EP0248838A1 - Compositions for combatting diarrhoea - Google Patents
Compositions for combatting diarrhoeaInfo
- Publication number
- EP0248838A1 EP0248838A1 EP19860906963 EP86906963A EP0248838A1 EP 0248838 A1 EP0248838 A1 EP 0248838A1 EP 19860906963 EP19860906963 EP 19860906963 EP 86906963 A EP86906963 A EP 86906963A EP 0248838 A1 EP0248838 A1 EP 0248838A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substances
- composition according
- adhesine
- diarrhoea
- combatting
- 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.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 206010012735 Diarrhoea Diseases 0.000 title claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 10
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 8
- 210000004347 intestinal mucosa Anatomy 0.000 claims abstract description 7
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 6
- 150000001413 amino acids Chemical group 0.000 claims description 6
- 230000000903 blocking effect Effects 0.000 claims description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims 1
- 235000004279 alanine Nutrition 0.000 claims 1
- 229960000310 isoleucine Drugs 0.000 claims 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 3
- QCTFKEJEIMPOLW-JURCDPSOSA-N Ala-Ile-Phe Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QCTFKEJEIMPOLW-JURCDPSOSA-N 0.000 abstract 1
- DPTBVFUDCPINIP-JURCDPSOSA-N Ile-Ala-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 DPTBVFUDCPINIP-JURCDPSOSA-N 0.000 abstract 1
- VZQRNAYURWAEFE-KKUMJFAQSA-N Ser-Leu-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VZQRNAYURWAEFE-KKUMJFAQSA-N 0.000 abstract 1
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 abstract 1
- 239000000427 antigen Substances 0.000 description 12
- 102000036639 antigens Human genes 0.000 description 12
- 108091007433 antigens Proteins 0.000 description 12
- 241000894006 Bacteria Species 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 231100000249 enterotoxic Toxicity 0.000 description 5
- 230000002242 enterotoxic effect Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 238000002255 vaccination Methods 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 244000309466 calf Species 0.000 description 3
- 239000000147 enterotoxin Substances 0.000 description 3
- 231100000655 enterotoxin Toxicity 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 101710146739 Enterotoxin Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000283903 Ovis aries Species 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000035931 haemagglutination Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000003307 slaughter Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
- C07K14/245—Escherichia (G)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
Definitions
- compositions for combatting diarrhoea Compositions for combatting diarrhoea
- V. cholearae ⁇ .coli appears to be the main procreator. No reliable figures are known with respect to slaughter cattle but the loss will certainly run into a year.
- Enterotoxic E.coii stems distinguish themselves from commensal non-patho ⁇ eneous stems in that they comprise two important virulence factors, to wit: the production of enterotoxins and the presence of adhesion antigens.
- the adhesion antigens of ⁇ .coli consist of electron microscopically visible thread-like appendixes on the bacterium surface indicated as fi briae or pili. Said fimbriae appear to be consisting of hundreds of identical protein sub-units having a molecular weight in the order of magnitude of 25,000. Through the fimbriae the bacterium appears to be capable of colonizing .the intestinalepitheliumand of proliferating the intestine in this way. As soon as the colonisation is effected the produced and excreted enterotoxin causes the development of diarrhoea.
- K88 One of the adhesion antigens in enterotoxic E.coli- stems from piglets is indicated as K88.
- Three variants of the K88 adhesine are known which can properly be immunologically distinguished.
- the primary structure of the subunit,of which the adhesine is composed, of each of said variants has been completely elucidated by us.
- conserved areas identical amino acid sequences in the subunit variants
- variable amino acid sequences appear to be present on certain sites in which the three variants distinguish themselves from - . -
- each variant fragment can be isolated which can block the binding of the adhesine carrying bacteria to erythrocytes (haemagglutination reaction) or to intestinal epithelial cells in low concentrations. Said fragments originate from the conserved parts of the subunit variants. Analysis of three isolated fragments showed that there is question here of the following tripeptides: serine-leucine-phenylalanine, isoleucine-alanine-phenylalanine and alanine-isoleucine- phenylalanine. Said peptides are resistant to decomposition by proteolytic enzymes from the gastro-intestinai tract.
- amino acid sequences are present on certain sites which show a strong affinity for the adhesine receptors. Said amino acid sequences, therefore, possibly form an essential part of the natural receptor binding site.
- the possibly occurring absorption of said substances by the intestinal epithelium can be prevented by coupling said substances to inert macromolecular carriers.
- compositions according to the invention can also be used with adults to combat diarrhoea caused by enterotoxic E.coli-stems.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Une composition thérapeutique pour le traitement et la prévention de la diarrhée comprend une ou plusieurs substances qui arrêtent les récepteurs d'adhésine présents sur l'épithélium intestinal. Lesdites substances sont de préférence des peptides, en particulier de Ser-Leu-Phe, de Ile-Ala-Phe et/ou de Ala-Ile-Phe.A therapeutic composition for the treatment and prevention of diarrhea comprises one or more substances which stop the adhesin receptors present on the intestinal epithelium. Said substances are preferably peptides, in particular Ser-Leu-Phe, Ile-Ala-Phe and / or Ala-Ile-Phe.
Description
Compositions for combatting diarrhoea
The most important procreators of neonataldiarrhoea with human beings and animals are the enterotoxical E. coli stems. With babies or very young children and with new-bo cattle this infection almost always has a lethal course. It appears from recent figures from the WHO that each year 500 million babies and young children (in particular in the developing countries) suffer from diarrhoea which causes over 5 million victims.
Besides V. cholearae Ξ.coli appears to be the main procreator. No reliable figures are known with respect to slaughter cattle but the loss will certainly run into milliards a year.
Enterotoxic E.coii stems distinguish themselves from commensal non-pathoσeneous stems in that they comprise two important virulence factors, to wit: the production of enterotoxins and the presence of adhesion antigens. The adhesion antigens of Ξ.coli consist of electron microscopically visible thread-like appendixes on the bacterium surface indicated as fi briae or pili. Said fimbriae appear to be consisting of hundreds of identical protein sub-units having a molecular weight in the order of magnitude of 25,000. Through the fimbriae the bacterium appears to be capable of colonizing .the intestinalepitheliumand of proliferating the intestine in this way. As soon as the colonisation is effected the produced and excreted enterotoxin causes the development of diarrhoea.
Experiments with mutated stems which cannot produce either adhesion antigens or enterotoxin anymore proved that said stems cause no or a very slight, passing form of diarrhoea.
For some time various research teams have been occupied wi the question whether prevention of this type of infections
•
through induction of protecting antibodies is possible. It appeared that administration of toxoid does raise antitoxin immuno-globulins , but that these antibodies do not or only partly give protection.
A second approach is based on inducing antibodies directed against the adhesion antigens. This approach appeared to be successful. Vaccination with purified adhesine preparations in most cases appears to give a sufficiently high respons of protectinσ antibodies to protect new-born descendants against the infe ion. . All these experiments relate to infections with piglets, calves or lambs. Various companies bring this type of vaccir.s on rhe market.
It is a problem, wit rhe vaccination of slauσhter cattle with purified antigen, preparations that Ξ.coli can produce various different adhesion antigens, so that now it is clear that more and more different adhesion antigens have to be added to the commercial vacci s.
Some stems only produce oneadhesion antigen, others can synthetize 2 or even 3 adhesion antigens simultaneously.
It is a second problem relating to this type of combatting diarrhoea that vaccination of the parent animals (cows, sows) indeed has a preventive effect and protects the descendants, but, in view of the costs that go with it, this usually can only be used in companies in trouble. From a therapeutical point of view vaccination at the moment at which the infection manifests itself is useless, of course.
In regard of the fact that vaccination is usually only used if problems are to be expected diarrhoea is still combatted on a large scalewith antibiotics, which has L
many disadvantages (costs, side-effects, etc.). Therefore, other forms of therapeutics are searched for. The approach chosen is directed to the prevention of colonization, i.e. attaching of the bacteria to the intestinal~epithelium.lt appeared to be possible to combatdiarrhoea by oral administration of (monoclonal) antibodies directed against the adhesion antigens on the bacteria surface. A first composition for combatting neonatal diarrhoea with calves is now commercially available (Molecular Genetics) but relatively little is known about its success. Disadvantages are for instance the costs and the tenabilitv of the preparation.
The above mentioned therapeutical approach is directed against the infecting microorganism. Now it has appeared that a novel therapy can be directed to blocking the achnsir.e receptors resen on the intestinal epithelium.
Until recently of none of the adhesines of enterotoxic E.coli-stems it was known which part (or parts) of the structure is (are) of importance for the receptor recognition.
Surprisingly it has appeared now that here it concerns spatially very restricted structures.
One of the adhesion antigens in enterotoxic E.coli- stems from piglets is indicated as K88. Three variants of the K88 adhesine are known which can properly be immunologically distinguished. The primary structure of the subunit,of which the adhesine is composed, of each of said variants has been completely elucidated by us. Besides conserved areas (identical amino acid sequences in the subunit variants) variable amino acid sequences appear to be present on certain sites in which the three variants distinguish themselves from
- . -
each other. With digestions of denatured subunits with proteol tic enzymes it has appeared now that of each variant fragments can be isolated which can block the binding of the adhesine carrying bacteria to erythrocytes (haemagglutination reaction) or to intestinal epithelial cells in low concentrations. Said fragments originate from the conserved parts of the subunit variants. Analysis of three isolated fragments showed that there is question here of the following tripeptides: serine-leucine-phenylalanine, isoleucine-alanine-phenylalanine and alanine-isoleucine- phenylalanine. Said peptides are resistant to decomposition by proteolytic enzymes from the gastro-intestinai tract.
All of the three isolated and identified tripeptides have been synthetized. The synthetic peptides have the same effect and activity as the peptides isolated from the adhesine.
Therefore, in the K88 adhesine known amino acid sequences are present on certain sites which show a strong affinity for the adhesine receptors. Said amino acid sequences, therefore, possibly form an essential part of the natural receptor binding site.
Provisional research with respect to the adhesine antigen K99 of enterotoxic E.coli-stems from calves and lambs points out that here spatially very restricted structures are responsible for attaching to the receptor as well.
As the above-mentioned peptides as it were form an imitation of the natural receptor binding site as it occurs on the adhesine at the bacterium surface, said peptides will compete in the intestine with the bacterium for attaching to the intestinal epithelium. Once bound bacteria can also be removed from the intestinal
epithelium by the peptides.
With respect to the short duration of the infection (1-2 days) blockade of the intestinal epithelium receptors will only have to last for a short period of time. This limitation of the duration of the blockade is effected by the host himself as intestinal epithelial cells (enterocytes) are replaced and released fast (usually within 24 hours) by new making.
On account of the above invention substances' with the spatially very restricted structures meant will be inserted into food or into therapeutical compositions.
The possibly occurring absorption of said substances by the intestinal epithelium, can be prevented by coupling said substances to inert macromolecular carriers.
The above mentioned spatially very restricted structures such as tripeptides can be isolated or synthetized cheaply and can be preserved very well. They do not have any disadvantageous effect upon the host.
Besides use with new-born descendants the therapeutical compositions according to the invention can also be used with adults to combat diarrhoea caused by enterotoxic E.coli-stems.
Claims
1. Therapeutical composition for combatting and preventin diarrhoea, characterized by the presence of one or more substances which block the adhesine receptors present on the intestinal epithelium.
2. Composition according to claim 1, characterized by the presence of substances which block specifically adhesine receptors.
3. Composition according to claim 1 or 2, characterized by the presence of one or more substances, the molecules of which comprise one or more amino acid units or derivatives.
4. Composition according to claim 3, characterized by the presence of one cr more peptides.
5. Composition according to claim 3 or 4, characterized by the presence of one or more substances having in their molecules at least one amino acid unit belonging to the group consisting of serine, leucine, isoleucine, alanine and phenyl-aianine.
6 . Composition according to claim 5, characterized by the presence of serine-leucine-phenylalanine, isoleucine-alanine-phenvlalanine and/or alanine- isoleucine-phenylalanine.
7. Composition according to one of the preceding claims, characterized in that the adhesine receptors blocking substances are used in combination with an inert macromolecular carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8503413 | 1985-12-11 | ||
| NL8503413A NL8503413A (en) | 1985-12-11 | 1985-12-11 | PREPARATIONS FOR THE PREVENTION OF DIARRHEE. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0248838A1 true EP0248838A1 (en) | 1987-12-16 |
Family
ID=19847002
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19860906963 Withdrawn EP0248838A1 (en) | 1985-12-11 | 1986-12-09 | Compositions for combatting diarrhoea |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0248838A1 (en) |
| JP (1) | JPS63501950A (en) |
| NL (1) | NL8503413A (en) |
| WO (1) | WO1987003485A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK53291D0 (en) * | 1991-03-25 | 1991-03-25 | Carlbiotech Ltd As | SMALL PEPTIDES AND PEPTID RELATED SUBSTANCES AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH COMPOUNDS |
| US6818585B2 (en) * | 1998-12-30 | 2004-11-16 | Univation Technologies, Llc | Catalyst compounds, catalyst systems thereof and their use in a polymerization process |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU76538A1 (en) * | 1977-01-07 | 1978-09-18 | ||
| SU921712A1 (en) * | 1979-12-10 | 1982-04-23 | Ереванский политехнический институт им.К.Маркса | Machine tool for working crank shaft connecting rod necks |
| DE3213740A1 (en) * | 1982-04-14 | 1983-12-15 | Oerlikon-Boehringer GmbH, 7320 Göppingen | Whirl device |
| JPS591101A (en) * | 1982-05-24 | 1984-01-06 | Komatsu Ltd | Crankshaft miller |
-
1985
- 1985-12-11 NL NL8503413A patent/NL8503413A/en not_active Application Discontinuation
-
1986
- 1986-12-09 JP JP50002387A patent/JPS63501950A/en active Pending
- 1986-12-09 WO PCT/NL1986/000041 patent/WO1987003485A1/en not_active Application Discontinuation
- 1986-12-09 EP EP19860906963 patent/EP0248838A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8703485A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63501950A (en) | 1988-08-04 |
| WO1987003485A1 (en) | 1987-06-18 |
| NL8503413A (en) | 1987-07-01 |
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Legal Events
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| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
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| 17P | Request for examination filed |
Effective date: 19871214 |
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| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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| 18D | Application deemed to be withdrawn |
Effective date: 19890704 |
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| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: DE GRAAF, FRITS, KAREL Inventor name: JACOBS, ANTONIUS, ARNOLDUS, CHRISTIAAN |