CN101972477B - Zinc phosphate vaccine adjuvant - Google Patents

Zinc phosphate vaccine adjuvant Download PDF

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CN101972477B
CN101972477B CN201010513414A CN201010513414A CN101972477B CN 101972477 B CN101972477 B CN 101972477B CN 201010513414 A CN201010513414 A CN 201010513414A CN 201010513414 A CN201010513414 A CN 201010513414A CN 101972477 B CN101972477 B CN 101972477B
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adjuvant
zinc phosphate
vaccine
zinc
vaccine adjuvant
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胡云章
胡凝珠
王海漩
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Institute of Medical Biology of CAMS and PUMC
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Abstract

The invention relates to a zinc phosphate vaccine adjuvant, in particular to an application of zinc phosphate as the vaccine adjuvant, and the application of the zinc phosphate vaccine adjuvant in the preparation of vaccines. The zinc phosphate can effectively enhance the humoral immune response of the vaccines by being combined with the vaccines for application as the vaccine adjuvant, the immune enhancement effect of the zinc phosphate is better than an aluminum adjuvant and a zinc hydroxide adjuvant, and the results of animal experiments show that the sensitization and the safety of the zinc phosphate are better than the aluminum adjuvant and the zinc hydroxide adjuvant as the vaccine adjuvant.

Description

The zinc phosphate vaccine adjuvant
Technical field
The present invention relates to a kind of vaccine adjuvant, relate in particular to a kind of zinc phosphate vaccine adjuvant, and the application of this zinc phosphate vaccine adjuvant in the preparation vaccine, field of immunology belonged to.
Background technology
Zinc is indispensable element in the human body.Zinc has the important physical function: zinc is the ingredient of 100 plurality of enzymes in the human body; Zinc is the essential ingredient of archaeal dna polymerase; Zinc is participated in sialoprotein and is constituted; Zinc is participated in the synthetic of vitamin A reductase and RBP ELISA; Zinc can promote sexual organ's normal development, to keep normal sexual function; Zinc can be protected skin health, safeguards immunologic function; Zinc helps to remove the body inner cholesterol, prevents and treats atherosclerosis; Zinc helps generation that suppresses cancer etc.The growth promoter of human body be unable to do without zinc, and the height of zinc level can exert an influence to nerve, reproduction and immune system in the body.Zinc is the essential trace element of all organisms.Zinc preparation has been widely used in the middle of the auxiliary treatment of multiple diseases such as infectious disease, autoimmune disease.
Vaccine adjuvant is current vaccine research hot of research and development, ideal vaccine adjuvant need possess safety, effectively, targeting and economic characteristics.Existing aluminium adjuvant is to use the time to grow most and uses the vaccine adjuvant that is approved for human body the most widely, and it mainly relies on storage vault effect and two kinds of mechanism of immune-stimulating effect to significantly improve the immunne response of body.But as adjuvant; Still there is defective in it aspect safety and the targeting property, reason is: discover through many scientists that in recent years senile dementia and aluminum have substantial connection; Find also that simultaneously aluminum all has infringement to brain, the heart, liver, renal function and the immunologic function of human body.Therefore, World Health Organization (WHO) formally confirmed as food contaminant with aluminum in 1989 and controls, and stipulated that the aluminum amount that the adult allows to take in every day is no more than 60mg.Some other material of studying or confirming adjuvant effect, because aspects such as safety, effectiveness or economy, approval is not used for human body as yet.
Zinc phosphate is nontoxic, have higher similarity at aspects such as physics, chemistry and aluminum phosphate, and it is general, with low cost to be widely used, to originate.
Similar with zinc phosphate as vaccine adjuvant and aluminium adjuvant, be particulate adjuvants, the effect of such adjuvant is: can form the coherency bulky grain behind the adsorption antigen; Thereby easily by macrophage phagocytic and the immunogenicity of enhancement antigen; In addition, its antigenic degradation speed that can also slow down prolongs the antigen time of staying in vivo; Prolong the time that stimulates body, thereby improve the titre of antibody.For this reason; We as immunological adjuvant, are applied to the preparation of vaccine with this zinciferous chemical compound of zinc phosphate, and in zoopery, check its immunological enhancement; The result shows that zinc phosphate is as adjuvant and vaccine Combined application; Can effectively strengthen the HI of vaccine, its immunoenhancement result is superior to aluminium adjuvant and zinc hydroxide adjuvant, and its sensitization is lower than aluminium adjuvant and zinc hydroxide adjuvant.
Summary of the invention
For solving the defective of existing vaccine aluminium adjuvant at aspects such as safeties, and other adjuvant as yet approval be used for human body, thereby restricting vaccine research and development; The present invention provides a kind of safety, and is effectively, stable; Inexpensive, and the zinc phosphate vaccine adjuvant with immunological enhancement.
The present invention provides the application of zinc phosphate as vaccine adjuvant.
The present invention provides the application of zinc phosphate in the preparation vaccine adjuvant.
The present invention provides the application of zinc phosphate vaccine adjuvant in the preparation vaccine.
The present invention provides the application of zinc phosphate vaccine adjuvant in the preparation hepatitis A vaccine.
The hydrate chemical formula of said zinc phosphate is Zn 3(PO 4) 22H 20, formula weight is 422.08, and after it lost two water of crystallization, the anhydride chemical formula was Zn 3(PO 4) 2, formula weight is 386.08.
Said zinc phosphate as the RD that vaccine adjuvant is applied to human body is: 1mg.
Said zinc phosphate is commercial analytical pure Zn 3(PO 4) 22H 2The O powder, perhaps commercial analytical pure Zn 3(PO 4) 2Powder.
The preparation of said zinc phosphate vaccine adjuvant: with the analytically pure Zn of required dosage 3(PO 4) 22H 2O powder or analytically pure Zn 3(P0 4) 2Powder joins suspendible in an amount of water for injection, promptly gets the zinc phosphate adjuvant.
The present invention compared with prior art has advantage and effect: adopt such scheme; Make zinc phosphate vaccine adjuvant safety, nontoxic; Because zinc phosphate wide material sources, with low cost; Be very suitable for vaccine adjuvant, the zinc phosphate vaccine adjuvant can efficiently stimulate immune response, immunoenhancement result to be superior to aluminium adjuvant and zinc hydroxide adjuvant; The zinc phosphate vaccine adjuvant has the characteristics of low irritability, therefore, also is superior to aluminium adjuvant and zinc hydroxide adjuvant on the one hand at this.Behind the HAV mixed antigen immune animal of zinc phosphate vaccine adjuvant and deactivation, the remarkable specific HI of enhancement antigen.
Description of drawings
Fig. 1 is in 28 weeks, uses the influence of the zinc phosphate of various dose to mice serum specific anti HAV IgG antibody horizontal.
Fig. 2 is in 35 days, and zinc phosphate is to the influence of mice serum specific anti OVA IgE antibody horizontal.
Fig. 3 is in 28 weeks, uses the influence of the zinc phosphate of various dose to mice serum specific anti HBV IgG antibody horizontal.
The specific embodiment
Below in conjunction with embodiment the present invention is done and to further describe.
Embodiment 1
A, zinc phosphate are observed as the immune effect of hepatitis A vaccine adjuvant
In zoopery, the application dose of every mice is zinc phosphate: zinc phosphate 0.5～1.5mg, deactivation HAV antigen 1 2.8EU as the HAV antigen of vaccine adjuvant and deactivation.
The preparation of a, zinc phosphate adjuvant mother solution
A1, precision take by weighing analytically pure Zn 3(PO 4) 22H 2O powder 0.1093g joins suspendible in the 10ml water for injection, processes Zn 3(PO 4) 2Concentration is the zinc phosphate adjuvant of 10mg/ml;
A2, precision take by weighing analytically pure Zn 3(PO 4) 2Powder 0.1000g joins suspendible in the 10ml water for injection, processes Zn 3(PO 4) 2Concentration is the zinc phosphate adjuvant of 10mg/ml;
B, animal immune
42 ICR mices are divided into six groups, every group 7 immunity of dividing into groups, and scheme is following:
1. HAV organizes: every mouse peritoneal injection deactivation HAV antigen 1 2.8EU;
2. HAV+Al (OH) 3Group: every mouse peritoneal injection deactivation HAV antigen 1 2.8EU reaches the adjuvant that in an amount of water for injection, is dissolved with the 1mg aluminium hydroxide;
3. HAV+Zn (OH) 2Group: every mouse peritoneal injection deactivation HAV antigen 1 2.8EU reaches the adjuvant that in an amount of water for injection, is dissolved with the 1mg zinc hydroxide;
4. HAV+Zn 3(PO 4) 20.5mg group: every mouse peritoneal is injected the zinc phosphate adjuvant 0.05ml (0.5mg) of a1 in deactivation HAV antigen 1 2.8EU and a step;
5. HAV+Zn 3(PO 4) 2The 1mg group: every mouse peritoneal is injected the zinc phosphate adjuvant 0.1ml (1mg) of a1 in deactivation HAV antigen 1 2.8EU and a step;
6. HAV+Zn 3(PO 4) 21.5mg group: every mouse peritoneal is injected the zinc phosphate adjuvant 0.15ml (1.5mg) of a1 in deactivation HAV antigen 1 2.8EU and a step;
The collection of c, mice serum
After grouping immunity described in the step b; 4th, 8,12,16,20,24,28 weeks were taked mouse tail vein blood, taked the about 100 μ l of whole blood for every, the Eppendorf pipe that places autoclaving to cross; 37 ℃ left standstill 1 hour; 4 ℃ of hold over night are got upper serum after next day is centrifugal afterwards, and-20 ℃ of preservations of Eppendorf pipe that place autoclaving to cross are to be checked;
Get the antibody titer of anti--HAV IgG in the mice serum among d, the ELISA method determination step c:
Measure the antibody titer of getting anti--HAV IgG in the mice serum in the c step with the said method of conventional ELISA commercially available reagent box by specification.The antigen that wherein encapsulates 96 hole ELISA Plates is the deactivation HAV antigen of purification; Testing sample be got in the c step respectively organize mice serum; The positive wherein is mouse anti-male serum of HAV IgG with reference to article, and is negative with reference to the anti--negative serum of HAV IgG that is the antigenic mice of not contacted HAV;
E, data analysis
Experimental data to being obtained is carried out one factor analysis of variance with the SPSS11.5 statistical software, and P＜0.05 has statistical significance.
Table 1 is in 28 weeks, the mice serum IgG level (1: N) of using the immunity of deactivation HAV antigen and various dose zinc phosphate vaccine adjuvant to obtain.
Table 1
Figure BSA00000311156700051
Can find out through data analysis, around the, each experimental group can both produce anti--HAV IgG antibody, and generally reach peak value in the 8th week.HAV+Zn wherein 3(PO 4) 2The immune effect that the 1mg group is obtained is best, and its antibody titer level all is significantly higher than no adjuvant deactivation hepatitis A vaccine group within 28 weeks, P＜0.05, and can between detection period, keep higher level.After the 8th week, all experimental grouies that add adjuvant have all produced the antibody horizontal that is significantly higher than the HAV group.HAV+Zn wherein 3(PO 4) 21mg group, HAV+Zn 3(PO 4) 21.5mg group and HAV+Zn (OH) 2The group antibody horizontal all is significantly higher than HAV+Al (OH) 3Group, P＜0.05.The prompting zinc phosphate has the effect that can strengthen the antigenic immune effect of HAV, and its humoral immunization reinforced effects is higher than aluminium adjuvant and zinc hydroxide adjuvant.See Fig. 1.
B. zinc phosphate causes that ovalbumin is the effect analysis of OVA specific IgE
A, best zinc phosphate the dosage preferred and immune effect confirming to obtain as adjuvant is 1mg from the experiment of step 1; With the BALB/c mouse is laboratory animal; The ovalbumin that uses the V level is OVA produces specific IgE as inducing mouse a antigen; Mix with zinc hydroxide, detect the effect that zinc hydroxide is induced body IgE.
Concrete grammar is following: get 24 of BALB/c mouses, and 6 every group, be divided into 4 groups, scheme is following:
1. simple immune OVA group: in chart, be expressed as OVA, every Mus was respectively at the 0th and the 7th day lumbar injection OVA 100 μ g;
2. OVA+ aluminum hydroxide adjuvant group: in chart, be expressed as OVA+Al (OH) 3, every Mus reaches the adjuvant that in an amount of water for injection, is dissolved with the 1mg aluminium hydroxide respectively at the 0th and the 7th day lumbar injection OVA 100 μ g;
3. OVA+ zinc phosphate adjuvant 1mg organizes: in chart, be expressed as OVA+Zn 3(PO 4) 21mg, every Mus is respectively at the zinc phosphate adjuvant 0.1ml (1mg) of a2 in the 0th and the 7th day lumbar injection OVA 100 μ g and the A step;
4. OVA+ zinc hydroxide adjuvant group: in chart, be expressed as OVA+Zn (OH) 2, every Mus reaches the adjuvant that in an amount of water for injection, is dissolved with the 1mg zinc hydroxide respectively at the 0th and the 7th day lumbar injection OVA 100 μ g;
The collection of b, mice serum
Respectively at taking mouse tail vein blood on the 8th, 14,21 and 35 day after the first immunisation of the said method of a in the B step, method is identical with the c of A step.
C, ELISA method are measured the titre that goes up the anti-OVA-IgE in the mice serum that gets among the step 2.B
Measure the antibody titer of getting anti--OVA IgE in the mice serum in the b step with the said method of conventional ELISA commercially available reagent box by specification; The antigen that wherein encapsulates 96 hole ELISA Plates is OVA; Testing sample is by being got mice serum among the step 2.B; The positive wherein is the positive serum of mouse anti OVA-IgE with reference to article, and negative reference is the negative serum of OVA-IgE of the antigenic mice of not contacted OVA;
D, data analysis
Experimental data to being obtained is carried out one factor analysis of variance with the SPSS11.5 statistical software, and P＜0.05 has statistical significance.
The table 2 mice serum IgE level (1: N) that to be ovalbumin (OVA) obtain with different adjuvant immunities.
Table 2
Figure BSA00000311156700071
Can obtain following result through data analysis: after first sensitization the 8th, 14,21,35 day the time, OVA+Zn 3(PO 4) 2Anti--OVA IgE level of group mice significantly is lower than OVA+Al (OH) 3Group and OVA+Zn (OH) 2Group, P＜0.05; Explain that the zinc phosphate sensitization is lower than aluminium adjuvant and zinc hydroxide adjuvant.See Fig. 2.
Embodiment 2
A, zinc phosphate are observed as the immune effect of Hepatitis B virus vaccine adjuvant
In zoopery, the application dose of every mice is zinc phosphate: zinc phosphate 0.5～1.5mg, HBV subunit vaccine 2 μ g as vaccine adjuvant and HBV subunit vaccine.
The preparation of a, zinc phosphate adjuvant mother solution
A1, precision take by weighing analytically pure Zn 3(PO 4) 22H 2O powder 0.1093g joins suspendible in the 10ml water for injection, processes Zn 3(PO 4) 2Concentration is the zinc phosphate adjuvant of 10mg/ml;
A2, precision take by weighing analytically pure Zn 3(PO 4) 2Powder 0.1000g joins suspendible in the 10ml water for injection, processes Zn 3(PO 4) 2Concentration is the zinc phosphate adjuvant of 10mg/ml;
B, animal immune
42 ICR mices are divided into six groups, every group 7 immunity of dividing into groups, and scheme is following:
1. HBV organizes: every mouse peritoneal injection HBV subunit vaccine 2 μ g;
2. HBV+Al (OH) 3Group: every mouse peritoneal injection HBV subunit vaccine 2 μ g reach the adjuvant that in an amount of water for injection, is dissolved with the 1mg aluminium hydroxide;
3. HBV+Zn (OH) 2Group: every mouse peritoneal injection HBV subunit vaccine 2 μ g reach the adjuvant that in an amount of water for injection, is dissolved with the 1mg zinc hydroxide;
4. HBV+Zn 3(PO 4) 20.5mg group: every mouse peritoneal is injected the zinc phosphate adjuvant 0.05ml (0.5mg) of a1 in HBV subunit vaccine 2 μ g and a step;
5. HBV+Zn 3(PO 4) 2The 1mg group: every mouse peritoneal is injected the zinc phosphate adjuvant 0.1ml (1mg) of a1 in HBV subunit vaccine 2 μ g and a step;
6. HBV+Zn 3(PO 4) 21.5mg group: every mouse peritoneal is injected the zinc phosphate adjuvant 0.15ml (1.5mg) of a1 in HBV subunit vaccine 2 μ g and a step;
The collection of c, mice serum
After grouping immunity described in the step b; 4th, 8,12,16,20,24,28 weeks were taked mouse tail vein blood, taked the about 100 μ l of whole blood for every, the Eppendorf pipe that places autoclaving to cross; 37 ℃ left standstill 1 hour; 4 ℃ of hold over night are got upper serum after next day is centrifugal afterwards, and-20 ℃ of preservations of Eppendorf pipe that place autoclaving to cross are to be checked;
Get the antibody titer of anti--HBV IgG in the mice serum among d, the ELISA method determination step c:
Measure the antibody titer of getting anti--HBV IgG in the mice serum in the c step with the said method of conventional ELISA commercially available reagent box by specification.The antigen that wherein encapsulates 96 hole ELISA Plates is HBV subunit vaccine composition HBVsAg; Testing sample be got in the c step respectively organize mice serum; The positive wherein is mouse anti-male serum of HBV IgG with reference to article, and is negative with reference to the anti--negative serum of HBV IgG that is the mice of not contacted antigen of hepatitis B virus;
E, data analysis
Experimental data to being obtained is carried out one factor analysis of variance with the SPSS11.5 statistical software, and P＜0.05 has statistical significance.
Table 3 is in 28 weeks, the anti-HBV IgG of the mice serum level (1: N) of using the immunity of deactivation HBV antigen and various dose zinc phosphate vaccine adjuvant to obtain.
Table 3
Figure BSA00000311156700091
Can find out through data analysis, around the, each experimental group can both produce anti--HBV IgG antibody, and generally reach peak value in the 8th week.HBV+Zn wherein 3(PO 4) 2The immune effect that the 1mg group is obtained is best, and its antibody titer level all is significantly higher than no adjuvant HBV subunit vaccine group P＜0.05 within 28 weeks, and can between detection period, keep higher level.After the 8th week, all experimental grouies that add adjuvant have all produced the antibody horizontal that is significantly higher than the HBV group.HBV+Zn wherein 3(PO 4) 21mg group, HBV+Zn 3(PO 4) 21.5mg group and HBV+Zn (OH) 2The group antibody horizontal all is significantly higher than HBV+Al (OH) 3Group, P＜0.05.The prompting zinc phosphate has the effect that can strengthen the antigenic immune effect of HBV, and its humoral immunization reinforced effects is higher than aluminium adjuvant and zinc hydroxide adjuvant.See Fig. 3.

Claims (6)

1. zinc phosphate is as the application of vaccine adjuvant.
2. the application of zinc phosphate in the preparation vaccine adjuvant.
3. the application of zinc phosphate vaccine adjuvant in the preparation vaccine.
4. the application of zinc phosphate vaccine adjuvant in the preparation hepatitis A vaccine.
5. like any application among the claim 1-4, the hydrate chemical formula that it is characterized in that said zinc phosphate is Zn 3(PO 4) 22H 2O, formula weight is 422.08, after it lost two water of crystallization, the anhydride chemical formula was Zn 3(PO 4) 2, formula weight is 386.08.
6. like any application among the claim 1-4, it is characterized in that said zinc phosphate as the RD that vaccine adjuvant is applied to human body is: 1mg.
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CN110665000B (en) * 2018-07-02 2022-11-11 厦门大学 Preparation of zinc-aluminum composite adjuvant and application of zinc-aluminum composite adjuvant as vaccine adjuvant
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EP3978014A4 (en) * 2019-05-30 2022-11-16 Xiamen University Preparation of risedronate zinc micronano-adjuvant, and use of same as vaccine adjuvant

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