CN118105473B - Oral immunogenic composition for preventing or treating Hp infection and application thereof - Google Patents
Oral immunogenic composition for preventing or treating Hp infection and application thereof Download PDFInfo
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- CN118105473B CN118105473B CN202410534785.4A CN202410534785A CN118105473B CN 118105473 B CN118105473 B CN 118105473B CN 202410534785 A CN202410534785 A CN 202410534785A CN 118105473 B CN118105473 B CN 118105473B
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- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229940044655 toll-like receptor 9 agonist Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- A61K39/00—Medicinal preparations containing antigens or antibodies
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Abstract
The invention discloses an oral immunogenic composition for preventing or treating Hp infection and application thereof, and relates to the technical field of biomedicine. The invention provides an oral vaccine composition, a vaccine active ingredient, an adjuvant and an absorption enhancer, wherein the vaccine active ingredient is selected from helicobacter pylori antigens; the antigen is selected from at least one of helicobacter pylori protein, polypeptide, polysaccharide and oligosaccharide; the absorption enhancer comprises deoxycholic acid or deoxycholate. Deoxycholic acid or deoxycholate can be used as an absorption accelerator to improve the immune response level of an organism, greatly improve the titer of antibodies in the organism, obviously improve the serum-specific IgG and the intestinal tract-specific sIgA of helicobacter pylori, and has good application prospect for preparing an oral vaccine composition.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to an oral immunogenic composition for preventing or treating Hp infection and application thereof.
Background
Helicobacter pylori (Helicobacter pylori, hp) is a gram-negative, helicobacter, microaerophilic bacterium that persists in the stomach, mucosa and duodenal epithelium. Hp infection has a high infection rate in all people worldwide, and the global infection rate is over 50%. The current antibiotic treatment of Hp infection has the following defects although having certain positive clinical significance: 1) Toxic and side effects; 2) Drug-resistant strains are easy to generate; 3) The cost is high; 4) The treatment course is long, and the patient compliance is poor; 5) Unstable curative effect, etc. The vaccine is the most economical and effective method for controlling infectious diseases, so that the Hp vaccine stimulates the organism to generate specific immune response against helicobacter pylori, and the aim of preventing or treating Hp infection can be achieved.
However, there are still serious difficulties in developing oral vaccines. On the one hand, oral delivery vaccines must be routed through the harsh gastrointestinal environment where the antigen undergoes, in addition to a wide range of pH gradient changes (1.2-8.6), various mechanical processes such as intestinal peristalsis, capture of mucous and polysaccharide coatings and attack by digestive enzymes (proteases, lipases, nucleases, bile, lactoferrin, enzymes and peroxidases) which can lead to dilution, degradation and even denaturation inactivation of the antigen. On the other hand, vaccine antigens are classified according to a biopharmaceutical classification system (Biopharmaceutics Classification System), most of the vaccine antigens are water-soluble macromolecules, and the water-solubility of the substances is good, but the permeability is low. Thus, the body produces low antibody titres after oral administration.
In addition, in the prior art (development of recombinant helicobacter pylori urease B subunit nasal cavity immune gel, gao Zhigang, etc., china's modern application pharmacy) although sodium deoxycholate is reported as a nasal cavity mucous membrane absorption promoter for preparing nasal cavity recombinant helicobacter pylori urease B subunit vaccine gel, the technical requirements of nasal drops and oral administration modes are completely different, the technical problems to be solved are also obviously different, and the application belongs to obviously different fields in pharmacy. First, the nasal mucosa is quite different from the gastrointestinal tract environment, and the nasal mucosa is not involved at all in mechanical processes such as intestinal peristalsis, relatively harsh pH environments, and attack by various digestive enzymes; helicobacter pylori is a gastrointestinal infectious bacterium, nasal administration requires an immune response at a distant mucosal site, whereas oral administration can produce an immune response at a nearby mucosal site; finally, nasal formulations have incorporated carbopol-934, which is capable of forming a gel, without the use of an adjuvant, in order to solve the problem of antigen retention.
（A. Yamamoto, E. Hayakawa, Y. Kato, A. Nishiura, V.H. Lee, A mechanistic study on enhancement of rectal permeability to insulin in the albino rabbit, J Pharmacol Exp Ther） In the study of insulin oral preparations, sodium deoxycholate was also reported. Sodium deoxycholate in this report can improve the opening of intestinal tight junctions, or help the drug to be absorbed through the cell bypass; simultaneously overcomes the absorption barrier, enzyme barrier and mucous barrier of insulin oral administration, and can improve the oral bioavailability of the medicine. Sodium deoxycholate is required to enter the blood circulation through intestinal epithelial cells or cell bypass pathways to promote insulin absorption, and then is distributed to the whole body to be combined with insulin receptors on the cell surfaces to play a role. However, antigen and adjuvant uptake is by intestinal M cells and goblet cells which uptake and deliver them to Dendritic Cells (DCs), or by mononuclear phagocytes (MNPs) which uptake antigen through tight junctions in the intestinal epithelium or by pore-extending dendritic cells in M cells. After antigen is taken up by the antigen presenting cells and activated by the adjuvant, the downstream T, B immune cells are then activated, generating an immune response. Thus, both the antigen and the adjuvant are significantly different from the insulin oral formulation, both into the target cells of the body and into the target tissue that is functioning. Moreover, as the object treated by the insulin oral preparation is diabetes, the difference between the insulin oral preparation and the Hp infection technical field and the treatment mechanism is obvious, and whether the deoxycholate sodium can improve the antibody titer of the organism after the vaccine is orally taken is doubtful. Therefore, how to increase the antibody titer of the body after oral administration of a vaccine is a problem to be solved.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide an oral immunogenic composition for preventing or treating Hp infection and application thereof so as to solve the technical problems.
The invention is realized in the following way:
In a first aspect, the present invention provides an oral vaccine composition comprising: the vaccine comprises a vaccine active ingredient, an adjuvant and an absorption promoter, wherein the vaccine active ingredient is selected from helicobacter pylori antigens, and the antigens are selected from at least one of helicobacter pylori proteins, polypeptides, polysaccharides and oligosaccharides; the absorption enhancer comprises deoxycholic acid or deoxycholate.
Types of adjuvants include, but are not limited to: oil-in-water emulsions, water-in-oil-in-water emulsions.
In a preferred embodiment of the present invention, the deoxycholate is selected from at least one of sodium deoxycholate, potassium deoxycholate and calcium deoxycholate.
Especially, when deoxycholate is selected from sodium deoxycholate, the deoxycholate has good effect of improving the immune response level of the organism and can greatly improve the titer of antibodies in the organism.
Through a large number of experiments for a long time, the invention discovers that the reason for low antibody titer generated by the body after oral administration of the vaccine is as follows: the harsh gastric acid environment and proteolytic degradation severely affect the stability of the antigen in the gastrointestinal tract; various physiological barriers in the intestinal tract reduce the penetration capacity of the antigen at the mucous membrane part, and finally, the oral immunity is failed, so that the antibody titer of the organism after the vaccine is taken orally is low.
Based on the above, the invention provides an absorption promoter, namely deoxycholic acid or deoxycholate, which is found to be capable of being used as the absorption promoter to improve the immune response level of the organism, greatly improve the titer of antibodies in the organism, obviously improve the serum specificity IgG and intestinal tract specificity sIgA of helicobacter pylori, and has good application prospect for preparing oral vaccine compositions.
The term "subject" as used herein refers to a mammal, preferably a human.
Deoxycholic acid or deoxycholate has various mechanisms of action through absorption promoters in oral immunogenic compositions of helicobacter pylori (e.g., oral subunit vaccines): 1. the intestinal epithelial cell surface is covered with a mucus layer composed of mucin, electrolyte, and the like. The sodium deoxycholate can reduce viscosity and elasticity of the mucus layer and promote the penetration of helicobacter pylori antigens through the mucus layer. 2. The sodium deoxycholate can interact with a phospholipid bilayer of a cell membrane to change the distribution of lipid and protein in the membrane, reduce the order of the phospholipid bilayer and increase the fluidity and the permeability, thereby promoting the helicobacter pylori antigen to permeate the epithelial cell membrane of the gastrointestinal tract. 3. The sodium deoxycholate can form reverse micelles on the surface of a cell membrane, thereby creating hydrophilic pores on the surface of the cell membrane and further promoting the absorption of helicobacter pylori antigens by epithelial cells. 4. Sodium deoxycholate can bind Ca 2+ to influence the distribution and function of myoglobin, and loose the tight connection between cells, so that the cell bypass transport is increased, and the intake of helicobacter pylori antigen is increased. 5. The sodium deoxycholate can form a complex with helicobacter pylori antigen, so that the permeability of the antigen to a biological membrane is increased, and the bioavailability of the antigen is further increased. 6. Sodium deoxycholate inhibits the efflux of P-glycoprotein (P-gp) and thus increases the absorption of H.pylori antigen. 7. Sodium deoxycholate also resists degradation of helicobacter pylori antigens by proteases, thereby increasing mucosal absorption of the antigen.
In a preferred embodiment of the invention, the antigen of helicobacter pylori is selected from UreA、UreB、CagA、VacA、KatA、HspA、HpaA、HpA、Hp-NAP、OMP、SOD、Tpx、VacA、GGT、babA、sabA、fecA、omp16、NapA、CAT、Lpp20、 from a modification of any one of the above antigens, and from mutants of any one of the above antigens, from fusion proteins of at least one of the above antigens and from any one of the above epitope peptides.
Modifications of antigens include, but are not limited to: methylation, acetylation, phosphorylation, ubiquitination, ADP ribosylation, alkylation, acylation EMTS modification and DTNB modification of amino acid residues on the antigen.
Epitope peptides are also known as antigenic determinants or epitopes (ANTIGENIC DETERMINANT, AD), which refer to specific chemical groups in an antigen molecule that determine the specificity of an antigen. Typically one to six monosaccharides or five to eight amino acid residues on the antigen surface. Since the antigenic molecule is in a spatial environment, the epitope recognized by an antibody may depend on the three-dimensional antigen conformation that is actually present (e.g., a unique site formed by the interaction of two native protein loops or subunits). This is the so-called conformational epitope. Epitopes can also correspond to simple linear sequences of amino acids, such epitopes being termed linear epitopes.
In a preferred embodiment of the use of the invention, the adjuvant is selected from at least one of Toll-like receptor agonists, RIG-I like receptor agonists, NOD-like receptor agonists, C-lectin receptors, STING agonists, bacterial toxins and derivatives thereof, saponins, cytokines and other adjuvants; the other adjuvant is at least one selected from heat shock protein, A151, GTP-GDP, sodium fluoride, alkyl polypropylene ester polymer, dimethyl dioctadecyl quaternary amine bromide (DDA).
In a preferred embodiment of the use of the invention, the Toll-like receptor agonist is selected from at least one of CpG-ODN, cpG 1018, peptidoglycan, lipoteichoic acid, MPLA (monophosphoryl lipid A), imiquimod, resiquimod, bacterial flagellin and PolyI: C (polyinosinic cell). In addition, toll-like receptor agonists include agonists not limited to TLR1, TLR2, TLR4, TLR5 and TLR 9.
CpG 1018 adjuvant is a TLR9 agonist, which can stimulate B fineness and promote humoral immunity; and simultaneously, the dendritic cells can be stimulated to activate, so that specific T cells are stimulated to generate memory cells, and the effect is remarkably stronger than that of the traditional aluminum adjuvant.
CpG ODN adjuvant, namely CpG oligonucleotide (CpG oligodeoxynucleotides, cpG ODN) refers to an oligonucleotide sequence taking unmethylated CG dinucleotide as a core, and the CpG ODN can activate TLR9 receptor, is a potential vaccine adjuvant and can enhance the immune response intensity, breadth and durability of the vaccine. Ext> CpGext> ODNext> adjuvantsext> includeext>,ext> butext> areext> notext> limitedext> toext>,ext> Aext>,ext> Bext>,ext> Cext> classesext>,ext> namelyext> CpGext> -ext> Aext> ODNext>,ext> CpGext> -ext> Bext> ODNext>,ext> andext> CpGext> -ext> Cext> ODNext>;ext> Including, but not limited to ODN 2216, ODN 2006, ODN 2395.
Ext> multimericext> CpGext> -ext> Aext> ODNsext> areext> mainlyext> localizedext> toext> earlyext> lysosomesext>,ext> inext> plasmacytoidext> dendriticext> cellsext>,ext> whichext> leadext> toext> strongext> inductionext> ofext> IFNext> -ext> αext>.ext> The monomeric CpG-B ODNs concentrate in late endosomal compartments and can promote cell maturation of plasmacytoid dendritic cells and B cells. CpG-C ODNs localize to two compartments, inducing IFN- α production and cell maturation. Other structural modifications that affect the biological effects of CpG-containing sequences include linking two or more short phosphorothioate backbone CpG ODNs via non-nucleoside chemical linkers to produce formulations of linear chimeric immunomodulatory compounds and/or CpG nanoparticle-containing compounds.
The RIG-I like receptor agonist is selected from at least one of 3pRNA and short double-stranded RNA;
the NOD-like receptor agonist is selected from at least one of Muramyl Dipeptide (MDP) and N-acetylglucosamine;
The C-type lectin receptor is selected from at least one of beta-glucan and trehalose diborate.
The STING agonist is selected from at least one of cGAMP, c-di-AMP and c-di-GMP; cGAMP includes, but is not limited to, 3'-3' cGAMP and 2'-3' cGAMP.
The bacterial toxin and its derivative are selected from cholera toxin and its subunit and at least one of coliform thermolabile enterotoxin and its subunit.
Cholera Toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) both belong to the family of A-B bacterial protein toxins and the amino acid sequences of both are 80% identical. CT is a hexamer protein of AB type structure composed of A, B subunits, the A subunit (CTA) has 240 amino acids, and after the 192 st amino acid is cleaved by protease, two parts of CTA1 and CTA2 can be generated, which are connected by disulfide bond. CTA1 has the action of ADP-ribosyl transferase. The main function of CTA2 is to link CTA1 and B Subunits (CTBs).
The sequences of cpgs can be divided into three major classes: ext> CpGext> -ext> Aext>,ext> CpGext> -ext> Bext> andext> CpGext> -ext> Cext>.ext>
The saponins are selected from at least one of QS21, tomato glycoside and Quil-A;
The cytokine is selected from at least one of GM-CSF, IL-2, IL-12, IL-6, IFN-gamma, flt-3, and lymphokines.
In a preferred embodiment of the use of the invention, the cholera toxin subunit is selected from CTB and the escherichia coli heat-labile enterotoxin subunit is selected from LTB.
The general process of action of CT (LT) on toxins is that CTB binds to GM1 receptor on the cell surface via binding site of ganglioside 1 (GM 1), and is actively transported into the endoplasmic reticulum via phagocytosis CT, where CTA is separated from CTB and enters the cytoplasm. It is currently believed that LT and CT induce mucosal immune responses primarily by 1 increasing the permeability of epithelial cells, enhancing antigen absorption; 2, enhancing antigen presentation by different antigen presenting cells; 3, regulating the differentiation of B cells to increase the formation of sIgA; 4, inducing Dendritic Cells (DC) to secrete interleukin 1 beta (IL-1 beta); 5, by up-regulating L-10 and down-regulating L-12, the expression of cell surface molecules is selectively influenced, the generation of Thl cells is inhibited, and the regulatory activity of T cells is enhanced. It is noted, however, that the adjuvant effect of bacterial toxins does not involve only one mechanism, but rather the result of the synergistic effect of multiple mechanisms.
In a preferred embodiment of the application of the present invention, the mass ratio of the vaccine active ingredient, the adjuvant and the absorption enhancer in the composition includes, but is not limited to: (1-10): (0.1-10): (1-80). In the composition, the mass ratio of the vaccine active ingredient, the adjuvant and the absorption enhancer is 1:1:80, 2:1:80, 4:1:80, 5:1:80, 6:1:80, 7:1:80, 8:1:80, 9:1:80, 10:1:80, 1:10:50, 1:5:5, or 1:10:60.
In a second aspect, the invention also provides application of the oral vaccine composition in preparing an oral product for preventing or treating helicobacter pylori infection, wherein the oral product is a vaccine.
The morphology of the drug or vaccine includes, but is not limited to: solid, liquid or semi-solid.
The invention has the following beneficial effects:
The invention provides an absorption accelerator, namely deoxycholic acid or deoxycholate, which can be used as the absorption accelerator to improve the immune response level of an organism, greatly improve the titer of antibodies in the organism, obviously improve the serum-specific IgG and intestinal tract-specific sIgA of helicobacter pylori, and has good application prospect for preparing an oral immunogenic composition.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a statistical chart of the serum IgG detection results of oral subunit vaccines for helicobacter pylori infection provided in examples 1-3 and comparative examples 1-3 of the present invention;
FIG. 2 is a statistical graph of the results of intestinal sIgA detection of oral subunit vaccines infected with helicobacter pylori provided in examples 1-3 and comparative examples 1-3 of the present invention;
FIG. 3 is a statistical chart of serum IgG detection results for oral subunit vaccines for helicobacter pylori infection provided in example 1, examples 4-6 and comparative examples 1, comparative examples 4-6 of the present invention;
FIG. 4 is a statistical plot of results of intestinal sIgA detection of oral subunit vaccines for helicobacter pylori infection provided in example 1, examples 4-6 and comparative examples 1, comparative examples 4-6 of the present invention;
FIG. 5 shows the results of serum IgG (left) and intestinal sIgA (right) tests for oral subunit vaccines for helicobacter pylori infection provided in example 7 and comparative examples 7-9 of the present invention.
Detailed Description
Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.
Unless otherwise indicated, practice of the present invention will employ conventional techniques of cell biology, molecular biology (including recombinant techniques), microbiology, biochemistry and immunology, which are within the ability of a person skilled in the art. This technique is well explained in the literature, as is the case for molecular cloning: laboratory Manual (Molecular Cloning: A Laboratory Manual), second edition (Sambrook et al, 1989); oligonucleotide Synthesis (Oligonucleotide Synthesis) (M.J.Gait, eds., 1984); animal cell Culture (ANIMAL CELL Culture) (r.i. freshney, 1987); methods of enzymology (Methods in Enzymology) (academic Press Co., ltd. (ACADEMIC PRESS, inc.)), experimental immunology handbook (Handbook of Experimental Immunology) (D.M.Weir and C.C. Blackwell, inc.), gene transfer Vectors for mammalian cells (GENE TRANSFER vector for MAMMALIAN CELLS) (J.M.Miller and M.P.Calos, inc., 1987), methods of contemporary molecular biology (Current Protocols inMolecular Biology) (F.M.Ausubel et al, 1987), polymerase chain reaction (PCR: the Polymerase Chain Reaction) (Mullis et al, 1994), and methods of contemporary immunology (Current Protocols in Immunology) (J.E.Coligan et al, 1991), each of which are expressly incorporated herein by reference.
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising helicobacter pylori UreB antigen as vaccine active ingredient, cpG1018 adjuvant and absorption enhancer sodium deoxycholate. Per 0.8ml of unit volume, 0.5mg of UreB antigen, 0.05mg of CpG1018 adjuvant and 4mg of sodium deoxycholate are contained.
CpG1018 manufacturer is Kaileying medicine group (Tianjin) Co., ltd, and has lot number of CKs128503-01-03-01.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Example 2
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising helicobacter pylori UreB antigen as vaccine active ingredient, LTB adjuvant and absorption enhancer sodium deoxycholate. Per 0.8ml of unit volume, 0.5mg of UreB antigen, 0.5mg of LTB adjuvant and 4mg of sodium deoxycholate are contained.
The LTB adjuvant is self-made, and the specific amino acid sequence of the LTB adjuvant is shown in SEQ ID NO. 1:
APQSITELCSEYRNTQIYTINDKILSYTESMAGKREMVIITFKSGATFQVEVPGSQHIDSQKKAIERMKDTLRITYLTETKIDKLCVWNNKTPNSIAAISMEN.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Example 3
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising helicobacter pylori UreB antigen as vaccine active ingredient, CTB adjuvant and absorption enhancer sodium deoxycholate. Per 0.8ml of unit volume, 0.5mg of UreB antigen, 0.5mg of CTB adjuvant and 4mg of sodium deoxycholate are contained.
Cholera toxin B subunit (CTB) adjuvant manufacturer is ai bixin (Shanghai) biotechnology limited, lot number: 22040701.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Example 4
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising helicobacter pylori UreA antigen as vaccine active ingredient, cpG1018 adjuvant and absorption enhancer sodium deoxycholate. Per 0.8ml of unit volume, 0.5mg of UreA antigen, 0.05mg of CpG1018 adjuvant and 4mg of sodium deoxycholate are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Example 5
The present example provides an oral subunit vaccine for helicobacter pylori infection, which comprises the vaccine active ingredient helicobacter pylori Hp-NAP antigen, cpG1018 adjuvant and absorption enhancer sodium deoxycholate. Each 0.8ml of the kit contains 0.5mg of Hp-NAP antigen, 0.05mg of CpG1018 adjuvant and 4mg of sodium deoxycholate per unit volume.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Example 6
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredients helicobacter pylori HpaA antigen, cpG1018 adjuvant and absorption enhancer sodium deoxycholate. Per 0.8ml of unit volume, 0.5mg of HpaA antigen, 0.5mg of CpG1018 adjuvant and 4mg of sodium deoxycholate are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Example 7
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising helicobacter pylori UreB antigen as vaccine active ingredient, cpG1018 adjuvant and absorption enhancer sodium deoxycholate. Per 0.8ml of unit volume, 0.5mg of UreB antigen, 0.5mg of CpG1018 adjuvant and 4mg of sodium deoxycholate are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 1
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredient helicobacter pylori UreB antigen and CpG1018 adjuvant. Per 0.8ml unit volume, 0.5mg UreB antigen and 0.05mg CpG1018 adjuvant are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 2
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredients helicobacter pylori UreB antigen and LTB adjuvant. Per 0.8ml of unit volume, 0.5mg of UreB antigen and 0.5mg of LTB adjuvant are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 3
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredients helicobacter pylori UreB antigen and CTB adjuvant. Per 0.8ml of the unit volume, 0.5mg of UreB antigen and 0.5mg of CTB adjuvant are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 4
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredient helicobacter pylori UreA antigen and CpG1018 adjuvant. Per 0.8ml unit volume, 0.5mg UreA antigen and 0.05mg CpG1018 adjuvant are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 5
This example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredients helicobacter pylori Hp-NAP antigen and CpG1018 adjuvant. Each 0.8ml of the kit contains 0.5mg of Hp-NAP antigen and 0.05mg of CpG1018 adjuvant.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 6
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredient helicobacter pylori HpaA antigen and CpG1018 adjuvant. Per 0.8ml unit volume, contains 0.5mg HpaA antigen and 0.05mg CpG1018 adjuvant.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 7
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredients helicobacter pylori UreB antigen, cpG1018 adjuvant and sodium caprate. Per 0.8ml of unit volume, 0.5mg of UreB antigen, 0.05mg of CpG1018 adjuvant and 4mg of sodium caprate are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 8
The present example provides an oral subunit vaccine for helicobacter pylori infection, comprising the vaccine active ingredients helicobacter pylori UreB antigen, cpG1018 adjuvant and SNAC. SNAC is sodium (8- [ 2-hydroxybenzoyl ] -amino) caprylate. Each 0.8ml of the kit contains 0.5mg of UreB antigen, 0.05mg of CpG1018 adjuvant and 4mg of SNAC per unit volume.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Comparative example 9
The present example provides an oral subunit vaccine for helicobacter pylori infection, which comprises helicobacter pylori UreB antigen as an active ingredient of the vaccine and CpG1018 adjuvant. Per 0.8ml unit volume, 0.5mg UreB antigen and 0.05mg CpG1018 adjuvant are contained.
The preparation method comprises the following steps: mixing the above raw materials to obtain the oral subunit vaccine for helicobacter pylori infection.
Experimental example 1
The oral subunit vaccines for helicobacter pylori infection prepared in examples 1 to 3 and comparative examples 1 to 3 were subjected to an immunoassay, and the experimental group and the immunization program are specifically shown in table 1:
Table 1 test group and immunization program summary table
A plurality of female BALB/c mice are immunized, and the immunization is performed, and the gastric lavage immunity is referred to the standard operation procedure of pharmacodynamics experiments of oral recombinant helicobacter pylori vaccine (Escherichia coli), and the female BALB/c mice are fed by taking the vaccine for one day in advance and are disconnected from water in the morning the next day.
Pretreatment of immunization: and (3) immediately pouring the gastric acid neutralization solution (completing the whole immune process within 30 min), and continuing to eat for 2 hours to recover the food and water of the mice.
2. Sampling
After the last immunization, 14d, tail blood is collected, igG is detected, sIgA is measured from the intestines, and the standard operation procedure of pharmacodynamics experiment of oral recombinant helicobacter pylori vaccine (Escherichia coli) is referred.
3. Sample detection
ELISA detects serum IgG and intestinal tissue supernatant sIgA, and determines each group of coating UreB/HpaA (UreB (5. Mu.g/ml) and HpaA (5. Mu.g/ml)) according to the immune antigen; eight gradients of serum were made 1:50, 1:200, 1:800, 1:3200, 1:12800, 1:51200, 1:204800, and 1:819200, and eight titers of intestinal tissue supernatants were made 1:10, 1:20, 1:40, 1:80, 1:160, 1:320, 1:640, and 1:1280.
The ELISA detection steps are specifically as follows:
1) Experimental instrument
Pure water apparatus (model ZYMICRO-II-20T Sichuan Zhou water treatment equipment Co., ltd.), enzyme-labeled plate (model), enzyme-labeled apparatus (model A51119600 Thermo FISHER SCIENTIFIC), micro plate washer (model 1575 Bio-Rad Laboratories), electric heating constant temperature incubator (model DHP-9052 Shanghai-Henry science instruments Co., ltd.), pipettor (model 10uL, 100uL, 200uL, 300uL, 1000uL, 5mL,10mLeppendorf Co.).
2) Experimental reagent
Purified water (resistivity no less than 18.25mΩ·cm), sodium carbonate (Na 2CO3), sodium bicarbonate (NaHCO 3), disodium hydrogen phosphate 12 (Na 2HPO4·12H2 O), sodium dihydrogen phosphate 2 (NaH 2PO4·2H2 O), sucrose, casein, BSA, proclin 300, aminopyrine, calf blood, polysorbate 20 (Tween 20), sodium chloride (NaCl), potassium chloride (KCl), potassium dihydrogen phosphate (KH 2PO 4), sodium thimerosal, TMB color developing solution, sulfuric acid, HRP-labeled goat anti-mouse IgG secondary antibody.
3) Experimental reagent preparation
Coating liquid: weighing 30.68g of Na 2CO314.345g,NaHCO3 on an electronic balance, adding 500mL of distilled water, dissolving and mixing uniformly, and then fixing the volume to 1000mL, and marking: 10xCBS, and the coating is diluted by 10 times to 1xCBS with UP water.
Antibody dilution (enzyme dilution): 0.592g of Na 2HPO4·12H2O 5.80g,NaH2PO4·2H2 O, 5.00g of casein and 0.50g of aminopyrine are weighed on an electronic balance, 500mL of distilled water is added, dissolved and mixed uniformly, 0.5mL of Tween20 is added by a pipette, the volume is fixed to 1000mL, and the calf serum 1000mL,Proclin 300 1mL is added and mixed uniformly.
Washing liquid: the solution of 23.48 g/bag PBS was dissolved in 2000 mL g pure water, 1mL Tween 20 was added and mixed well.
Sealing liquid: 0.59g of Na 2HPO4·12H2O 5.80g,NaH2PO4·2H2 O, 100.00g of sucrose, 1.00g of casein and 10.00g of BSA are weighed on an electronic balance, 500mL of distilled water is added, the mixture is dissolved and mixed uniformly, the volume is fixed to 1000mL, and 300 1mL of Proclin is added and mixed uniformly.
Stop solution (2 mol/L sulfuric acid): 443.9mL of ultrapure water was weighed into the reagent bottle, and then 56.1mL of concentrated sulfuric acid was slowly added by a pipette and thoroughly mixed.
4) Experimental method
(1) Coating: diluting the antigen to the required concentration (Ureb ug/mL coating concentration, hpaA coating concentration 5ug/mL, SS1 holoprotein 50 ug/mL), coating the ELISA plate with 100 mu L/hole, shaking and spreading thoroughly, and standing overnight at 4deg.C in a refrigerator or at 37deg.C 2 h.
(2) Closing: the plate was washed 3 times with washing liquid, 300. Mu.L each time, shaken 30 s, and pipetted 2.5. 2.5 s. Blocking solution 200. Mu.L/well blocking ELISA strips were placed in a refrigerator at 4℃overnight or at 37℃2 h.
(3) Adding primary antibody: the plate was washed 3 times with washing liquid, 300. Mu.L each time, shaken 30 s, and pipetted 2.5. 2.5 s. The serum of animal immunized by vaccine is diluted to 1:12800 by antibody diluent, and the serum obtained by animal immunized by normal saline is used as negative control, diluted according to the lowest dilution of serum of corresponding experimental group, shaking and shaking, and incubating for 2h at 37 ℃.
(4) Adding a secondary antibody: the plate was washed 3 times with washing liquid, 300. Mu.L each time, shaken 30 s, and pipetted 2.5. 2.5 s. HRP-labeled secondary anti-IgG was diluted 1:10000 times with antibody dilution, added at 100. Mu.L/well, shaken well and incubated for 1h at 37 ℃.
(5) Color development: the plate was washed 5 times with washing solution, 300. Mu.L each time, shaken 30 s, and pipetted 2.5. 2.5 s. 100. mu.L/well of TMB developing solution was added and developed 15min in a dark place at 37℃in an incubator.
(6) Terminating the reaction: the reaction was terminated by adding 2 mol/L H 2SO4 to 50. Mu.L/well at the end of the development. The OD value of each well at 450 nm was measured using a microplate reader.
(7) The statistical method comprises the following steps: a sample/A negative >2.1 was used as positive standard.
Serum IgG and intestinal sIgA test results are shown in fig. 1 and 2, and blank refers to blank. Under the condition that the adjuvants are CpG1018, LTB and CTB respectively, the addition of sodium deoxycholate obviously improves the serum IgG and the intestinal sIgA of UreB specificity.
Experimental example 2
The oral subunit vaccines for helicobacter pylori infection prepared in example 1, examples 4-6 and comparative examples 1, comparative examples 4-6 were subjected to an immunoassay, and the experimental group and the immunization program are specifically shown in table 2:
Table 2 test group and immunization program summary table
The results of the immune test, serum IgG and intestinal sIgA tests were carried out according to the method shown in experimental example 1, and are shown in fig. 3 and 4, respectively, and in the case of CpG1018 as an adjuvant, the addition of sodium deoxycholate significantly increased the serum IgG and intestinal sIgA specific to UreB, ureA, hp-NAP and HpaA, respectively.
Experimental example 3
The oral subunit vaccines for helicobacter pylori infection prepared in example 7 and comparative examples 7 to 9 were subjected to an immunoassay, and the experimental group and the immunization program are specifically shown in table 3:
TABLE 3 test group and immunization program summary table
The results of the immunization test by the method shown in Experimental example 1, serum IgG (left) and intestinal sIgA (right) are shown in FIG. 5. Blank in fig. 5 refers to a blank. The results show that replacement of sodium deoxycholate with both sodium caprate and SNAC absorption promoters resulted in a significant decrease in serum IgG levels and intestinal sIgA levels.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. An oral vaccine composition, comprising: a vaccine active ingredient, an adjuvant and an absorption enhancer, the vaccine active ingredient being selected from antigens of helicobacter pylori;
The absorption enhancer comprises deoxycholate; the antigen is selected from any one antigen of UreA, ureB, hp-NAP and HpaA or fusion protein of at least two antigens selected from the antigens; the adjuvant is CpG 1018.
2. The oral vaccine composition of claim 1, wherein the deoxycholate is selected from at least one of sodium deoxycholate, potassium deoxycholate, and calcium deoxycholate.
3. The oral vaccine composition according to claim 1, wherein the mass ratio of vaccine active ingredient, adjuvant and absorption enhancer in the oral vaccine composition is (1-10): (0.1-10): (1-80).
4. Use of an oral vaccine composition according to any one of claims 1-3 for the preparation of an oral product for the prevention or treatment of helicobacter pylori infection, characterized in that the oral product is a vaccine.
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| WO1999021959A2 (en) * | 1997-10-28 | 1999-05-06 | Genome Therapeutics Corporation | Helicobacter pylori vaccine formulations |
| CN100460013C (en) * | 2006-09-05 | 2009-02-11 | 重庆康卫生物科技有限公司 | Oral administration recombinant helicobacterpylori vaccine and preparing method thereof |
| CN101863965B (en) * | 2010-05-21 | 2012-06-06 | 中国人民解放军军事医学科学院生物工程研究所 | Helicobacter pylori urease B antigenic epitope polypeptide and application thereof |
| CN101863964B (en) * | 2010-05-21 | 2013-06-05 | 中国人民解放军军事医学科学院生物工程研究所 | Helicobacter pylori urease B antigen epitope polypeptide and application thereof |
| RU2682249C2 (en) * | 2012-05-31 | 2019-03-18 | Терумо Кабусики Кайся | Ph-sensitive carrier and method for production thereof, ph-sensitive medicine and ph-sensitive pharmaceutical composition each containing said carrier, and culture method using said ph-sensitive medicine or said ph-sensitive pharmaceutical composition |
| US10092644B2 (en) * | 2013-11-22 | 2018-10-09 | Brock University | Use of fluorinated cyclic dinucleotides as oral vaccine adjuvants |
| WO2015079952A1 (en) * | 2013-11-29 | 2015-06-04 | テルモ株式会社 | Adjuvant composition, vaccine composition comprising same, and method for producing same |
| EP3603668A4 (en) * | 2017-03-29 | 2021-01-06 | Terumo Kabushiki Kaisha | Adjuvant composition, and vaccine composition and drug kit containing same |
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| CN1259960A (en) * | 1997-06-12 | 2000-07-12 | 阿斯特拉公司 | Vaccine compositions comprising the helicobacter pylori FlgE polypeptide |
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