CN1259960A - Vaccine compositions comprising the helicobacter pylori FlgE polypeptide - Google Patents
Vaccine compositions comprising the helicobacter pylori FlgE polypeptide Download PDFInfo
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- CN1259960A CN1259960A CN98806101A CN98806101A CN1259960A CN 1259960 A CN1259960 A CN 1259960A CN 98806101 A CN98806101 A CN 98806101A CN 98806101 A CN98806101 A CN 98806101A CN 1259960 A CN1259960 A CN 1259960A
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- helicobacter pylori
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- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/205—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Campylobacter (G)
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- A—HUMAN NECESSITIES
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- A61P37/04—Immunostimulants
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
- G01N2333/205—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Campylobacter (G)
Abstract
The present invention relates to polypeptides and vaccine compositions for inducing a protective immune response to Helicobacter pylori infection. The invention furthermore relates to the use of Helicobacter pylori polypeptides in the manufacture of compositions for the treatment or prophylaxis of Helicobacter pylori infection.
Description
Technical field
The present invention relates to cause polypeptide and vaccine at the protective immune response of helicobacter pylori.The invention still further relates to the purposes of helicobacter pylori polypeptide in the composition of production for treating or prevention helicobacter pylori infection.
Background technology
Helicobacter pylori
Gram negative bacterium helicobacter pylori (Helicobacter pylori) is a kind of important human pathogen, and is relevant with several gastroduodenal diseases.Bacterium causes activity inflammation and carrying out property chronic gastritis to settling down of Weishang skin, makes to develop into the big increase of having a big risk of digestive tract ulcer.The lifelong inflammation of stomach mucous membrane and the probability of cancer of the stomach increase closely related.
In order to be settled in stomach mucous membrane, helicobacter pylori is used multiple virulence factor.These virulence factors comprise several adhesins, and urase and proteolytic ferment, adhesin make bacterium combine with mucosal adhesive or with epithelial cell, and during urase helps and sour environment, proteolytic ferment makes the mucous membrane fluidization.In addition, helicobacter pylori is a high degree of motion, can move about in mucous membrane and penetrates glandular tube.Seemingly a kind of necessary virulence factor of mobility is because non-mobility helicobacter pylori can not infect mucous membrane (Eaton et al.Infection ﹠amp in experimental model; Immunity 64 (7), 2445-2448,1996).This there is multiple possible reason, is apparent that the most and can't moves about to mucomembranous cell and adhere to, can not evade the toxic ingredient in the stomach.
Although the host can produce the intensive immunne response to helicobacter pylori, produce local (mucous membrane) and whole body antibody, this pathogenic agent continues to exist in host's stomach mucous membrane, normally exists all the life.Reason may be that the immunne response that automatically causes is not enough or at antigenic wrong epi-position.Perhaps, may be the type error of immunne response, because immunity system may be treated (being inferred by lifelong host/bacterium relation) to helicobacter pylori as symbiosis.
For pathogenesis and the immunology of understanding helicobacter pylori infection, the antigenic structure of illustrating this bacterium is significant.Particularly, need to identify that the surface exposes, surface bonding with excretory albumen, in many bacterial pathogens, these albumen have been proved to be and have constituted main virulence factor, can be used for the diagnosis of helicobacter pylori and the production of vaccine composition.If these albumen are except being the albumen of surface bonding, to the survival of bacterium and/or to settle down also be necessary, then its purposes as the immunotherapy target of vaccine mediation increases.
When being coerced or threaten, the helicobacter pylorus mycetocyte from shaft-like be transformed into spherical.Under balled form, the antagonism of helicobacter pylorus mycetocyte is given birth to plain more insensitive with other antibacterial agent.Circumstantial evidence shows that the globular helicobacter pylori can be propagated between individuality, may be by water or indirect contact (mouth-mouth, or excrement-mouth).Therefore effectively vaccine composition should all can cause immunne response at the helicobacter pylori of spherical and shaft-like form.Because it is limited that general immunity may act in to the protection of mucosal infections, it is also significant that vaccine composition increases the partial protective immune response mechanism of stomach.
Flagellum hook albumen
Be proved to be FlgE subunit by 78kDa from the flagellum hook of helicobacter pylori and formed (O ' Toole et al.Molecular Microbiology, 14 (4), 691-703,1994).The effect of flagellum hook is the flagellum starter that connects under flagellum and the film.It is shorter that the flagellum hook stretches out the outer part of cytolemma, is approximately 60 nanometers (flagellum is approximately 10 microns by contrast).As flagellum, the flagellum hook may also be covered with sheath (Geis et al. (1993) J.Med.Microbiol.38 (5), 371-377).
FlgE amino acid sequence of polypeptide and other known hook albumen have tangible similarity, comprise and the limited homology of other Helicobacter pylori kind such as mole Helicobacter pylori (O ' Toole etal. above).Show at the polyclonal antibody of FlgE polypeptide and to show cross reactivity at flagellin A and B to have the common epi-position.The helicobacter pylori that FlgE knocks out is atrichous non-mobility bacterium, wherein still produces the FlgE polypeptide, but is detected in the tenuigenin.
The accompanying drawing summary
Fig. 1: with the therapeutic action of FlgE polypeptide immune inoculation helicobacter pylori infection mouse.The result be expressed as in the hole (=A), (=B) or all (A+C) (=C) mean value ± standard error of helicobacter pylori quantity in the body.The abbreviation implication is: CFU=colony forming unit (number of bacteria); Blank cylinder=DOC+CT, every mouse contains the phosphate-buffered saline and the 10 μ g Toxins,exo-, choleras of 0.5% Septochol; Shade cylinder=FlgE+CT, every mouse gives 100 μ g FlgE and 10 μ g Toxins,exo-, choleras.The calculated value of CFU in hole and full stomach descends obviously.
* p<0.01; * p<0.05 (Wilcoxon-Mann-Whittney rank test)
The mice serum IgG that Fig. 2: ELISA measures: to replying and replying of infecting to the FlgE immunization.Numeric representation is average titer ± standard error.Every group of 9-10 of n=.ELISA helicobacter pylori 244 bacterial strain bag quilts:, in the animal serum of DOC+CT treatment (=A contrast/244), can see specific antibody as the index of helicobacter pylori infection.After FlgE+ Toxins,exo-, cholera (=B FlgE/244) immunization, this activity has increased by 4 times of (* * p<0.01; The Wilcoxon-Mann-Whittney rank test).C=FlgE is special.Specificity FlgE IgG increases in giving the animal of FlgE+CT, but in control animal, detect less than.
Summary of the invention
The purpose of this invention is to provide antigenicity helicobacter pylori polypeptide, it can be used for causing at the protective immune response of helicobacter pylori infection with to helicobacter pylori infection diagnoses.The recombinant clone of the helicobacter pylori gene by the conservative essential polypeptide of encoding has been realized this purpose.The nucleotide sequence of this gene is similar to the flgE gene order of (Molecular Microbiology, 14 (4), 691-703,1994) reports such as O ' Toole.Because be the essential albumen of motion, the flgE gene all has expression in all helicobacter pylorus bacteria strains.
Although it is outer and may be coated with sheath to have only small portion hook albumen to be present in bacterium, we find that unexpectedly with the administration of adjuvant Toxins,exo-, cholera, helicobacter pylori FlgE polypeptide can be used as therapeutic antigen in the helicobacter pylori infection mouse.Therefore following experimental data shows, helicobacter pylori FlgE polypeptide is as oral immunity when former, but immune stimulatory reply, cause the remarkable decline that helicobacter pylori is settled down in the experiment mice, experiment mice was used helicobacter pylori infection in preceding 1 month in immunization.
These results effectively are supported in and use the FlgE polypeptide to treat and prevent helicobacter pylori infection in the human oral vaccine preparation.Therefore, the FlgE polypeptide can be used for detecting helicobacter pylori infection and produces vaccine composition, and this vaccine composition can cause at the protectiveness or the therapeutic immunization of these infection and reply with suitable pharmaceutical dosage forms administration the time.
Therefore, one aspect of the present invention provides helicobacter pylori FlgE polypeptide, is used to cause the protective immune response to helicobacter pylori infection." helicobacter pylori FlgE polypeptide " refers to (Molecular Microbiology such as O ' Toole, 14 (4), 691-703,1994) disclosed polypeptide, the nucleotides sequence of its encoding gene is shown in SEQ ID NO:1, or can perhaps also comprise the basic similarly modified forms of the described polypeptide of antigen function equivalence available from NCBI (going into Tibetan U09549).
" protective immune response " is interpreted as making composition to be suitable for treating and/or preventing the immunne response of purpose.
" antigen function equivalence " is interpreted as causing general and mucosal immune response and reduces helicobacter pylori cell quantity in the stomach mucous membrane.Those skilled in the art can identify the modified forms of the FlgE polypeptide of antigen function equivalence by the epitope mapping of inducing antibody in currently known methods such as the body.
In a preferred embodiment of the invention; the helicobacter pylori FlgE polypeptide that is used for causing at the protective immune response of helicobacter pylori infection has the aminoacid sequence shown in sequence table SEQ IDNO:2 basically, or its modified forms of antigen function equivalence.
Therefore, the definition that should be appreciated that helicobacter pylori FlgE polypeptide is not limited only to the identical polypeptide of SEQ ID NO:2 in aminoacid sequence and the sequence table.The present invention also comprise have displacement, modified polypeptides such as little disappearance, insertion or reversing, but this polypeptide has and essentially identical biological activity of helicobacter pylori FlgE polypeptide and antigen function equivalence.Therefore, the definition of helicobacter pylori FlgE polypeptide comprises following polypeptide: at least 90% homology of aminoacid sequence shown in the SEQ IDNO:2, preferably at least 95% homology in its aminoacid sequence and the sequence table.
On the other hand; the invention provides a kind of vaccine composition; be used to cause the protective immune response at helicobacter pylori infection, said composition comprises the helicobacter pylori FlgE polypeptide as mentioned above of immune significant quantity, also can choose wantonly to comprise pharmaceutically useful carrier or thinner.
In this article, " immune significant quantity " is interpreted as causing the obvious protective immune response at helicobacter pylori, and eradicate helicobacter pylori infects or the amount of preventing infection in the susceptible Mammals in infecting Mammals.Generally, the immunity significant quantity comprises about 1 μ g to 1000mg when oral, and preferably approximately 10 μ g comprise the Heliobacter pylori antigen that approximately is less than 100 μ g to the 100mg Heliobacter pylori antigen during parenteral admin.
Except that pharmaceutically acceptable carrier or thinner, also can choose wantonly in the vaccine composition and contain one or more other preventions or treatment immuno-activated-antigen.Carrier and thinner that physiology is compatible are well known to those skilled in the art, and comprise phosphate-buffered saline (PBS) for example or be preparation or enteron aisle dressing pulvis based on supercarbonate when oral vaccine.
Vaccine composition also can be chosen wantonly and contain or with the acid secretion inhibitors administration, be preferably proton pump inhibitors such as omeprazole (PPI).Vaccine can be formulated in known transporting in the system, (see Rabinovich et al (1994) Science 265 as liposome, ISCOM, cochlear body (cochleate) etc., 1401-1404), perhaps be incorporated into or be included in degradation property or the biostable polymers microballoon.Antigen can combine with living toxic-reduced bacteria, virus or phage or its carrier that kills.Antigen can chemistry or hereditary going up and inertia or adjuvant type (being cholera B subunit) carrier protein couplet.Therefore, the present invention provides above-mentioned vaccine composition on the other hand, wherein also comprises adjuvants such as Toxins,exo-, cholera.The Toxins,exo-, cholera of these pharmaceutically acceptable forms is known in this area, as can be referring to Rappuoliet al (1995) Int.Arch.Allergy ﹠amp; Immunol.108 (4), 327-333; Dickinson et al (1995) Infection ﹠amp; Immunity63 (5), 1617-1623.
Vaccine composition of the present invention can be used for treatment and prevention purpose.Therefore, the present invention includes a kind of above-mentioned vaccine composition, can be used as treatment or vaccine that the Mammals that has infected helicobacter pylori comprises the people." prevention purpose " is meant the immunne response of inducing protection to avoid helicobacter pylori infection in the future in this article, and " therepic use " is meant and induces the immunne response that can eradicate existing helicobacter pylori infection.
Vaccine composition of the present invention preferably gives any Mammals mucous membrane, for example cheek, nose, tonsilla, stomach, intestines (small intestine and large intestine), rectum and vaginal mucosa.Mucosal vaccine can be with suitable adjuvant administration for this purpose.But vaccine is oral administration, parenteral, subcutaneous, intracutaneous or muscle administration also, and is optional with suitable adjuvant administration.Vaccine composition also can be chosen wantonly with antimicrobial therapy agent administration.
On the other hand, the invention provides the purposes of above-mentioned helicobacter pylori FlgE polypeptide in the production of following product:
The composition of (i) treatment, prevention or diagnosing helicobacter pylori infection;
(ii) be used to cause vaccine at the protective immune response of helicobacter pylori;
The (iii) diagnostic kit of diagnosing helicobacter pylori infection.
On the other hand, the invention provides the method for in-vitro diagnosis helicobacter pylori infection, comprise at least one step, wherein use above-mentioned helicobacter pylori FlgE polypeptide, can choose wantonly with the solid phase carrier mark or with its coupling.This method can comprise that for example step (a) makes helicobacter pylori FlgE polypeptide contact with mammalian body fluid, and described polypeptide can be chosen wantonly with solid phase carrier and combine; (b) antibody of detection and the described body fluid of described FlgE polypeptide bonded.The preferred method that detects antibody is ELISA well known in the art (enzyme linked immunosorbent assay) method.
On the other hand, the invention provides and detect the diagnostic kit that Mammals comprises the helicobacter pylori infection of philtrum, comprising the composition that can carry out above-mentioned in-vitro diagnosis method.Described diagnostic kit for example can comprise: (a) helicobacter pylori FlgE polypeptide; (b) detect and this FlgE polypeptide bonded antibody.The reagent of described detection antibody can be the anti-immunoglobulin of for example enzyme labelling and the chromogenic substrate of this enzyme.
Again on the one hand; the invention provides and cause the method that Mammals comprises the people at the protective immune response of helicobacter pylori infection; this method comprises the step that gives the above-mentioned helicobacter pylori FlgE polypeptide of immune significant quantity to this Mammals, or gives the above-mentioned vaccine composition of immune significant quantity to this Mammals.
Experimental technique
In this manual, when relating to molecule clone technology " standard method " or " standard step " be interpreted as method and the step on the common laboratory manual, laboratory manual is as " modern molecular biology method ", editors such as F.Ausubel, John Wiley and Sons, Inc.1994, or Sambrook, J., Fritsch, E.F. and Maniatis, T., " molecular cloning: laboratory manual ", the 2nd edition, Cold Spring Harbor LaboratoryPress, Cold Spring Harbor, NY 1989.
The preparation of recombinant helicobacterpylori FlgE polypeptide
Dna sequence dna information
The sequence information of the gene of coding FlgE polypeptide (is gone into Tibetan U09549 available from NCBI; SEQ ID NO:1).
The pcr amplification and the clone that contain the dna sequence dna of helicobacter pylori J99 bacterial strain membranin and secretory protein ORF
Described sequence uses polymerase chain reaction (PCR) to clone from helicobacter pylori J99 bacterial strain by the amplification clone.5 ' and 3 ' terminal special synthetic oligonucleotide primer thing (seeing below) of gene is by producer's design and buy (GibcoBRL Life Technologies, Gaithersburg, MD, USA).The forward primer of FlgE (special 5 ' end at sequence) is designed to comprise a NcoI cloning site at 5 ' least significant end, and reverse primer comprises an EcoRI site at least significant end, so that allow each helicobacter pylori sequence to be cloned in the frame of pET28b carrier into.Insertion fragment and one section carrier DNA sequence of being cloned into the NcoI-EcoRI site of pET-28b carrier merge, and this carrier sequence encoding comprises 20 C-terminal amino acid of 6 histidine residues (at C end least significant end).
Forward primer (SEQ ID NO:3)
5’-TAT?ACC?ATG?GTG?CTT?AGG?TCT?TTA?T-3’
Reverse primer (SEQ ID NO:4)
5’-GCC?AAT?TCA?ATT?GCT?TAA?GAT?TCA?A-3’
By the genomic dna of helicobacter pylori J99 bacterial strain preparation as the template source of pcr amplification reaction (" modern molecular biology method ", editors such as F.Ausubel, John Wileyand Sons, Inc.1994).The dna sequence dna that contains helicobacter pylori ORF in order to increase adds the 50ng genomic dna in the reaction tubes, contains the 2mM magnesium chloride in the reaction tubes, 1 μ M and helicobacter pylori ORF are complementary and extend to the synthetic oligonucleotide primer thing (forward and reverse primer) of its flank, dATP, dGTP, dCTP, each 0.2mM of cTTP and the 2.5 thermostability archaeal dna polymerase (Amplitaq of unit, Roche Molecular Systems, Inc., Branchburg, NJ, USA), final volume is 100 μ l.Use following thermal cycle conditions and Perkin Elmer Cetus/GeneAmp PCR System 9600 thermal cyclers to obtain the DNA amplification product of every kind of ORF:
94 ℃ of sex change 2 minutes;
94 ℃ 15 seconds, 30 ℃ of 15 seconds and 72 ℃ of 2 circulations in 1.5 minutes;
94 ℃ 15 seconds, 58 ℃ of 15 seconds and 72 ℃ of 23 circulations in 1.5 minutes;
72 ℃ of 6 minutes afterreactions finish.
After thermal cycle reaction finishes, wash each DNA amplification sample and use Qiaquick SpinPCR purification kit purifying (Qiagen, Gaithersburg, MD, USA).The DNA sample of amplification uses restriction enzyme NdeI and EcoRI digestion, electrophoresis on 1.0% NuSeive (FMC BioProducts, Rockland, ME USA) sepharose then by standard method.DNA uses ethidium bromide and long wave UV radiation observation.Use Bio 101GeneClean Kit method (Bio 101 Vista, CA USA) purifying by separated DNA in the gel adhesive tape.
The helicobacter pylori dna sequence dna is cloned into pET-28b prokaryotic expression carrier
The pET-28b carrier that is used to clone prepares by NcoI and EcoRI digestion according to standard step.After the digestion, DNA inserts fragment is cloned into prior digestion according to standard step pET-28b expression vector.The ligation product is used to transform the following stated e. coli strain bl21 then.
Use the recombinant plasmid transformed competence colibacillus bacterium
Use the reorganization pET expression plasmid transformed competence colibacillus bacteria Escherichia coli BL21 bacterial strain or e. coli bl21 (DE53) bacterial strain of the helicobacter pylori sequence that carries the clone according to standard method.In brief, 1 μ l ligation thing and 50 μ l electroreception attitude cytomixis, and impose high voltage pulse, then, sample is at 0.45ml SOC substratum (0.5% yeast extract, 2.0% tryptone, 10mM NaCl, 2.5mM KCl, 10mM MgCl
2, 10mM MgSO
4And 20mM glucose) 37 ℃ of vibration incubations 1 hour in.Sample is coated on grow overnight on the LB agar plate that contains 25 μ g/ml sulphuric acid kanamycins then.The BL21 bacterium colony that transforms of picking and analyzing then so that evaluation as described below clone's insertion fragment.
The reorganization pET expression plasmid of helicobacter pylori sequence is carried in evaluation
Independent BL21 with the gene transformation of reorganization pET-28b helicobacter pylori clones following analysis: use with original pcr amplification cloning reaction in identical, the sequence-specific forward of each helicobacter pylori and reverse primer the insertion fragment of cloning is carried out pcr amplification.Successful amplification according to standard step has confirmed that the helicobacter pylori sequence is incorporated in the expression vector.
From the BL21 transformant, separate and the preparation plasmid DNA
Picking carries the independent clone of reorganization pET-28b carrier of correct clone's helicobacter pylori ORF, is incubated overnight in 5ml has added the LB nutrient solution of 25 μ g/ml sulphuric acid kanamycins.Use Qiagen plasmid purification method (Qiagen Inc., Chatsworth, CA, USA) separation and plasmid DNA purification next day.
The expression of recombinant helicobacterpylori sequence in intestinal bacteria
Be clone or preparation plasmid, the pET carrier can be at any e. coli k-12 bacterial strain such as HMS174, HB101, propagation among the JM109, DH5 α etc.Expressive host comprises the coli strain of the chromosome copies that contains the T7 rna polymerase gene.These hosts be bacteriophage DE3 lysogen, carry the lacI gene, the λ derivative of lacUV5 promotor and T7 RNA polymerase.The T7 RNA polymerase is induced by adding isopropyl-(IPTG), and the T7 rna polymerase transcribe carries any target plasmid such as the pET-28b of its target gene.The bacterial strain that we use in the laboratory comprises: and BL21 (DE3) (Studier, F.W., Rosenberg, A.H., Dunn, J.J. and Dubendorff, J.W. (1990) Enzymology method, 185,60-89).
For express recombinant helicobacter pylori sequence, the above-mentioned isolating plasmid DNA of 50ng is used for transforming above-mentioned competence BL21 (DE3) bacterium (being provided with the part of pET expression system test kit by Novagen).Transformant was cultivated 1 hour in the SOC substratum, and the culture coating contains the LB flat board of 25 μ g/ml sulphuric acid kanamycins then.Next day, merge bacterial colony, growing to 600 nanometer optical density(OD) in the LB substratum of sulfur acid kantlex (25 μ g/ml) is 0.5 to 1.0 O.D. unit, and added 1mM IPTG 3 hours this moment in substratum, to induce the genetic expression of helicobacter pylori recombinant DNA constructs.
After the IPTG inducible gene expression, at 3500 * g, 4 ℃ made bacterial precipitation in centrifugal 15 minutes with Sorvall RC-3B whizzer.Precipitation is resuspended in 50 milliliters of cold STE damping fluids (10mM Tris-HCl, pH8.0,0.1M NaCl and 0.1mM EDTA).Cell is then at 4 ℃, centrifugal 20 minutes of 2000 * g.Moist precipitate is weighed and is frozen in order to carrying out protein purification at-80 ℃.
Analytical procedure
The concentration of purifying protein prepared product use the uptake factor that calculates by aminoacids content with spectrophotometry determine (Perkins, S.J.1986 Eur.J.Biochem.157,169-180).Protein concentration also uses bovine serum albumin to determine (Bradford, M.M. (1976) Anal.Biochem.72,248-254, Lowry, O.H., Rosebrough, N.Farr, A.L.﹠amp as standard with another kind of method; Randall, R.J. (1951)).
(Hercules, CA USA), and use coomassie brilliant blue staining to sodium lauryl sulphate-polyacrylamide (SDS-PAGE) gel (12% or 4-25% gradient acrylamide) available from BioRad.Molecular weight marker comprises rabbit skeletal muscle myosin (200kDa), intestinal bacteria beta-galactosidase enzymes (116kDa), rabbit muscle phosphatase-1 b (97.4kDa), bovine serum albumin (66.2kDa), ovalbumin (45kDa), BCA (31kDa), Trypsin inhibitor SBTI (21.5kDa), and egg-white lysozyme (14.4kDa) and ox press down enzyme peptide (6.5kDa).
By inclusion body purification FlgE
Carry out following steps at 4 ℃.Cell precipitation is resuspended in the lysis buffer, contains 10% glycerine in the damping fluid, 100 μ g/ml N,O-Diacetylmuramidases, 5mM EDTA, 1mM PMSF and 0.1% beta-mercaptoethanol.Behind the cytoclasis device, the homogenate of gained adds 0.2%DOC, stirs 10 minutes, centrifugal then (10000g * 30min).Precipitation is at first with containing 10% glycerine, 10mM EDTA, and 1%Triton X-100, the lysis buffer washing of 1mM PMSF and 0.1% beta-mercaptoethanol, with containing 1M urea, the lysis buffer of 1mM PMSF and 0.1% beta-mercaptoethanol washs then.The white precipitate of gained mainly is made up of inclusion body, does not contain not broken cell and film component.
Carry out following steps in room temperature.Solubilization of inclusion bodies contains 1mM EDTA in 20 milliliters, in the lysis buffer of 1mMPMSF and 0.1% beta-mercaptoethanol and 8M urea, and room temperature incubation 1 hour.Insoluble material is removed by centrifugal (100,000 * g, 30 minutes).Filter limpid supernatant liquor, be splined on the lysis buffer equilibrated Ni that contains 8M urea
2+-NTA agarose column.Wash post with the lysis buffer that 250 milliliters (5 times of bed volumes) contain 1mM PMSF, 0.1% beta-mercaptoethanol and 8M urea, successively with containing 8M urea, 1mM PMSF, 0.1% beta-mercaptoethanol and 20,100,200 and the lysis buffer wash-out of 500mM imidazoles.Pass through OD
280Absorption value monitor each fraction, the peak value fraction is analyzed with SDS-PAGE.Can see two bands with coomassie brilliant blue staining, the molecular weight of main band is 78kDa, and the molecular weight of less important band is 60kDa.The purity of FlgE (78kDa) recombinate by analysis greater than 90%.Purifying with soluble proteins is the same, and the fraction that contains recombinant protein elutes with the 100mM imidazoles.
To containing the TBS dialysis of 0.5%DOC, reduce urea concentration: 6M in the following order successively, 4M, 3M, 2M, 1M, 0.5M are 0M then, slowly remove urea from the FlgE polypeptide.Each dialysis step was at least at room temperature carried out 4 hours.
After the dialysis, use the Amicon teeter column to make sample concentration by pressure filtration.By Perkins, Bradford and Lowry method are measured protein concentration then.
Embodiment
Embodiment 1: therapeutic immunization
1. materials and methods
1.1 animal
Female SPF BALB/c mouse is available from Bomholt breeding center (Denmark).In common makrolon rearging cage, raise, freely get food and drinking-water.Animal was 4 to 6 ages in week when arriving at.
1.2 infect
After at least one week of domestication, with helicobacter pylori 2 type bacterial strains (bacterial strain 244, initial separation is from the ulcer patient) infection animal.This bacterial strain had been proved in the past and had been settled in easily in the mouse stomach.The original seed bacterium of-70 ℃ of preservations is at 37 ℃ of (10% CO under little aerobic atmosphere
2, 5%O
2) grow overnight in adding the Brucella nutrient solution of 10% foetal calf serum.Animal orally give omeprazole (400 μ mol/kg), (every the animal about 10 of oral vaccination helicobacter pylori after 3-5 hour
7-10
8CFU).Inoculation 2-3 checks in control animal after week and infects.
1.3 immunization
Infect after 1 month, two groups of mouse (10 every group) inoculated 4 times (the 1st, 15,25,35 day) in 34 days.Purification of Recombinant FlgE is dissolved among the PBS that is added with 0.5% Septochol (DOC), and dosage is every mouse 100 micrograms.
During each immunization, control group and every mouse of FlgE group all give 10 microgram Toxins,exo-, choleras as adjuvant.Preceding 3-5 hour of immunization, orally give omeprazole (400 μ mol/kg) is used for protecting antigen to avoid acid degradation.Last immunity back 1-2 week is put to death animal.
The 1st group: 300 μ l PBS+0.5% DOC+10 μ g CT
The 2nd group: 300 μ l PBS+0.5% DOC+10 μ g CT+100 μ g FlgE
1.4 infection analysis
Mouse passes through CO
2Put to death with disconnected neck.Open thoracic cavity and abdominal cavity, by the heart puncturing extracting blood sample.Take out stomach then.Cut stomach along greater gastric curvature, use the salt water washing, be cut into equal two then.Scrape 25mm from stomach hole and body of stomach respectively with scalpel
2Mucous membrane.The mucous membrane that scrapes is suspended in the Brucella nutrient solution, dilutes and is coated on the Blood Skirrow flat board.Dull and stereotyped under little aerobic condition incubation 3-5 days, counting colony quantity.Confirm that with direct microscopy or gramstaining culture is a helicobacter pylori by urase and catalase test.
1.5 TPPA
In blood sample, collect serum antibody.Before concentrating, blood sample dilutes with equivalent PBS.Serum-20 ℃ of preservations with to be analyzed.Use ELISA to measure serum antibody, dull and stereotyped with helicobacter pylorus bacteria strain 244 particulate fractions or FlgE covering, add different dilution serum then.ELISA develops the color with the anti-mouse Ig antibody of alkali phosphatase enzyme mark.Anti-Ig antibody is anti-heavy chain/anti-light chain type, should be able to detect various types of antibody.
2. result
2.1 therapeutic immunization: to the influence of CFU
Animal in this test infects with helicobacter pylorus bacteria strain 244 preceding 1 month of immunization.Every group of 10 mouse are used Toxins,exo-, cholera (CT) or CT and the inoculation of reorganization FlgE polypeptide immune then.4 weeks after the last immunization, put to death animal, measure CFU (Fig. 1).Only animal body of stomach and the stomach Dou Jun that handles with CT infects in a large number.Compare the stomach hole with CT processing animal with the animal of reorganization FlgE polypeptide and CT immunization and (be respectively p<0.01, p<0.05 with obvious decline of full stomach CFU value; The test of Wilcoxon-Mann-Whittney symbol level).
2.2 therapeutic immunization: antagonist forms and the excretory influence
As the indication of infecting helicobacter pylori, in serum, can see specific antibody (contrast/244).In giving the animal of FlgE+CT, the titre (as membranin) of anti-244 bacterial strains has increased by 4 times (p<0.01).Only in giving the animal of FlgE+CT, can detect the special serum IgG titre (Fig. 2) of anti-FlgE.
The special IgG of FlgE increases in giving the animal of FlgE+CT, but in control animal, detect less than.
This paper result shows at oral administration and gives Toxins,exo-, cholera as adjuvant time reorganization FlgE helicobacter pylori polypeptide is a hyperimmunization originality, can detect the increase of whole body FlgE specificity Ig antibody.Also cause the remarkable increase of the Ig titre of anti-helicobacter pylori grain fraction with the FlgE immunization.In addition, behind immunization FlgE and Toxins,exo-, cholera, the quantity that the infecting mouse stomach mucous membrane is settled down helicobacter pylori significantly descends.
Sequence table (1) physical data: (i) applicant:
(A) addressee: Astra AB
(B) street: Vastra Malarehamnen 9
(C) city: Sodertalje
(E) country: Sweden
(F) postcode: S-151 85
(G) phone :+46855326000
(H) fax :+46855328820 (ii) denomination of invention: vaccine composition V (iii) sequence number: 4 (iv) computer-reader form:
(A) medium type: floppy disk
(B) computer: IBM PC compatibility
(C) operating system: PC-DOS/MS-DOS
(D) software: PatentIn Release#1.0, Version#1.30 (EPO) (2) SEQ ID NO:1 data: (i) sequence signature:
(A) length: 2550 base-pairs
(B) type: nucleic acid
(C) chain: two strands
(D) topological structure: linear (ii) molecule type: cDNA (vi) primary source
(A) organism: helicobacter pylori (ix) feature:
(A) title/keyword: CDS
(B) position: 321..2477
(D) out of Memory :/product=" FlgE flagellum hook albumen " is public information (x):
(A) author: O ' Toole, Paul W.
(B) title: the non-motility mutant of helicobacter pylori and mole helicobacter
The flagellum hook generates the defective body
(C) magazine: molecular microbiology
(D) reel number: 14
(E) issue: 4
(F) page number: 691-703
(G) date: 1994 (xi) sequence description: SEQ ID NO:1:AACAAAGCGA TAACTCCTTT GTCTTATTAG CGACACAATT TAACCCATTG ACTTTAAATC 60 GCGCTTCAGC CGAAGAGATT CAAGATCATG AATGCGCGAT TTTGCACTAA AGCGAGTTAG 120 ATTCTTAAAT TTGAGCGATA ACCTTTAAAA AGCGTAATTA AGGGGTGGTG TTACAAAACC 180 CCCTATCCCC TTATGAATTT GACCGATCTT TTTGATTAAC AAAACTTTAA AATCCGCAAT 240 CAATCATTCT AAAAAGCTAT TTAGGAACAA CTTTTGCTTT ATTTTGCATA GATTGAATTT 300 CTTTAAATTA AAGGATAACC ATG CTT AGG TCT TTA TGG TCT GGT GTC AAT 350
Met Leu Arg Ser Leu Trp Ser Gly Val Asn
1 5 10
GGG ATG CAA GCC CAC CAA ATC GCT TTG GAT ATT GAG AGT AAC AAT ATT 398
Gly Met Gln Ala His Gln Ile Ala Leu Asp Ile Glu Ser Asn Asn Ile
15 20 25
GCG AAC GTG AAT ACC ACT GGT TTT AAG TAT TCT AGG GCT TCT TTT GTG 446
Ala Asn Val Asn Thr Thr Gly Phe Lys Tyr Ser Arg Ala Ser Phe Val
30 35 40
GAT ATG CTT TCT CAA GTC AAA CTC ATC GCT ACC GCA CCC TAT AAA AAC 494
Asp Met Leu Ser Gln Val Lys Leu Ile Ala Thr Ala Pro Tyr Lys Asn
45 50 55
GGG TTA GCA GGG CAG AAT GAT TTT TCT GTG GGG CTT GGG GTA GGC GTG 542
Gly Leu Ala Gly Gln Asn Asp Phe Ser Val Gly Leu Gly Val Gly Val
60 65 70
GAT GCG ACG ACT AAA ATC TTT TCA CAA GGC AAT ATC CAA AAC ACA GAT 590
Asp Ala Thr Thr Lys Ile Phe Ser Gln Gly Asn Ile Gln Asn Thr Asp
75 80 85 90
GTC AAA ACC GAT CTA GCG ATT CAA GGC GAT GGC TTT TTT ATC ATT AAC 638
Val Lys Thr Asp Leu Ala Ile Gln Gly Asp Gly Phe Phe Ile Ile Asn
95 100 105
CCT GAT AGG GGG ATC ACG CGC AAT TTC ACT AGA GAT GGG GAG TTC CTT 686
Pro Asp Arg Gly Ile Thr Arg Asn Phe Thr Arg Asp Gly Glu Phe Leu
110 115 120
TTT GAC TCG CAA GGG AGT TTG GTT ACC ACC GGC GGG CTT GTG GTG CAA 734
Phe Asp Ser Gln Gly Ser Leu Val Thr Thr Gly Gly Leu Val Val Gln
125 130 135
GGG TGG GTG AGA AAT GGG AGC GAT ACC GGC AAT AAA GGG AGC GAT ACA 782
Gly Trp Val Arg Asn Gly Ser Asp Thr Gly Asn Lys Gly Ser Asp Thr
140 145 150
GAC GCT TTA AAA GTG GAT AAC ACC GGT CCT TTA GAA AAC ATT AGG ATT 830
Asp Ala Leu Lys Val Asp Asn Thr Gly Pro Leu Glu Asn Ile Arg Ile
155 160 165 170
GAT CCT GGA ATG GTG ATG CCA GCC AGA GCG AGT AAC CGC ATT TCT ATG 878
Asp Pro Gly Met Val Met Pro Ala Arg Ala Ser Asn Arg Ile Ser Met
175 180 185
AGG GCG AAT TTA AAC GCT GGA AGG CAT GCC GAT CAA ACA GCG GCG ATA 926
Arg Ala Asn Leu Asn Ala Gly Arg His Ala Asp Gln Thr Ala Ala Ile
190 195 200
TTC GCT TTG GAT TCT TCA GCC AAA ACC CCT TCA GAT GGC ATT AAT CCG 974
Phe Ala Leu Asp Ser Ser Ala Lys Thr Pro Ser Asp Gly Ile Asn Pro
205 210 215
GTG TAT GAT TCA GGC ACG AAT CTT GCT CAA GTC GCC GAA GAC ATG GGA 1022
Val Tyr Asp Ser Gly Thr Asn Leu Ala Gln Val Ala Glu Asp Met Gly
220 225 230
TCT TTA TAC AAT GAA GAT GGC GAC GCT CTT TTG TTG AAT GAA AAT CAA 1070
Ser Leu Tyr Asn Glu Asp Gly Asp Ala Leu Leu Leu Asn Glu Asn Gln
235 240 245 250
GGG ATT TGG GTG AGC TAT AAG AGT CCA AAA ATG GTC AAA GAC ATC CTC 1118
Gly Ile Trp Val Ser Tyr Lys Ser Pro Lys Met Val Lys Asp Ile Leu
255 260 265
CCT TCT GCA GAA AAC AGC ACG CTT GAA TTG AAT GGC GTT AAG ATT TCT 1166
Pro Ser Ala Glu Asn Ser Thr Leu Glu Leu Asn Gly Val Lys Ile Ser
270 275 280
TTC ACA AAC GAT TCA GCG GTG AGC CGG ACT TCA AGC TTA GTG GCG GCT 1214
Phe Thr Asn Asp Ser Ala Val Ser Arg Thr Ser Ser Leu Val Ala Ala
285 290 295
AAA AAT GCG ATC AAT GCA GTC AAA AGC CAA ACA GGC ATT GAA GCT TAT 1262
Lys Asn Ala Ile Asn Ala Val Lys Ser Gln Thr Gly Ile Glu Ala Tyr
300 305 310
TTA GAC GGC AAG CAA TTG CGT TTG GAA AAC ACC AAT GAA TTA GAC GGC 1310
Leu Asp Gly Lys Gln Leu Arg Leu Glu Asn Thr Asn Glu Leu Asp Gly
315 320 325 330
GAT GAA AAG CTT AAA AAC ATT GTA GTT ACT CAA GCC GGA ACC GGA GCG 1358
Asp Glu Lys Leu Lys Asn Ile Val Val Thr Gln Ala Gly Thr Gly Ala
335 - 340 345
TTC GCT AAC TTT TTA GAC GGC GAT AAA GAT GTA ACG GCT TTC AAA TAC 1406
Phe Ala Asn Phe Leu Asp Gly Asp Lys Asp Val Thr Ala Phe Lys Tyr
350 355 360
AGC TAC ACG CAT TCT ATT AGC CCT AAC GCC AAT AGC GGG CAG TTT AGG 1454
Ser Tyr Thr His Ser Ile Ser Pro Asn Ala Asn Ser Gly Gln Phe Arg
365 370 375
ACC ACT GAA GAC TTG CGC GCC TTA ATC CAG CAT GAC GCT AAT ATC GTT 1502
Thr Thr Glu Asp Leu Arg Ala Leu Ile Gln His Asp Ala Asn Ile Val
380 385 390
AAA GAT CCT AGC CTA GCG GAC AAT TAC CAA GAC TCA GCC GCT TCT ATA 1550
Lys Asp Pro Ser Leu Ala Asp Asn Tyr Gln Asp Ser Ala Ala Ser Ile
395 400 405 410
GGA GTT ACA ATC AAC CAA TAC GGC ATG TTT GAA ATC AAC AAT AAA GAC 1598
Gly Val Thr Ile Asn Gln Tyr Gly Met Phe Glu Ile Asn Asn Lys Asp
415 420 425
AAT AAA AAT GTC ATT AAA GAA AAT CTT AAT ATC TTT GTG AGC GGG TAT 1646
Asn Lys Asn Val Ile Lys Glu Asn Leu Asn Ile Phe Val Ser Gly Tyr
430 435 440
TCT TCA GAC AGC GTA ACG AAC AAT GTT TTG TTT AAA AAT GCG ATG AAA 1694
Ser Ser Asp Ser Val Thr Asn Asn Val Leu Phe Lys Asn Ala Met Lys
445 450 455
GGG CTT AAT ACC GCT TCT TTA ATT GAA GGG GGA GCG TCA GCG AGC AGT 1742
Gly Leu Asn Thr Ala Ser Leu Ile Glu Gly Gly Ala Ser Ala Ser Ser
460 465 470
TCT AAA TTC ACC CAC GCT ACG CAT GCG ACA AGC ATT GAT GTG ATA GAC 1790
Ser Lys Phe Thr His Ala Thr His Ala Thr Ser Ile Asp Val Ile Asp
475 480 485 490
AGC TTA GGC ACT AAA CAC GCC ATG CGC ATT GAG TTT TAT AGG AGT GGG 1838
Ser Leu Gly Thr Lys His Ala Met Arg Ile Glu Phe Tyr Arg Ser Gly
495 500 505
GGA GCG GAT TGG AAT TTT AGA GTG ATC GTG CCT GAG CCT GGG GAA TTA 1886
Gly Ala Asp Trp Asn Phe Arg Val Ile Val Pro Glu Pro Gly Glu Leu
510 515 520
GTA GGG GGG TCA GCG GCT AGG CCT AAT GTG TTT GAA GGA GGC CGT TTG 1934
Val Gly Gly Ser Ala Ala Arg Pro Asn Val Phe Glu Gly Gly Arg Leu
525 530 535
CAC TTC AAT AAT GAC GGA TCG CTT GCA GGC ATG AAC CCG CCT CTT TTG 1982
His Phe Asn Asn Asp Gly Ser Leu Ala Gly Met Asn Pro Pro Leu Leu
540 545 550
CAA TTT GAC CCT AAA AAT GGT GCT GAT GCC CCC CAA CGC ATC AAT TTA -2030
Gln Phe Asp Pro Lys Asn Gly Ala Asp Ala Pro Gln Arg Ile Asn Leu
555 560 565 570
GCT TTT GGT TCC TCA GGG AGT TTT GAC GGG CTA ACG AGC GTG GAT AAG 2078
Ala Phe Gly Ser Ser Gly Ser Phe Asp Gly Leu Thr Ser Val Asp Lys
575 580 585
ATT TCT GAA ACT TAT GCG ATT GAG CAA AAC GGC TAT CAA GCG GGC GAT 2126
Ile Ser Glu Thr Tyr Ala Ile Glu Gln Asn Gly Tyr Gln Ala Gly Asp
590 595 600TTG?ATG?GAT?GTC?CGC?TTT?GAT?TCA?GAT?GGG?GTG?CTT?TTA?GGA?GCG?TTC 2174Leu?Met?Asp?Val?Arg?Phe?Asp?Ser?Asp?Gly?Val?Leu?Leu?Gly?Ala?Phe
605 610 615AGT?AAT?GGC?AGG?ACT?TTA?GCG?CTC?GCT?CAA?GTG?GCT?TTA?GCG?AAT?TTC 2222Ser?Asn?Gly?Arg?Thr?Leu?Ala?Leu?Ala?Gln?Val?Ala?Leu?Ala?Asn?Phe
620 625 630GCT?AAC?GAT?GCG?GGC?TTG?CAG?GCT?TTA?GGC?GGG?AAT?GTC?TTT?TCT?CAA 2270Ala?Asn?Asp?Ala?Gly?Leu?Gln?Ala?Leu?Gly?Gly?Asn?Val?Phe?Ser?Gln635 640 645 650ACC?GGA?AAC?TCA?GGG?CAA?GCC?TTA?ATC?GGT?GCG?GCT?AAT?ACG?GGG?CGT 2318Thr?Gly?Asn?Ser?Gly?Gln?Ala?Leu?Ile?Gly?Ala?Ala?Asn?Thr?Gly?Arg
655 660 665AGG?GGT?TCA?ATT?TCA?GGA?TCT?AAA?CTG?GAG?TCT?AGT?AAT?GTG?GAT?TTG 2366Arg?Gly?Ser?Ile?Ser?Gly?Ser?Lys?Leu?Glu?Ser?Ser?Asn?Val?Asp?Leu
670 675 680AGC?CGG?AGT?TTA?ACG?AAT?TTG?ATT?GTG?GTT?CAA?AGG?GGC?TTT?CAA?GCA 2414Ser?Arg?Ser?Leu?Thr?Asn?Leu?Ile?Val?Val?Gln?Arg?Gly?Phe?Gln?Ala
685 690 695AAC?TCT?AAA?GCG?GTA?ACC?ACA?TCC?GAT?CAA?ATC?CTT?AAT?ACC?CTA?TTG 2462Asn?Ser?Lys?Ala?Val?Thr?Thr?Ser?Asp?Gln?Ile?Leu?Asn?Thr?Leu?Leu
700 705 710AAT CTT AAG CAA TAA ACTAAAGGAT TACTCTAATA CAATATAATA GGGGCTAATT 2517Asn Leu Lys Gln * 715TAAAGATTAA GGTTTAGTAT GCATGAATAC TCG, 2550 (2) SEQ ID NO:2 data: (i) sequence signature:
(A) length: 719 amino acid
(B) type: amino acid
(D) topological framework: linear (ii) molecule type: albumen (xi) sequence description: SEQ ID NO:2:Met Leu Arg Ser Leu Trp Ser Gly Val Asn Gly Met Gln Ala His Gln 15 10 15Ile Ala Leu Asp Ile Glu Ser Asn Asn Ile Ala Asn Val Asn Thr Thr
20 25 30Gly?Phe?Lys?Tyr?Ser?Arg?Ala?Ser?Phe?Val?Asp?Met?Leu?Ser?Gln?Val
35 40 45Lys?Leu?Ile?Ala?Thr?Ala?Pro?Tyr?Lys?Asn?Gly?Leu?Ala?Gly?Gln?Asn
50 55 60Asp?Phe?Ser?Val?Gly?Leu?Gly?Val?Gly?Val?Asp?Ala?Thr?Thr?Lys?Ile?65 70 75 80Phe?Ser?Gln?Gly?Asn?Ile?Gln?Asn?Thr?Asp?Val?Lys?Thr?Asp?Leu?Ala
85 90 95Ile?Gln?Gly?Asp?Gly?Phe?Phe?Ile?Ile?Asn?Pro?Asp?Arg?Gly?Ile?Thr
100 105 110Arg?Asn?Phe?Thr?Arg?Asp?Gly?Glu?Phe?Leu?Phe?Asp?Ser?Gln?Gly?Ser
115 120 125Leu?Val?Thr?Thr?Gly?Gly?Leu?Val?Val?Gln?Gly?Trp?Val?Arg?Asn?Gly
130 135 140Ser?Asp?Thr?Gly?Asn?Lys?Gly?Ser?Asp?Thr?Asp?Ala?Leu?Lys?Val?Asp145 150 155 160Asn?Thr?Gly?Pro?Leu?Glu?Asn?Ile?Arg?Ile?Asp?Pro?Gly?Met?Val?Met
165 170 175Pro?Ala?Arg?Ala?Ser?Asn?Arg?Ile?Ser?Met?Arg?Ala?Asn?Leu?Asn?Ala
180 185 190Gly?Arg?His?Ala?Asp?Gln?Thr?Ala?Ala?Ile?Phe?Ala?Leu?Asp?Ser?Ser
195 200 205Ala?Lys?Thr?Pro?Ser?Asp?Gly?Ile?Asn?Pro?Val?Tyr?Asp?Ser?Gly?Thr
210 215 220Asn?Leu?Ala?Gln?Val?Ala?Glu?Asp?Met?Gly?Ser?Leu?Tyr?Asn?Glu?Asp225 230 235 240Gly?Asp?Ala?Leu?Leu?Leu?Asn?Glu?Asn?Gln?Gly?Ile?Trp?Val?Ser?Tyr
245 250 255Lys?Ser?Pro?Lys?Met?Val?Lys?Asp?Ile?Leu?Pro?Ser?Ala?Glu?Asn?Ser
260 265 270Thr?Leu?Glu?Leu?Asn?Gly?Val?Lys?Ile?Ser?Phe?Thr?Arg?Asp?Ser?Ala
275 280 285Val?Ser?Arg?Thr?Ser?Ser?Leu?Val?Ala?Ala?Lys?Asn?Ala?Ile?Asn?Ala
290 295 300Val?Lys?Ser?Gln?Thr?Gly?Ile?Glu?Ala?Tyr?Leu?Asp?Gly?Lys?Gln?Leu305 310 315 320Arg?Leu?Glu?Asn?Thr?Asn?Glu?Leu?Asp?Gly?Asp?Glu?Lys?Leu?Lys?Asn
325 330 335Ile?Val?Val?Thr?Gln?Ala?Gly?Thr?Gly?Ala?Phe?Ala?Asn?Phe?Leu?Asp
340 345 350Gly?Asp?Lys?Asp?Val?Thr?Ala?Phe?Lys?Tyr?Ser?Tyr?Thr?His?Ser?Ile
355 360 365Ser?Pro?Asn?Ala?Asn?Ser?Gly?Gln?Phe?Arg?Thr?Thr?Glu?Asp?Leu?Arg
370 375 380Ala?Leu?Ile?Gln?His?Asp?Ala?Asn?Ile?Val?Lys?Asp?Pro?Ser?Leu?Ala385 390 395 400Asp?Asn?Tyr?Gln?Asp?Ser?Ala?Ala?Ser?Ile?Gly?Val?Thr?Ile?Asn?Gln
405 410 415Tyr?Gly?Met?Phe?Glu?Ile?Asn?Asn?Lys?Asp?Asn?Lys?Asn?Val?Ile?Lys
420 425 430Glu?Asn?Leu?Asn?Ile?Phe?Val?Ser?Gly?Tyr?Ser?Ser?Asp?Ser?Val?Thr
435 440 445Asn?Asn?Val?Leu?Phe?Lys?Asn?Ala?Met?Lys?Gly?Leu?Asn?Thr?Ala?Ser
450 455 460Leu?Ile?Glu?Gly?Gly?Ala?Ser?Ala?Ser?Ser?Ser?Lys?Phe?Thr?His?Ala465 470 475 480Thr?His?Ala?Thr?Ser?Ile?Asp?Val?Ile?Asp?Ser?Leu?Gly?Thr?Lys?His
485 490 495Ala?Met?Arg?Ile?Glu?Phe?Tyr?Arg?Ser?Gly?Gly?Ala?Asp?Trp?Asn?Phe
500 505 510Arg?Val?Ile?Val?Pro?Glu?Pro?Gly?Glu?Leu?Val?Gly?Gly?Ser?Ala?Ala
515 520 525Arg?Pro?Asn?Val?Phe?Glu?Gly?Gly?Arg?Leu?His?Phe?Asn?Asn?Asp?Gly
530 535 540Ser?Leu?Ala?Gly?Met?Asn?Pro?Pro?Leu?Leu?Gln?Phe?Asp?Pro?Lys?Asn545 550 555 560Gly?Ala?Asp?Ala?Pro?Gln?Arg?Ile?Asn?Leu?Ala?Phe?Gly?Ser?Ser?Gly
565 570 575Ser?Phe?Asp?Gly?Leu?Thr?Ser?Val?Asp?Lys?Ile?Ser?Glu?Thr?Tyr?Ala
580 585 590Ile?Glu?Gln?Asn?Gly?Tyr?Gln?Ala?Gly?Asp?Leu?Met?Asp?Val?Arg?Phe
595 600 605Asp?Ser?Asp?Gly?Val?Leu?Leu?Gly?Ala?Phe?Ser?Asn?Gly?Arg?Thr?Leu
610 615 620Ala?Leu?Ala?Gln?Val?Ala?Leu?Ala?Asn?Phe?Ala?Asn?Asp?Ala?Gly?Leu625 630 635 640Gln?Ala?Leu?Gly?Gly?Asn?Val?Phe?Ser?Gln?Thr?Gly?Asn?Ser?Gly?Gln
645 650 655Ala?Leu?Ile?Gly?Ala?Ala?Asn?Thr?Gly?Arg?Arg?Gly?Ser?Ile?Ser?Gly
660 665 670Ser?Lys?Leu?Glu?Ser?Ser?Asn?Val?Asp?Leu?Ser?Arg?Ser?Leu?Thr?Asn
675 680 685Leu?Ile?Val?Val?Gln?Arg?Gly?Phe?Gln?Ala?Asn?Ser?Lys?Ala?Val?Thr
690 695 700Thr Ser Asp Gln Ile Leu Asn Thr Leu Leu Asn Leu Lys Gln *, 705 710 715 (2) SEQ ID NO:3 data: (i) sequence signature:
(A) length: 25 base pairs
(B) type: nucleic acid
(C) chain: strand
(D) topological framework: linear (ii) molecule type: other nucleic acid
(A) describe :/desc=" PCR primer " is sequence description (xi): SEQ ID NO:3:TATACCATGG TGCTTAGGTC TTTAT 25 (2) SEQ ID NO:4 data: (i) sequence signature:
(A) length: 25 base pairs
(B) type: nucleic acid
(C) chain: strand
(D) topological framework: linear (ii) molecule type: other nucleic acid
(A) describe :/desc=" PCR primer "
(xi) sequence description: SEQ ID NO:4:GCGAATTCAA TTGCTTAAGA TTCAA 25
Claims (17)
1. its modified forms of helicobacter pylori FlgE polypeptide or antigen function equivalence is used to cause the protective immune response at helicobacter pylori infection.
2. the helicobacter pylori FlgE polypeptide of claim 1 has the aminoacid sequence shown in SEQ ID NO:2 in the sequence table basically, is used to cause the protective immune response at helicobacter pylori infection.
3. initiation comprises the claim 1 or 2 helicobacter pylori FlgE polypeptides that limit of immune significant quantity at the vaccine composition of the protective immune response of helicobacter pylori infection, can choose wantonly to comprise pharmaceutically acceptable carrier or thinner.
4. the vaccine composition of claim 3 also comprises adjuvant.
5. the vaccine composition of claim 4, wherein adjuvant is the Toxins,exo-, cholera of pharmaceutically acceptable form.
6. each vaccine composition is used as the therapeutic vaccine that the Mammals that has infected helicobacter pylori comprises the people in the claim 3 to 5.
7. each vaccine composition comprises that as the protection Mammals people avoids the preventative vaccine of helicobacter pylori infection in the claim 3 to 5.
8. claim 1 or 2 the purposes of helicobacter pylori FlgE polypeptide in the composition of production for treating, prevention or diagnosing helicobacter pylori infection.
9. claim 1 or 2 helicobacter pylori FlgE polypeptide are being produced the purposes that causes in the vaccine of the protective immune response of helicobacter pylori.
10. claim 1 or 2 the helicobacter pylori FlgE polypeptide purposes in the diagnostic kit of producing diagnosing helicobacter pylori infection.
11. the method for in-vitro diagnosis helicobacter pylori infection comprises at least one step, the helicobacter pylori FlgE polypeptides that wherein use claim 1 or 2 to limit, this polypeptide can choose wantonly with the solid phase carrier mark or with its coupling.
12. the method for claim 11 may further comprise the steps:
(a) described helicobacter pylori FlgE polypeptide is contacted with mammalian body fluid, described polypeptide can be chosen wantonly with solid phase carrier and combine; With
(b) antibody of detection and the described body fluid of described FlgE polypeptide bonded.
13. comprise among the people diagnostic kit that detects helicobacter pylori infection Mammals, comprise the composition that the method that makes claim 11 or 12 is carried out.
14. the diagnostic kit of claim 13 comprises:
(a) helicobacter pylori FlgE polypeptide: and
(b) reagent of detection and described FlgE polypeptide bonded antibody.
15. cause the method at the protective immune response of helicobacter pylori infection in Mammals, this method comprises claim 1 or 2 helicobacter pylori FlgE polypeptides that limit that give immune significant quantity to described Mammals.
16. cause the method at the protective immune response of helicobacter pylori infection in Mammals, this method comprises the vaccine composition that gives in the claim 3 to 7 of immune significant quantity each to described Mammals.
17. the method for claims 15 or 16, wherein said Mammals is the people.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE97022420 | 1997-06-12 | ||
SE9702242A SE9702242D0 (en) | 1997-06-12 | 1997-06-12 | Vaccine compositions V |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1259960A true CN1259960A (en) | 2000-07-12 |
Family
ID=20407351
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98806101A Pending CN1259960A (en) | 1997-06-12 | 1998-06-08 | Vaccine compositions comprising the helicobacter pylori FlgE polypeptide |
Country Status (21)
Country | Link |
---|---|
EP (1) | EP1009764A1 (en) |
JP (1) | JP2002507118A (en) |
KR (1) | KR20010013699A (en) |
CN (1) | CN1259960A (en) |
AR (1) | AR012896A1 (en) |
AU (1) | AU8048798A (en) |
BR (1) | BR9810026A (en) |
CA (1) | CA2293293A1 (en) |
EE (1) | EE9900566A (en) |
HU (1) | HUP0003164A3 (en) |
ID (1) | ID23052A (en) |
IL (1) | IL133144A0 (en) |
IS (1) | IS5288A (en) |
NO (1) | NO996132L (en) |
NZ (1) | NZ501427A (en) |
PL (1) | PL337503A1 (en) |
SE (1) | SE9702242D0 (en) |
SK (1) | SK173099A3 (en) |
TR (1) | TR199903060T2 (en) |
WO (1) | WO1998056816A1 (en) |
ZA (1) | ZA984696B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104784687A (en) * | 2015-04-27 | 2015-07-22 | 苏州大学附属第一医院 | Application of flagellar hook protein FlgE of reorganized pseudomonas aeruginosa |
CN113425717A (en) * | 2021-04-22 | 2021-09-24 | 成都欧林生物科技股份有限公司 | Medicament for improving efficacy of oral helicobacter pylori vaccine and application thereof |
CN116535472A (en) * | 2023-05-31 | 2023-08-04 | 四川大学华西医院 | Helicobacter pylori recombinant protein antigen FlgK, and preparation method and application thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5459041A (en) * | 1988-02-18 | 1995-10-17 | Enteric Research Laboratories, Inc. | Campylobacter pylori antigens and uses thereof for detection of Campylobacter pylori infection |
AR003125A1 (en) * | 1995-06-01 | 1998-07-08 | Astra Ab | BACTERIAL ANTIGENS FOR THE DIAGNOSIS OF INFECTIONS WITH HELICOBACTER PYLORI, A DNA MOLECLE THAT CODES IT, A VECTOR, A HOST CELL, A PROCEDURE FOR PRODUCING THE POLIPEPTIDE, USE OF ELEPIPETICO, AND PROAPILY USE |
-
1997
- 1997-06-12 SE SE9702242A patent/SE9702242D0/en unknown
-
1998
- 1998-06-01 AR ARP980102558A patent/AR012896A1/en unknown
- 1998-06-01 ZA ZA984696A patent/ZA984696B/en unknown
- 1998-06-08 BR BR9810026-2A patent/BR9810026A/en not_active IP Right Cessation
- 1998-06-08 NZ NZ501427A patent/NZ501427A/en unknown
- 1998-06-08 PL PL98337503A patent/PL337503A1/en unknown
- 1998-06-08 IL IL13314498A patent/IL133144A0/en unknown
- 1998-06-08 CN CN98806101A patent/CN1259960A/en active Pending
- 1998-06-08 ID IDW991542A patent/ID23052A/en unknown
- 1998-06-08 EP EP98928772A patent/EP1009764A1/en not_active Withdrawn
- 1998-06-08 HU HU0003164A patent/HUP0003164A3/en unknown
- 1998-06-08 JP JP50228399A patent/JP2002507118A/en active Pending
- 1998-06-08 TR TR1999/03060T patent/TR199903060T2/en unknown
- 1998-06-08 SK SK1730-99A patent/SK173099A3/en unknown
- 1998-06-08 EE EEP199900566A patent/EE9900566A/en unknown
- 1998-06-08 KR KR1019997011714A patent/KR20010013699A/en not_active Application Discontinuation
- 1998-06-08 WO PCT/SE1998/001093 patent/WO1998056816A1/en not_active Application Discontinuation
- 1998-06-08 CA CA002293293A patent/CA2293293A1/en not_active Abandoned
- 1998-06-08 AU AU80487/98A patent/AU8048798A/en not_active Abandoned
-
1999
- 1999-12-08 IS IS5288A patent/IS5288A/en unknown
- 1999-12-10 NO NO996132A patent/NO996132L/en not_active Application Discontinuation
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104784687A (en) * | 2015-04-27 | 2015-07-22 | 苏州大学附属第一医院 | Application of flagellar hook protein FlgE of reorganized pseudomonas aeruginosa |
CN113425717A (en) * | 2021-04-22 | 2021-09-24 | 成都欧林生物科技股份有限公司 | Medicament for improving efficacy of oral helicobacter pylori vaccine and application thereof |
CN116535472A (en) * | 2023-05-31 | 2023-08-04 | 四川大学华西医院 | Helicobacter pylori recombinant protein antigen FlgK, and preparation method and application thereof |
CN116535472B (en) * | 2023-05-31 | 2024-04-30 | 四川大学华西医院 | Helicobacter pylori recombinant protein antigen FlgK and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
WO1998056816A1 (en) | 1998-12-17 |
BR9810026A (en) | 2000-09-19 |
ID23052A (en) | 2000-01-20 |
AU8048798A (en) | 1998-12-30 |
IS5288A (en) | 1999-12-08 |
EE9900566A (en) | 2000-06-15 |
PL337503A1 (en) | 2000-08-28 |
SE9702242D0 (en) | 1997-06-12 |
AR012896A1 (en) | 2000-11-22 |
HUP0003164A2 (en) | 2000-12-28 |
TR199903060T2 (en) | 2000-09-21 |
CA2293293A1 (en) | 1998-12-17 |
NO996132L (en) | 2000-01-28 |
IL133144A0 (en) | 2001-03-19 |
KR20010013699A (en) | 2001-02-26 |
HUP0003164A3 (en) | 2001-10-29 |
ZA984696B (en) | 1999-01-04 |
NZ501427A (en) | 2000-09-29 |
EP1009764A1 (en) | 2000-06-21 |
SK173099A3 (en) | 2000-06-12 |
JP2002507118A (en) | 2002-03-05 |
NO996132D0 (en) | 1999-12-10 |
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