WO1994018997A1 - Method of enhancing immune response to oral vaccines - Google Patents

Method of enhancing immune response to oral vaccines Download PDF

Info

Publication number
WO1994018997A1
WO1994018997A1 PCT/US1994/001764 US9401764W WO9418997A1 WO 1994018997 A1 WO1994018997 A1 WO 1994018997A1 US 9401764 W US9401764 W US 9401764W WO 9418997 A1 WO9418997 A1 WO 9418997A1
Authority
WO
WIPO (PCT)
Prior art keywords
bacteria
vaccine
immune response
lactobacillus
immunoadjuvant
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1994/001764
Other languages
French (fr)
Inventor
Sherwood L. Gorbach
Erika Isolauri
Seppo J. Salminen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Valio Oy
Original Assignee
Valio Oy
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21806215&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1994018997(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Valio Oy filed Critical Valio Oy
Priority to EP94909696A priority Critical patent/EP0686039B1/en
Priority to AU62440/94A priority patent/AU6244094A/en
Publication of WO1994018997A1 publication Critical patent/WO1994018997A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • 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
    • C12N1/00—Microorganisms; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55588—Adjuvants of undefined constitution
    • A61K2039/55594—Adjuvants of undefined constitution from bacteria
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus

Definitions

  • the present invention relates to methods of enhancing immune response to oral vaccines.
  • oral vaccines have inadequate immuno-genicity to ensure immunization with a single dose, particularly when administered to children.
  • a number of chemical substances have been used as immunoadjuvants, i.e., substances that are administered with a vaccine to enhance cell-mediated immunity or to increase the humoral response to the immunogen used for vaccination. These substances have traditionally not been used with oral vaccines because they may cause undesirable side effects or are not suitable for oral administration.
  • immunoadjuvant refers to substances which enhance the immune response to a vaccine.
  • the invention features a method of enhancing the immune response to an oral vaccine of a recipient of the vaccine.
  • an immunoadjuvant comprising an effective amount of a strain of Lactobacillus bacteria is administed to the recipient, with the oral vaccine or close enough in time to bring about immune response enhancement.
  • the Lactobacillus bacteria are able to survive at low pH and produce large amounts of an antimicrobial substance.
  • Preferred strains having these properties are described in U.S. 4,839,281 and 5,032,399, the disclosures of which are incorporated herein by reference.
  • Preferred bacteria are able to colonize the intestinal tract, as evidenced by the presence of the bacteria in the feces of the subject after oral administration, and preferably also have substantially the same properties exhibited by the Lactobacillus bacteria deposited in the American Type Culture Collection and given ATCC Accession No. 53103. Most preferably, the Lactobacillus bacteria is Lactobacillus Strain GG.
  • the immunoadjuvant is administered in a pharmaceutically acceptable carrier, e.g., a fermented dairy product or a culture-containing powder, capsule or tablet.
  • the Lactobacillus bacteria is preferably coadministered to the person given the vaccine, then administered alone to the person for a period of one or more days after administration of the vaccine.
  • the immunoadjuvant of the invention enhances immunity after administration of an oral vaccine.
  • the immunoadjuvant may allow immunity to be obtained from a single dose of an oral vaccine which, due to its characteristics or other factors, would otherwise require multiple doses, or may enhance the immune response to an oral vaccine.
  • Al ⁇ o as the
  • Lactobacillus bacteria is a harmless naturally occurring substance, present in, e.g., yogurt, it produces no significant harmful side effects.
  • Lactobacillus Strain GG refers to a particular strain of Lactobacillus bacteria, a lactic acid bacteria. This strain is described in U.S. Patent Nos. 4,839,281 and 5,032,399, incorporated above by reference.
  • the GG strain has been deposited in the American Type Culture Collection (ATCC) , Rockville, Mass., and has been given ATCC Accession No. 53103. Lactobacillus Strain GG may be cultured on any appropriate sterilized fermentation medium.
  • a cryoprotectant e.g. monosodium glutar ⁇ ate sodium ascorbate, saccharose or lactose, be added to the cells after culturing.
  • the Lactobacillus Strain GG bacteria is administered in an amount which is sufficient to colonize the intestinal tract of the patient.
  • a dosage of at least 10 8 cfu, preferably 10 8 to 10 10 cfu, is generally adequate for mo ⁇ t patients. Dosages of 10 10 cfu are likely to completely colonize the intestinal tract of sub ⁇ tantially all patient ⁇ . Higher dosages may be administered, if desired, but dosages above about 5xl0 10 cfu typically require impractically large volumes of the bacteria-containing material to be administered.
  • the bacteria be administed to the patient over a ⁇ erie ⁇ of days, with the preferred dosage (above) given on each day.
  • the bacteria i ⁇ fir ⁇ t coadministered with the vaccine then administered alone for a period of 1 to 4 day ⁇ , preferably 2 days, after admini ⁇ tration of the vaccine. It ha ⁇ been found that this cour ⁇ e of treatment provides optimal enhancement of the immune response.
  • the bac eria may be mixed with a pharmaceutically acceptable carrier or a food product, for ease of administration.
  • a pharmaceutically acceptable carrier or a food product for ease of administration.
  • the bacteria may be provided in the form of a powder.
  • the bacteria may be provided in tablet or capsule form, as a freeze-dried powder which may be mixed with food or drink, or in any other suitable form.
  • the bacteria may also be provided in the form of a actoJacillus-containing cultured dairy product, provided the product contains an effective amount of the bacteria.
  • Oral vaccines which are suitable for use in the invention include, but are not limited to, vaccines for rotaviru ⁇ , typhoid, cholera, adenoviru ⁇ , polio, E. coli and the like.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Mycology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

The invention features a method of enhancing immune response to an oral vaccine of a recipient of the vaccine by administering, with the oral vaccine or close enough in time to bring about immune response enhancement, an immunoadjuvant comprising an effective amount of a strain of Lactobacillus bacteria that has the ability to colonize the intestinal tract of the recipient, preferably Lactobacillus Strain GG.

Description

METHOD OF ENHANCING IMMUNE RESPONSE TO ORAL VACCINES Background of the Invention The present invention relates to methods of enhancing immune response to oral vaccines.
The development of oral vaccines offers great promise in the prevention of disease world-wide. Vaccines which successfully immunize after a single dose are preferred as they eliminate the problems associated with making sure that each subject receives the proper number of subsequent doses.
However, some oral vaccines have inadequate immuno-genicity to ensure immunization with a single dose, particularly when administered to children. A number of chemical substances have been used as immunoadjuvants, i.e., substances that are administered with a vaccine to enhance cell-mediated immunity or to increase the humoral response to the immunogen used for vaccination. These substances have traditionally not been used with oral vaccines because they may cause undesirable side effects or are not suitable for oral administration.
The term "immunoadjuvant", as used herein, refers to substances which enhance the immune response to a vaccine.
Summary of the Invention The invention features a method of enhancing the immune response to an oral vaccine of a recipient of the vaccine. To enhance the immune response, an immunoadjuvant comprising an effective amount of a strain of Lactobacillus bacteria is administed to the recipient, with the oral vaccine or close enough in time to bring about immune response enhancement. Preferably, the Lactobacillus bacteria are able to survive at low pH and produce large amounts of an antimicrobial substance. Preferred strains having these properties are described in U.S. 4,839,281 and 5,032,399, the disclosures of which are incorporated herein by reference. Preferred bacteria are able to colonize the intestinal tract, as evidenced by the presence of the bacteria in the feces of the subject after oral administration, and preferably also have substantially the same properties exhibited by the Lactobacillus bacteria deposited in the American Type Culture Collection and given ATCC Accession No. 53103. Most preferably, the Lactobacillus bacteria is Lactobacillus Strain GG. In other preferred embodiments, the immunoadjuvant is administered in a pharmaceutically acceptable carrier, e.g., a fermented dairy product or a culture-containing powder, capsule or tablet. For optimal enhancement of the immune response, the Lactobacillus bacteria is preferably coadministered to the person given the vaccine, then administered alone to the person for a period of one or more days after administration of the vaccine.
Advantageously, the immunoadjuvant of the invention enhances immunity after administration of an oral vaccine. The immunoadjuvant may allow immunity to be obtained from a single dose of an oral vaccine which, due to its characteristics or other factors, would otherwise require multiple doses, or may enhance the immune response to an oral vaccine. Alεo, as the
Lactobacillus bacteria is a harmless naturally occurring substance, present in, e.g., yogurt, it produces no significant harmful side effects. Other features and advantages of the invention will be apparent from the description of the preferred embodiment thereof, and from the claims.
Detailed Description of the Preferred Embodiment The term "Lactobacillus Strain GG" as used herein refers to a particular strain of Lactobacillus bacteria, a lactic acid bacteria. This strain is described in U.S. Patent Nos. 4,839,281 and 5,032,399, incorporated above by reference. The GG strain has been deposited in the American Type Culture Collection (ATCC) , Rockville, Mass., and has been given ATCC Accession No. 53103. Lactobacillus Strain GG may be cultured on any appropriate sterilized fermentation medium. When the Lactobacillus Strain GG is to be freeze-dried prior to addition to the vaccine, it is preferred that a cryoprotectant, e.g. monosodium glutarαate sodium ascorbate, saccharose or lactose, be added to the cells after culturing.
The Lactobacillus Strain GG bacteria is administered in an amount which is sufficient to colonize the intestinal tract of the patient. A dosage of at least 108 cfu, preferably 108 to 1010 cfu, is generally adequate for moεt patients. Dosages of 1010 cfu are likely to completely colonize the intestinal tract of subεtantially all patientε. Higher dosages may be administered, if desired, but dosages above about 5xl010 cfu typically require impractically large volumes of the bacteria-containing material to be administered.
It is preferred that the bacteria be administed to the patient over a εerieε of days, with the preferred dosage (above) given on each day. Preferably, the bacteria iε firεt coadministered with the vaccine, then administered alone for a period of 1 to 4 dayε, preferably 2 days, after adminiεtration of the vaccine. It haε been found that this courεe of treatment provides optimal enhancement of the immune response.
The bac eria may be mixed with a pharmaceutically acceptable carrier or a food product, for ease of administration. For infants and small children, it is generally preferable to provide the bacteria in the form of a powder. For other patients, the bacteria may be provided in tablet or capsule form, as a freeze-dried powder which may be mixed with food or drink, or in any other suitable form. The bacteria may also be provided in the form of a actoJacillus-containing cultured dairy product, provided the product contains an effective amount of the bacteria.
Oral vaccines which are suitable for use in the invention include, but are not limited to, vaccines for rotaviruε, typhoid, cholera, adenoviruε, polio, E. coli and the like.
Preferred embodiments of the invention have been described herein. Other variations and modifications are within the scope of the invention and claims.

Claims

1. A method of enhancing the immune response to an oral vaccine of a recipient of the vaccine comprising the step of administering, with the oral vaccine or close enough in time to bring about immune response enhancement, an immunoadjuvant comprising an effective amount of a strain of Lactobacillus bacteria that has the ability to colonize the intestinal tract of the recipient.
2. The method of claim 1 wherein the
Lactobacillus bacteria is a strain in which the bacteria have substantially the same properties exhibited by the Lactobacillus bacteria deposited in the American Type Culture Collection and given ATCC Accession No. 53103.
3. The method of claim 2 wherein the
Lactobacillus bacteria is Lactobacillus Strain GG.
4. The method of claim 1 wherein the immunoadjuvant is administered in a pharmaceutically acceptable carrier.
5. The method of claim 4 wherein the carrier is a fermented dairy product.
6. A method of claim 4 wherein the carrier is a culture-containing powder, capsule or tablet.
7. The method of claim 1 wherein the immunoadjuvant is coadministered to the patient with the vaccine, then administered alone to the patient for a period of one or more dayε after administration of the vaccine.
8. The method of claim 1 wherein the bacteria is administered in a dosage of at leaεt 108 cfu.
9. The method of claim 8 wherein each administration of the immunoadjuvant contains a dosage of at leaεt 108 cfu of the bacteria.
PCT/US1994/001764 1993-02-24 1994-02-23 Method of enhancing immune response to oral vaccines Ceased WO1994018997A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP94909696A EP0686039B1 (en) 1993-02-24 1994-02-23 Method of enhancing immune response to oral vaccines
AU62440/94A AU6244094A (en) 1993-02-24 1994-02-23 Method of enhancing immune response to oral vaccines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2179893A 1993-02-24 1993-02-24
US08/021,798 1993-02-24

Publications (1)

Publication Number Publication Date
WO1994018997A1 true WO1994018997A1 (en) 1994-09-01

Family

ID=21806215

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/001764 Ceased WO1994018997A1 (en) 1993-02-24 1994-02-23 Method of enhancing immune response to oral vaccines

Country Status (4)

Country Link
EP (1) EP0686039B1 (en)
AU (1) AU6244094A (en)
CA (1) CA2156859A1 (en)
WO (1) WO1994018997A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998006411A3 (en) * 1996-08-09 1998-05-07 Dicofarm Spa Use of lactobacillus gg in the rehydrating solution
WO1999010476A1 (en) 1997-08-21 1999-03-04 New Zealand Dairy Board Immunity enhancing lactic acid bacteria
US5935601A (en) * 1994-04-22 1999-08-10 Emisphere Technologies, Inc. Modified amino acids for drug delivery
WO2000007571A3 (en) * 1998-08-06 2000-05-11 Helmut Viernstein Formulations having probiotically active microorganisms
US7417022B2 (en) 1996-03-29 2008-08-26 Mhr Institutional Partners Iia Lp Compounds and compositions for delivering active agents
US7553872B2 (en) 1997-02-07 2009-06-30 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4238478A (en) * 1977-12-23 1980-12-09 Ljubinko Stojkovic Heterovaccine against the trichomonas syndrome, and process for its preparation
US4397838A (en) * 1978-12-19 1983-08-09 Pierre Fabre S.A. Preparations of purified bacterial membranal proteoglycans
US4839281A (en) * 1985-04-17 1989-06-13 New England Medical Center Hospitals, Inc. Lactobacillus strains and methods of selection
US5185321A (en) * 1989-12-13 1993-02-09 Nestec S.A. Process for producing immunostimulants

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4238478A (en) * 1977-12-23 1980-12-09 Ljubinko Stojkovic Heterovaccine against the trichomonas syndrome, and process for its preparation
US4397838A (en) * 1978-12-19 1983-08-09 Pierre Fabre S.A. Preparations of purified bacterial membranal proteoglycans
US4839281A (en) * 1985-04-17 1989-06-13 New England Medical Center Hospitals, Inc. Lactobacillus strains and methods of selection
US5032399A (en) * 1985-04-17 1991-07-16 Sherwood L. Gorbach L. acidophilus strains
US5185321A (en) * 1989-12-13 1993-02-09 Nestec S.A. Process for producing immunostimulants

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
Agric. Biol. Chem., Volume 48, No. 7, issued 1984, S. KAWATA et al.: "Preparation of Disaccharide Peptides with Immunostimulation from Microbial Cell Walls", pages 1783-1793. *
Biken Journal, Volume 18, No. 2, issued June 1975, S. KOTANI et al.: "Immunoadjuvant Activities of Peptidoglycan Subunits from the Cell Walls of Staphylococcus Aureus and Lactobacillus Plantarum", pages 93-103. *
Journal of Dairy Research, Volume 58, No. 4, issued 1991, G. PERDIGON et al.: "Immunoadjuvant Activity of Oral Lactobacillus Casei: Influence of Dose on the Secretory Immune Response and Protective Capacity in Intestinal Infections", pages 485-496, especially pages 486 and 495. *
Journal of Food Protection, Volume 53, No. 5, issued May 1990, G. PERDIGON et al.: "The Oral Administration of Lactic Acid Bacteria Increase the Mucosal Intestinal Immunity in Response to Enteropathogens", pages 404-410, entire document. *
Pediatric Research, Volume 32, No. 2, issued 1992, M. KAILA et al.: "Enhancement of the Circulating Antibody Secreting Cell Response in Human Diarrhea by a Human Lactobacillus Strain", pages 141-144, entire document. *
Res. Microbiol., Volume 141, issued 1990, K. GERRITSE et al.: "Oral Administration of TNP-Lactobacillus Conjugates in Mice: A Model for Evaluation of Mucosal and Systemic Immune Responses and Memory Formation Elicited by Transformed Lactobacilli", pages 955-962. *
See also references of EP0686039A4 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5935601A (en) * 1994-04-22 1999-08-10 Emisphere Technologies, Inc. Modified amino acids for drug delivery
US7417022B2 (en) 1996-03-29 2008-08-26 Mhr Institutional Partners Iia Lp Compounds and compositions for delivering active agents
WO1998006411A3 (en) * 1996-08-09 1998-05-07 Dicofarm Spa Use of lactobacillus gg in the rehydrating solution
US7553872B2 (en) 1997-02-07 2009-06-30 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
WO1999010476A1 (en) 1997-08-21 1999-03-04 New Zealand Dairy Board Immunity enhancing lactic acid bacteria
GB2338245A (en) * 1997-08-21 1999-12-15 New Zealand Dairy Board Immunity enhancing lactic acid bacteria
GB2338245B (en) * 1997-08-21 2001-11-21 New Zealand Dairy Board Immunity enhancing lactic acid bacteria
US6379663B1 (en) 1997-08-21 2002-04-30 New Zealand Dairy Board Immunity enhancing lactic acid bacteria
WO2000007571A3 (en) * 1998-08-06 2000-05-11 Helmut Viernstein Formulations having probiotically active microorganisms

Also Published As

Publication number Publication date
EP0686039A1 (en) 1995-12-13
CA2156859A1 (en) 1994-09-01
AU6244094A (en) 1994-09-14
EP0686039B1 (en) 2000-08-23
EP0686039A4 (en) 1997-07-02

Similar Documents

Publication Publication Date Title
EP0199535B1 (en) Lactobacillus acidophilus strains of bacteria and compositions thereof
AU673525B2 (en) Lactic acid bacterium
Kohwi et al. Antitumor effect of Bifidobacterium infantis in mice
EP0923293B1 (en) Treatment of diarrhea
RU2279282C2 (en) Agent for prophylaxis and/or treatment of undesired inflammation activity and cancer prophylaxis
Havenaar et al. Probiotics: a general view
KR100333113B1 (en) Treatment of h. pylori associated gastroduodenal disease
JP2004536106A5 (en)
JPH10309178A (en) Antiallergic agent and fermented food containing Bifidobacterium as active ingredient
US9056073B2 (en) Vaccine comprising lactobacilli for treating prostate inflammation and benign prostate hyperplasias
US20040037851A1 (en) Fusobacterium necrophorum vaccine and method for making such vaccine
EP0686039B1 (en) Method of enhancing immune response to oral vaccines
EP1608737A1 (en) Lactobacillus fermentum strain and uses thereof
JP3269890B2 (en) Vaccine effect enhancer and effect enhancer food
JP4509250B2 (en) Helicobacter pylori sanitizing medicine
CN110079477B (en) Lactobacillus plantarum for preventing and treating pullorum disease salmonella, preparation and application thereof
TW201216866A (en) Intestine immunomodulator
JP2004135669A6 (en) A lactic acid bacterial strain named Pediococcus pentosaceus CBT-8, which produces an antibacterial active substance that suppresses the growth of Helicobacter pylori and Listeria monocytogenes, is used as an antibacterial bacterium. Method for producing antibacterial substance having bioactive agent and method for utilizing antibacterial substance for functional foods and pharmaceuticals
SU1487815A3 (en) Method of producing biologically active substance having immunostimulating effect
US6682744B1 (en) Pro-gut maturation and anti-inflammatory effects of lactobacillus and lactobacillus secreted proteins, carbohydrates and lipids
US4379140A (en) Turkey rhinotracheitis vaccine
WO2001010448A1 (en) Pro-gut maturation and anti-inflammatory effects of lactobacillus and lactobacillus secreted proteins, carbohydrates and lipids
CS212234B2 (en) Method of making the immunotherapeutical means against the infection decease uf urine and digesting ways
WO1999007393A1 (en) Pharmaceutical product comprising bacterial strains for the colon therapy
Wainwright Biological control of microbial infections and cancer in humans: Historical use to future potential

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CN CZ DE DK ES FI GB HU JP KP KR KZ LK LU MG MN MW NL NO NZ PL PT RO RU SD SE SK UA VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2156859

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1994909696

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1994909696

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWG Wipo information: grant in national office

Ref document number: 1994909696

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1994909696

Country of ref document: EP