+

WO1999011284A1 - Vaccin oral - Google Patents

Vaccin oral Download PDF

Info

Publication number
WO1999011284A1
WO1999011284A1 PCT/GB1998/002631 GB9802631W WO9911284A1 WO 1999011284 A1 WO1999011284 A1 WO 1999011284A1 GB 9802631 W GB9802631 W GB 9802631W WO 9911284 A1 WO9911284 A1 WO 9911284A1
Authority
WO
WIPO (PCT)
Prior art keywords
urease
lactobacillus
nucleotide sequence
vaccine according
vaccine
Prior art date
Application number
PCT/GB1998/002631
Other languages
English (en)
Inventor
Soad Tabaqchali
Mark Wilks
Original Assignee
Queen Mary & Westfield College
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Queen Mary & Westfield College filed Critical Queen Mary & Westfield College
Priority to AU88779/98A priority Critical patent/AU8877998A/en
Publication of WO1999011284A1 publication Critical patent/WO1999011284A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/105—Delta proteobacteriales, e.g. Lawsonia; Epsilon proteobacteriales, e.g. campylobacter, helicobacter
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING OR TREATMENT THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
    • A23C9/123—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt
    • A23C9/1234—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt characterised by using a Lactobacillus sp. other than Lactobacillus Bulgaricus, including Bificlobacterium sp.
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING OR TREATMENT THEREOF
    • A23C2220/00—Biochemical treatment
    • A23C2220/20—Treatment with microorganisms
    • A23C2220/202—Genetic engineering of microorganisms used in dairy technology
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/523—Bacterial cells; Fungal cells; Protozoal cells expressing foreign proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates to modified Lactobacilli and their use in the treatment of gastric disorders.
  • Gastric disorders such as gastritis, peptic ulcer disease etc. have recently been discovered to be due to the presence of Helicobacter strains in the stomach, particularly Helicobacter pylori. Consequently, much effort has been invested in the research for agents that will minimise the effect of Helicobacter strains and specifically H. pylori.
  • Urease is the most prominent protein component of Helicobacter pylori and it has been proposed that urease is produced in order to hydrolyse urea thus increasing the pH of the environment to one favourable to colonisation by Helicobacter (Mobley HLT et al., Microbiol Rev (1995) 59 451-480).
  • the present invention therefore aims to provide a vaccine that is capable of delivering sufficient urease to the desired site such as to control/eradicate and/or prevent Helicobacter colonisation and thus treat Helicobacter related diseases.
  • the present invention relates to a vaccine comprising a Lactobacillus species that contains a nucleotide sequence that encodes a urease peptide capable of initiating an anti-urease humoral and/or cellular immune response upon administration to a mammalian species, preferably initiating the production of secretory IgA.
  • Suitable Lactobacillus species include any species or subspecies such as Lactobacillus delbrueckii and subspecies bulgaricus and lactis, Lactobacillus GG, a strain of L casei subspecies rhamnosus (Goldin et al., (1992) Dig Dis and Sciences 3_7 121-128), L fermentum, L. planatarum, L paraplantarum. L pentosus, L corvniformis. L casei, L paracasei, L brevis, L leichmannu and strains of Lactobacillus isolated from intestinal flora such as Lactobacillus rhamnosus 901.
  • Lactobacillus rhamnosus 901 is of particular benefit as it possesses resistance to both acid and bile juices.
  • the Lactobacillus spp is been modified such that the organism contains a nucleotide sequence either on a plasmid or in a chromosome capable of expressing a urease peptide as defined above.
  • the Lactobacillus strain used is L. planatarum. More preferably, the strain of L. planatarum is selected from L. planatarum NCIMB 8826, NC4Tsl, NC7Ts5 or ATCC 8014, most preferably the NCIMB strain 8826 of L. planatarum is used.
  • Urease is a protein that is encoded by an array of genes that are comprised of structural, accessory and regulatory subunits. These are all required in order to produce a biologically active enzyme, for example certain subunits are involved with the incorporation of nickel into the protein structure that is essential for enzymatic activity. As discussed below, the retention of enzymatic activity is not essential for the purposes of the present invention.
  • nucleotide sequences of use in the present invention must encode at least a fragment of urease capable of initiating an anti-urease humoral and/or cellular immune response upon administration to a mammalian species.
  • an immune response is defined herein as the ability to initiate the production of anti-urease antibodies, in particular systemic and local IgA, detectable by methods known in the art, preferably by ELISA.
  • Suitable nucleotide sequences that are able to express a urease peptide capable of initiating a anti-urease humoral and/or cellular immune response include those that encode the whole urease protein, fragments thereof, homologs or analogs thereof.
  • Helicobacter spp ureA peptide represents a fusion of ureA and ureB peptides in other microorganisms whereas the Helicobacter spp UreB peptide and H pylori UreH peptide are homologous to UreC and UreD peptides in other bacteria.
  • Mobley HLT et al., Microbiol Revs, (1995), vol 59, pages 451-480 provides a detailed description of known urease sequences and any of these sequences in whole or part that is capable of initiating an anti-urease immune response as defined above, may be used in the present invention.
  • a non-exhaustive list of nucleotide sequences encoding urease is given in Table 1. As used hereinafter, all reference to urease subunits relate to the nomenclature used for H. pylori in Clayton CL et al. (supra .
  • nucleotide sequences of use in the present invention may be used alone or as part of a larger sequence encoding a fusion protein comprising a urease moiety or peptides homologous with urease.
  • urease B subunit may be expressed as a chimeric protein together with the cholera toxin B subunit by the insertion into a Lactobacillus spp of the urease B subunit nucleotide sequence linked to the cholera toxin B subunit nucleotide sequence.
  • nucleotide sequences that are homologous to a known urease encoding sequence may be used in the present invention.
  • a sequence bears at least 70% homology to the H. pylori nucleotide sequence, more preferably at least 80% and most preferably at least 90 or 95% homology.
  • urease such as that encoding for jack bean urease bears about 70% homology with H pylori urease.
  • nucleotide sequence derived from H. pylori
  • suitable nucleotide sequences include other Helicobacter species such as H felis, H heilmannii or Morganella morganii.
  • the nucleotide sequence encodes for at least the urease A or B subunits or A and B subunits. More preferably the nucleotide sequence encodes for at least the urease B subunit.
  • the urease peptide may possess urease activity or alternatively be devoid of such activity.
  • the nucleotide sequence may be inserted into the Lactobacillus genome or Lactobacillus plasmid as a single entity or in clusters linked together such as to produce a multimeric protein comprising for example, from two to eight urease A subunits and from two to eight urease B subunits.
  • a multimeric protein comprising for example, from two to eight urease A subunits and from two to eight urease B subunits.
  • they may be inserted in equal or unequal numbers.
  • the appropriate nucleotide sequence capable of expressing a urease peptide may be amplified and isolated from a suitable source using PCR, fused with a Lactobacillus or Lactococcus promoter, ligated into a vector, plasmid or transposon such as Tn916 and then introduced into the Lactobacillus strain by for example, electroporation.
  • the transformed Lactobacillus may be used directly in the vaccine composition.
  • an advantage of the present invention is that the vaccine is easily prepared not requiring the lengthy purification involved when handling recombinant proteins.
  • the vaccine may be given alone or preferably included in foodstuffs that already contain a Lactobacillus spp such as yoghurt, fermented milk drink or cheese etc. as the sole source of Lactobacillus or in addition to the existing strains.
  • the vaccines of the present invention may be used in the treatment of gastrointestinal (duodenal) disorders including gastritis, peptic ulcer disease including both gastric and duodenal ulcers, gastric cancer, chronic dyspepsia with severe erosive gastroduodenitis, refractory ulcer dyspepsia, intestinal metaplasia, low grade MALT lymphoma, Helicobacter infection, Helicobacter pylori infection and Helicobacter felis infection.
  • gastrointestinal (duodenal) disorders including gastritis, peptic ulcer disease including both gastric and duodenal ulcers, gastric cancer, chronic dyspepsia with severe erosive gastroduodenitis, refractory ulcer dyspepsia, intestinal metaplasia, low grade MALT lymphoma, Helicobacter infection, Helicobacter pylori infection and Helicobacter felis infection.
  • the vaccines may further contain pharmaceutically acceptable excipients such as adjuvants, solvents, preservatives, stabilisers and the like. Furthermore, the vaccine may additionally contain other pharmacologically active ingredients such as antibiotics, antisecretory agents and bismuth salts.
  • a further aspect of the present invention relates to transformed Lactobacillus spp. containing a nucleotide sequence that encodes a urease peptide as defined above capable of initiating an anti-urease cellular and/or humoral immune response upon administration to a mammalian species.
  • the vaccine may be administered by methods known in the art. Thus it may be given by intravenous (I.V.), intramuscular (I.M.), subcutaneous (S.C.), intradermal (I.D.) or oral routes and the like.
  • the dose is administered at least once. Subsequent doses may be administered as indicated.
  • the vaccine may be administered orally. This advantage is assisted by the incorporation of Lactobacillus spp being incorporated into foodstuffs as discussed above.
  • Administration of the vaccine may involve a priming dose, optionally by an alternative route to the main dosage. For example, when the vaccine is to be adminstered orally, a subcutaneous priming dosage may be administered.
  • the dosage will vary depending upon such factors as the mammal's age, weight, height, sex, general medical condition, previous medical history, disease progression and the like.
  • L. plantarum NCIMB strain 8826 was readily transformed by electroporation using a variety of plasmids including pNZ12, pNZ17, pNZlO ⁇ l, pTG3237 (all obtained from Netherlands Institute for Dairy Research (NIZO), Bostbus 20, 6710
  • Optimum recovery of plasmid DNA was achieved with Lactobacillus plantarum strain NCIMB 8826 and the vector pNZlOc ⁇ . 13 ⁇ g DNA/ 100 ml culture is recovered using a modification of the method suggested by Frere (Letters in Applied Microbiology 18 227-9). In this modification, cell suspensions are incubated at 37°C for one hour and then vortexed for 1 min with an equal volume of glass beads (0.1-0.15 mm diameter) to disrupt the cell wall.
  • Example 2 Colonisation studies of Lactobacillus spp in BALB/c mice. Results and approach using Lactobacillus plantarum strain NCIMB 8826 and the vector pNZ17
  • mice 9 BALB/c mice are divided into 3 groups and fed with pNZ17-transformed Lactobacilli.
  • Transformants of Lactobacillus GG, Lactobacillus Sp. 901, and L. planatarum 8826 containing pNZ17 are prepared as described in Example 1, and then cultured in skimmed milk.
  • a single colony of each species of Lactobacilli is transferred into 100 ml of MRS (de Man, Rogosa & Sharpe) broth containing chloramphenicol 20 ⁇ g/ml, respectively. The cultures are incubated overnight at 37°C without shaking. Bacterial suspensions are harvested by centrifugation at 5,000g for 15 min at room temperature, the supernatant decanted and the bacterial pellet resuspended in 20 ml of skimmed milk.
  • MRS de Man, Rogosa & Sharpe
  • Viable counts of each strain are prepared by pipetting lOO ⁇ l of each bacterial suspension in 900 ⁇ l MRS broth and then making serial 10-fold dilution. lOO ⁇ l of each dilution is plated onto MRS agar plates and the number of colonies counted after 48 hours of incubation at 37°C.
  • Lactobacilli in skimmed mik were: Lactobacillus GG: 3 x 10 8 cfu/ml - 2 x 10 9 cfu/ml, Lactobacillus 901 : 2 x 10 9 cfu/ml,
  • Lactobacillus plantarum NCIMB 8826 3 x 10 9 cfu/ml.
  • mice are fed 1 ml of lactobacilli-rnilk twice daily for 18 days and faeces collected three times a week for culture on MRS agar plates with and without chloramphenicol 20 ⁇ g/ml.
  • Lactobacilli is detected in the faeces of all mice at high concentrations
  • Lactobacillus GG not detected Lactobacillus Sp. 901 not detected
  • Lactobacillus plantarum 8826 still detectable at a concentration of 7 x 10 2 cfu/g
  • Lactobacillus 901 1.35x10- cfu/g caecum 2.6 x 10 ⁇ cfu/g colon
  • Urease DNA encoding the structural subunits of urease gene, ureA and ureB (Clayton CL supra) is amplified by use of the polymerase chain reaction using Pfu Taq polymerase to ensure error free amplification.
  • the primers used are; YR1 : 5 * AAGGAT TTAAGGAGCGTTGC 3 and, YR2 : 5' GATTTCGTTATGTCTTCAAGG 3'
  • plasmid pTCP3 containing a 2.6kb insert encoding both the 66kDa ureB and 31kDa ureA subunits is used (Clayton CL et al and Infect Immun (1989) 57(2), 623-629). If so, pTCP3 is prepared by transformation into E. coli JM109 and digested using Taql to release the urease encoding fragment.
  • pNZ10 ⁇ 5 carries the amyS gene fused to part of the L. lactis promoter gene usp45 gene (van Asseldonk et al 1993 Molecular and General Genetics 240, 428-
  • a secretion plasmid containing translational fusions between usp45 from Lactococcus lactis and the ureA+B or ureB gene is constructed. This encodes a highly secreted protein which maximises exposure to the host's mucosal immune system.
  • Fusion expression is driven by the promoter (-35 and -10) sequences of usp45, its ribosome binding site, translational start site and signal peptide (27 aa from ATG to Ala 27 which is the cleavage site).
  • pNZ10 ⁇ 5 is cut with Pstl and Hindlll to provide the first 57bp (19 first aa) of the signal sequence.
  • a synthetic linker containing the final 24bp (8 aa) of the signal sequence and a restriction site is inserted into which the ureA and ureB or ureB only gene derived from PCR products or pTCP3 are cloned.
  • Anti-urease antibodies is detected in the sera of H pylori infected animals by ELISA as described in Tanaka K et al, Gut (1991) 32, 43-45.
  • Microtest III plates (Becton-Dickinson) are coated with urease at a concentration of 0.04 mg/ml in carbonate bicarbonate buffer pH 9.6. The plates are incubated overnight at 4°C and then washed three times with phosphate buffered saline (PBS) pH 7.4 containing 0.05% (v/v) Tween20 (PBS/T20).
  • Bovine serum albumin (l%w/v) Sigma
  • PBS/BSA Bovine serum albumin
  • Plates are incubated for two hours at room temperature, washed three times with PBS/T20, and stored at -20°C until needed.
  • lOO ⁇ l of mouse serum is diluted 1 :50 with PBS/BSA and added to the wells. After incubation overnight at 4°C, the plates were washed three times with PBS/T20.
  • lOO ⁇ l of anti-mouse IgG conjugate diluted according to the manufacturer's instruction is added to the wells. The plates are incubated for two hours at room temperature and washed three times with PBS/T20.
  • Highly pure urease for coating the wells may be obtained from H. pylori using the methods described in Icatlo FC et al, J Biol Chem (1998) 273(29), 18130-18138.
  • Western blotting is performed as in Tanaka K et al., supra with the modification that whole cell preparation of the Helicobacter pylori NCTC 11637 or 630 is used.
  • the protein concentration is determined by a modified Lowry technique, protein dissolved in 10% sodium dodecyl sulphate and approximately 25 ⁇ g of total protein is loaded in each lane and electrophoresed in a Hoefer Transblotter in a discontinuous buffer system at a constant current of 15 mA. Mice sera from vaccinated animals is diluted and tested at dilutions of 1/25 and 1/50.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Mycology (AREA)
  • General Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention se rapporte à un vaccin contenant une espèce Lactobacillus qui renferme une séquence nucléotidique codant une uréase peptide susceptible de déclencher une réponse immunitaire humorale anti-uréase et/ou une réponse immunitaire cellulaire après administration de ce vaccin à une espèce mammifère.
PCT/GB1998/002631 1997-09-02 1998-09-02 Vaccin oral WO1999011284A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU88779/98A AU8877998A (en) 1997-09-02 1998-09-02 Oral vaccine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9718616.7A GB9718616D0 (en) 1997-09-02 1997-09-02 Oral vaccine
GB9718616.7 1997-09-02

Publications (1)

Publication Number Publication Date
WO1999011284A1 true WO1999011284A1 (fr) 1999-03-11

Family

ID=10818424

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1998/002631 WO1999011284A1 (fr) 1997-09-02 1998-09-02 Vaccin oral

Country Status (3)

Country Link
AU (1) AU8877998A (fr)
GB (1) GB9718616D0 (fr)
WO (1) WO1999011284A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1084709A1 (fr) * 1999-09-17 2001-03-21 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Vaccin oral contenant des Lactobacilli recombinés
WO2005040387A1 (fr) * 2003-10-28 2005-05-06 Friesland Brands B.V. Production et/ou administration intestinale specifique de site de substances actives
KR102390694B1 (ko) * 2021-07-13 2022-04-29 한국식품연구원 락티플란티바실러스 파라플란타룸 WiKim0130을 포함하는 암의 예방, 개선 또는 치료용 조성물

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994016086A1 (fr) * 1992-12-30 1994-07-21 Bioteknologisk Institut Bacterie d'acide lactique recombinee contenant un promoteur insere, et son procede de construction
EP0654273A1 (fr) * 1993-11-18 1995-05-24 Harry H. Leveen Produit pharmaceutique et méthode pour traitement
WO1996033732A1 (fr) * 1995-04-28 1996-10-31 Oravax, Inc. Vaccin d'urease recombinante et multimere

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994016086A1 (fr) * 1992-12-30 1994-07-21 Bioteknologisk Institut Bacterie d'acide lactique recombinee contenant un promoteur insere, et son procede de construction
EP0654273A1 (fr) * 1993-11-18 1995-05-24 Harry H. Leveen Produit pharmaceutique et méthode pour traitement
WO1996033732A1 (fr) * 1995-04-28 1996-10-31 Oravax, Inc. Vaccin d'urease recombinante et multimere

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
POUWELS P.H. ET AL.: "The potential of Lactobacillus as a carrier for oral immunisation: development and preliminary characterisation of vector systems for targeted delivery of antigens", JOURN. BIOTECHNOL., vol. 44, 1996, AMSTERDAM, nl, pages 183 - 192, XP000572655 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1084709A1 (fr) * 1999-09-17 2001-03-21 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Vaccin oral contenant des Lactobacilli recombinés
WO2001021200A1 (fr) * 1999-09-17 2001-03-29 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Vaccins oraux a base de lactobacilles recombinees
WO2005040387A1 (fr) * 2003-10-28 2005-05-06 Friesland Brands B.V. Production et/ou administration intestinale specifique de site de substances actives
KR102390694B1 (ko) * 2021-07-13 2022-04-29 한국식품연구원 락티플란티바실러스 파라플란타룸 WiKim0130을 포함하는 암의 예방, 개선 또는 치료용 조성물
WO2023287202A1 (fr) * 2021-07-13 2023-01-19 한국식품연구원 Composition pour la prévention, la réduction ou le traitement du cancer, comprenant du lactiplantibacillus paraplantarum wik130

Also Published As

Publication number Publication date
AU8877998A (en) 1999-03-22
GB9718616D0 (en) 1997-11-05

Similar Documents

Publication Publication Date Title
Wells et al. Lactic acid bacteria as vaccine delivery vehicles
Reveneau et al. Comparison of the immune responses induced by local immunizations with recombinant Lactobacillus plantarum producing tetanus toxin fragment C in different cellular locations
Nouaille et al. Heterologous protein production and delivery systems for Lactococcus lactis
AU767143B2 (en) Lactobacilli harboring aggregation and mucin binding genes as vaccine delivery vehicles
US6221648B1 (en) Heterologous gene expression in lactococcus, and the expression products therefrom
Mercenier et al. Lactic acid bacteria as live vaccines
EP1789094B1 (fr) Vecteur d'administration bactérien
US7700104B2 (en) Attenuated Salmonella SP12 mutants as antigen carriers
JP2003509469A (ja) 経口用組換え乳酸桿菌ワクチン
Cárdenas et al. Stability, immunogenicity and expression of foreign antigens in bacterial vaccine vectors
JPH05192161A (ja) 安定ｐｕｒＡベクターおよびそれらの使用
AU2001297770A1 (en) Use of CLyA hemolysin for excretion of fusion proteins
EP1412502A2 (fr) Utilisation de l'hemolysine clya pour permettre l'excretion de proteines
WO2010061226A1 (fr) Composition et procédé pour la sécrétion augmentée de peptides et de protéines depuis des bactéries
US9187754B2 (en) Modified Bordetella pertussis strains
JP2000513203A (ja) ヘリコバクター・ピロリからの新規アドヘシン
EP0931093B1 (fr) Vaccin vivant contre helicobacter pylori
JPH09508012A (ja) 表面層タンパク質の発現
AU2010265799A1 (en) Synthetic operon
EP1490473A1 (fr) Spores bacteriennes
Wells et al. Progress in the development of mucosal vaccines based on Lactococcus lactis
CA2726293C (fr) Clya non hemolytique pour l'excretion de proteines
WO1999011284A1 (fr) Vaccin oral
Kajikawa et al. Development of a highly efficient protein-secreting system in recombinant Lactobacillus casei
CN113330119A (zh) 使用源自干酪乳杆菌的半乳糖变旋酶基因启动子用于组成型高表达的表面表达载体及其用途

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1999516459

Format of ref document f/p: F

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载