The hepatitis A vaccine of zinc adjuvant.
Wherein, zinc glycinate is commercial products, and for amino-acid chelate, molecular formula is, molecule
Amount is 213.5, and Zn content is 29.0～30.6wt%, purchased from Jin Sui bio tech ltd, Shanghai；HAV antigen is commercial
Titre is the 18EU HAV antigen liquid of 256EU/ml, purchased from Chinese Academy of Medical Sciences's Beijing Union Medical College Medical Biology research
Institute.
Embodiment 1 gained contains the immunity test of the hepatitis A vaccine of zinc glycinate adjuvant and effect is as follows:
A, immunity
The cleaning grade ICR mice of 6～8 week old, 18～22g is randomly divided into zinc glycinate adjuvant group, aluminum hydroxide adjuvant
Group, without adjuvant group and blank group, totally four groups, often group 8；Aluminium hydroxide used is conventional alumine hydroxide colloid adjuvant, its system
Method reference " Chinese Pharmacopoeia (three) ", (Chinese Pharmacopoeia Commission. Beijing: People's Health Publisher .2005:118-119), people
Dosage in body is 1.8～2.7mg.
To zinc glycinate adjuvant group: in the hepatitis A vaccine containing zinc glycinate adjuvant of injection embodiment 1 to Mice Body, note
Penetrating dosage is every mice 200 μ L, wherein containing zinc glycinate 0.5mg, hav antigen 18EU in 200 μ L vaccines.
To aluminum hydroxide adjuvant group: add normal saline with hav antigen 18EU after being mixed by aluminium hydroxide 0.5mg extremely
200uL, in the subcutaneous multi-point injection in abdominal cavity to Mice Body, injection dosage is every mice 200 μ L.
To without adjuvant group: hav antigen 18EU is mixed to 200uL with normal saline, then arrive through the subcutaneous multi-point injection in abdominal cavity
In Mice Body, injection dosage is every mice 200 μ L.
To blank group: only injecting normal saline, injection dosage is every mice 200uL.
Immunization protocol: at the 0th week in the subcutaneous multi-point injection in abdominal cavity to Mice Body, 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, separate serum, and ELISA detection serum is anti-
HAV IgG level, the mouse IgG ELISA kit description produced by KPL company carries out detection operation.
C, data analysis
The experimental data obtained is carried out one factor analysis of variance with SPSS16.0 statistical software, with P 0.05 as difference
Statistical significance.
After the adjuvant that table 1 provides for using embodiment 1, in 24 weeks, each experimental mice serum anti-HAV IgG level is (anti-
Body valence value).
Table 1
By data analysis it can be seen that from the beginning of the after immunity the 4th week, in addition to blank group, each experimental group can produce anti-
HAV IgG antibody, and generally reached peak value in the 16th week, wherein the immune effect acquired by aluminium adjuvant group is optimal, within 24 weeks
Antibody is all significantly higher than without Adjuvanted vaccines group, P ＜ 0.05, and is able to maintain that higher level.Zinc glycinate 0.5mg adjuvant group is produced
Raw antibody horizontal is all remarkably higher than without Adjuvanted vaccines group, but less than aluminium adjuvant group, illustrates that zinc glycinate 0.5mg dosage has body fluid
Immunological enhancement, its humoral immunization reinforced effects is close to aluminium adjuvant.
Embodiment 2
The hepatitis A vaccine containing zinc glycinate adjuvant that this example provides is: 1mg zinc glycinate is dissolved in the PBS of pH=7.5
In, then mix routinely with the most single part of HAV antigen (bolus doses i.e. used in zoopery), zinc glycinate must be contained
The hepatitis A vaccine of adjuvant, wherein, zinc glycinate, HAV antigen are with embodiment 1；
This example gained contains the immunity test of the hepatitis A vaccine of zinc glycinate adjuvant with embodiment 1, the results are shown in Table 2.
After the adjuvant that table 2 provides for using embodiment 2, in 24 weeks, each experimental mice serum anti-HAV IgG antibody water
Flat.
Table 2
By data analysis it can be seen that from the beginning of the after immunity the 4th week, in addition to blank group, each experimental group can produce anti-
HAV IgG antibody, and generally reached peak value in the 16th week, wherein the immune effect acquired by aluminium adjuvant group is optimal, within 24 weeks
Antibody horizontal is all significantly higher than without Adjuvanted vaccines group, P ＜ 0.05, and is able to maintain that higher level.Zinc glycinate adjuvant group
Antibody horizontal is also significantly greater than without adjuvant group.But from table 2 it can also be seen that when 24 weeks, resisting of zinc glycinate 1mg adjuvant group
Body level is close with the aluminium adjuvant group antibody horizontal of the same period, but difference between the two does not have statistical significance (P ＜ 0.05), table
Bright 1mg zinc glycinate adjuvant group can effectively strengthen humoral immune reaction and this effect sustainable long period.
Embodiment 3
The Hepatitis B virus vaccine containing zinc glycinate adjuvant that this example provides is: 0.5mg zinc glycinate is dissolved in the PBS of pH=7.5
In, then mix routinely with the most single part of hepatitis B surface antigen (bolus doses i.e. used in zoopery), must be containing sweet
The Hepatitis B virus vaccine of propylhomoserin zinc adjuvant.
Wherein, zinc glycinate is with embodiment 1, and hepatitis B surface antigen is the conventional commercial product containing hepatitis B surface antigen 1 μ g
Product, purchased from China Medical Sciences Academy Medical Biology Institute.
This example gained contains the immunity test of the Hepatitis B virus vaccine of zinc glycinate adjuvant with embodiment 1, and effect is shown in Table 3.
After the adjuvant that table 3 provides for using embodiment 3, in 24 weeks, each anti-hepatitis B surface antigen of experimental mice serum
IgG antibody level.
Table 3
By data analysis it can be seen that from the beginning of the after immunity the 4th week, in addition to blank group, each experimental group can produce anti-
Hepatitis B surface antigen IgG antibody, and generally reached peak value in the 16th week, wherein the immune effect acquired by aluminium adjuvant group is
Good, within 24 weeks, antibody horizontal is all significantly higher than without Adjuvanted vaccines group, P ＜ 0.05, and is able to maintain that higher level.Glycine
The antibody horizontal of zinc adjuvant group is also significantly greater than without adjuvant group.But from table 3 it can also be seen that when 24 weeks, zinc glycinate 1mg
The antibody horizontal of adjuvant group is slightly above the aluminium adjuvant group antibody horizontal of the same period, but difference between the two does not have statistical significance (P
＜ 0.05), show 0.5mg zinc glycinate adjuvant group can effectively strengthen humoral immune reaction and this effect sustainable longer time
Between.
Embodiment 4
The vaccine containing zinc glycinate adjuvant that the present invention provides is: be dissolved in the PBS of pH=8 by 1mg zinc glycinate, then
Mix routinely with the most single part of rabies virus antigen (bolus doses i.e. used in zoopery), zinc glycinate must be contained
The rabies vaccine of adjuvant.
Wherein, zinc glycinate is with embodiment 1；Rabies virus antigen is the conventional city containing rabies virus antigen 0.125IU
Purchase product, purchased from Dalian Hanxin Biology Pharmacy Co., Ltd.
This example gained contains the immunity test of the rabies vaccine of zinc glycinate adjuvant with embodiment 1, and effect is shown in Table 4.
After the adjuvant that table 4 provides for using embodiment 4, in 24 weeks, each experimental mice serum anti-rabies virus IgG antibody
Level.
Table 4
By data analysis it can be seen that from the beginning of the after immunity the 4th week, in addition to blank group, each experimental group can produce anti-mad
Dog virus IgG antibody, and generally reached peak value in the 16th week, wherein the immune effect acquired by aluminium adjuvant group is optimal, 24 weeks it
Interior antibody horizontal is all significantly higher than without Adjuvanted vaccines group, P ＜ 0.05, and is able to maintain that higher level.Zinc glycinate adjuvant group
Antibody horizontal be also significantly greater than without adjuvant group.But from table 4 it can also be seen that when 24 weeks, zinc glycinate 1mg adjuvant group
Antibody horizontal is close with the aluminium adjuvant group antibody horizontal of the same period, but difference between the two does not have statistical significance (P ＜ 0.05),
Show that 1mg zinc glycinate adjuvant group can effectively strengthen humoral immune reaction and this effect sustainable long period.
Embodiment 5
The vaccine containing zinc glycinate adjuvant that the present invention provides is: be dissolved in the PBS of pH=6 by 0.8mg zinc glycinate,
Mix routinely with the most single part of rabies virus antigen (bolus doses i.e. used in zoopery) again, glycine must be contained
The rabies vaccine of zinc adjuvant.
Wherein, zinc glycinate is with embodiment 1；Rabies virus antigen is the conventional city containing rabies virus antigen 0.125IU
Purchase product, purchased from Dalian Hanxin Biology Pharmacy Co., Ltd.
This example gained contains the immunity test of the rabies vaccine of zinc glycinate adjuvant with embodiment 1, and effect is shown in Table 5.
After the adjuvant that table 5 provides for using embodiment 5, in 24 weeks, each experimental mice serum anti-rabies virus IgG antibody
Level.
Table 5
By data analysis it can be seen that from the beginning of the after immunity the 4th week, in addition to blank group, each experimental group can produce anti-
Rabies virus IgG antibody, and generally reached peak value in the 16th week, wherein the immune effect acquired by aluminium adjuvant group is optimal, 24 weeks
Within antibody be all significantly higher than without Adjuvanted vaccines group, P ＜ 0.05, and be able to maintain that higher level.Zinc glycinate 1mg adjuvant group
Produce antibody horizontal to be all remarkably higher than without Adjuvanted vaccines group, but less than aluminium adjuvant group, illustrate that zinc glycinate 1mg dosage has body fluid
Immunological enhancement, its humoral immunization reinforced effects is close to aluminium adjuvant.
Claims (2)
1. the vaccine containing zinc glycinate adjuvant, it is characterised in that contain the glycine of 0.1 ~ 1mg in every 200 μ L vaccine liquid
Zinc adjuvant；And prepare through following method: add the amount of 0.1 ~ 1mg zinc glycinate by the most single part of vaccine dose, add in vaccine dose
Enter the zinc glycinate dissolved with the PBS of pH=6 ~ 8, then add normal saline to 200 μ L, routinely mix homogeneously, obtain containing sweet ammonia
The vaccine of acid zinc adjuvant.
2. the vaccine containing zinc glycinate adjuvant as claimed in claim 1, it is characterised in that described zinc glycinate is aminoacid
Chelate, molecular formula is, molecular weight is 213.5, and Zn content is: 29.0～30.6wt%.
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| WO2020207472A1 (en) | 2019-04-11 | 2020-10-15 | 厦门万泰沧海生物技术有限公司 | Preparation of zinc zoledronate micro-nanoparticle adjuvant and use thereof as vaccine adjuvant |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1519227A (en) * | 2003-01-22 | 2004-08-11 | 琼 吴 | Zine chelated amino acid as well as its preparation and application |
| CN101058782A (en) * | 2006-04-20 | 2007-10-24 | 缪锦来 | Sports beer |
| CN102627585A (en) * | 2012-03-26 | 2012-08-08 | 广州九益生物技术有限公司 | Carbamyl glycine dipeptide chelated zinc and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1519227A (en) * | 2003-01-22 | 2004-08-11 | 琼 吴 | Zine chelated amino acid as well as its preparation and application |
| CN101058782A (en) * | 2006-04-20 | 2007-10-24 | 缪锦来 | Sports beer |
| CN102627585A (en) * | 2012-03-26 | 2012-08-08 | 广州九益生物技术有限公司 | Carbamyl glycine dipeptide chelated zinc and preparation method thereof |
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Inventor after: Chen Zhenpu Inventor after: Wang Haixuan Inventor after: Hu Ningzhu Inventor after: Sun Jing Inventor after: Li Jianfang Inventor after: Shi Jiandong Inventor after: Wu Meini Inventor after: Li Yanhan Inventor after: Hu Yunzhang Inventor before: Chen Zhenpu Inventor before: Wang Haixuan Inventor before: Hu Ningzhu Inventor before: Hu Yunzhang |
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Free format text: CORRECT: INVENTOR; FROM: CHEN ZHENPU WANG HAIXUAN HU NINGZHU HU YUNZHANG TO: CHEN ZHENPU WANG HAIXUAN HU NINGZHU SUN JING LI JIANFANG SHI JIANDONG WU MEINI LI YANHAN HU YUNZHANG |
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