EP0969826A1 - Verwendung von ein chelatierungsmittel und/oder ein fungizid und/oder ein secropin enthaltenden liposomen zur verbesserung der impfung der schleimhaut - Google Patents
Verwendung von ein chelatierungsmittel und/oder ein fungizid und/oder ein secropin enthaltenden liposomen zur verbesserung der impfung der schleimhautInfo
- Publication number
- EP0969826A1 EP0969826A1 EP98909873A EP98909873A EP0969826A1 EP 0969826 A1 EP0969826 A1 EP 0969826A1 EP 98909873 A EP98909873 A EP 98909873A EP 98909873 A EP98909873 A EP 98909873A EP 0969826 A1 EP0969826 A1 EP 0969826A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mucosal
- pharmaceutical composition
- liposomes
- antigen
- phagocytic cells
- 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- Withdrawn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
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- PFYHYHZGDNWFIF-UHFFFAOYSA-N (+)-DMDP Natural products OCC1NC(CO)C(O)C1O PFYHYHZGDNWFIF-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- PFYHYHZGDNWFIF-KVTDHHQDSA-N 2,5-bis(hydroxymethyl)-3,4-dihydroxypyrrolidine Chemical compound OC[C@H]1N[C@H](CO)[C@@H](O)[C@@H]1O PFYHYHZGDNWFIF-KVTDHHQDSA-N 0.000 description 1
- PFYHYHZGDNWFIF-OMMKOOBNSA-N 2R,5R-Dihydroxymethyl-3R,4R-dihydroxy-pyrrolidine Natural products OC[C@@H]1N[C@@H](CO)[C@H](O)[C@@H]1O PFYHYHZGDNWFIF-OMMKOOBNSA-N 0.000 description 1
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- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
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- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
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- 230000001018 virulence Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
Definitions
- the invention relates to the field of mucosal immunity and to vaccination methods to specifically generate mucosal immunity .
- the immune system in general serves to protect animals, including man, against disease caused by invading foreign substances by actively mounting a cellular and humoral immune response directed against antigens present on or in the foreign substances. In this way, invading micro-organisms, pathogens, toxins, or other substances are rendered harmless to the animal .
- Vaccination makes use of the immune system; vaccines can be used to effectively generate a specific and selective immune response that prevents disease caused by the pathogens against which the animal is vaccinated.
- vaccines need to be administered parenterally, i.e. via injection, to be effective; vaccines that comprise replicating microorganisms can also effectively be administered at mucosal surfaces, e.g. orally, nasally or possibly via aerosols.
- the immune system of the mucosae is distinct from the general immune system that is present in most other parts of the body.
- the mucosae are, with the skin, the parts of the body where the most frequent contact with foreign substances is found. Inhalation of particles in the air and ingestion of food and other substances generates a constant load of antigens on the mucosae of lung and gut. An active immune response generated against these day-to-day recurring antigens would be very detrimental to the mucosae; therefore in the mucosae a different type of immune response can be found. Instead of every time mounting an active cellular and humoral immune response, the mucosae respond in a more tolerant and even immunosuppressive way and act mainly via thorough removal of foreign substances before an active humoral or cellular response to those substances can be initiated .
- the main line of defense of the mucosae is constituted by a layer of mucus covering the underlying epithelial cells.
- enzymes such as lysozyme can be found that enzy atically degrade possible harmful substances.
- phagocytic cells such as macrophages, are present, to phagocytize particles and micro-organisms. In this way, most antigens are effectively removed from the mucosal surface before they can invade the body further and no specific immune response will be generated.
- BALT bronchus-associated lymphoid tissue
- GALT gut-associated lymphoid tissue
- Both BALT and GALT are capable of mounting humoral and cellular immune responses.
- both BALT and GALT typically react with the formation of IgA antibodies which are excreted and transported to the mucosal surface where they can constitute a specific component of the otherwise mainly non-specific immune response of the mucosae.
- IgA recognizes and binds to the specific antigens present which are then earlier recognized and removed by phagocytizing cells.
- BALT and GALT migration and exchange of IgA-B-cells and IgA-memory cells assures a distribution of specific IgA throughout the mucosae.
- an IgA immune response generated in the lung also results in the same IgA immune response in the gut and other mucosae (Sminia et al . , Adv . Exp . Med . Biol. 216:981, 1987), facilitating antigen recognition throughout all mucosal surfaces .
- macrophages that return from the mucosal surface into the interstitium where BALT and GALT are located, is again detrimental for eliciting a specific immune response .
- These macrophages suppress the activities of the antigen presenting cells and the formation of specific T- cells present in the mucosal lymphoid system.
- the present invention provides a solution for the above disadvantages while it still is possible to achieve effective mucosal vaccination without having to resort to live-vaccines.
- the present invention thus provides effective mucosal vaccines.
- the invention firstly provides liposomes that do not contain the toxic substance CI2MDP but that instead contain or comprise a non-toxic substance that can eliminate phagocytic cells, such as macrophages, present on the mucosal surfaces of an animal.
- liposomes containing chelating agents such as ethylenediaminetetraacetic acid (EDTA) when incorporated in liposomes, are functionally analogous to liposomes containing CI2MDP without having the toxic side effects .
- EDTA ethylenediaminetetraacetic acid
- fungicides, and small peptides such as secropines can replace CI2MDP.
- Intratracheal application of the liposomes according to the invention effectively results in depletion or elimination of alveolar macrophages, and other phagocytic cells present on the mucosal surfaces of the respiratory tract of an animal .
- the invention further provides a vaccination proto- col in which elimination of alveolar macrophages and the immunization with an antigen take place in one simultaneous event. It was however found (see the experimental part) that the obvious solution comprising vaccination or immunization with a mixture of liposomes and antigen did not result in effective mucosal vaccination. Surprisingly, however, applying liposomes comprising the antigen was very successful in generating an effective mucosal immune response and thus mucosal vaccination.
- the invention thus also provides liposomes that comprise antigen and that can be used to simultaneously eliminate alveolar macrophages and immunize or vaccinate the mucosae against a specific antigen of choice.
- antigen-comprising liposomes according to the invention can be successfully performed against both respiratory as well as enteric disease and against diseases wherein the pathogen has its pathway-of-entry via the mucosae such as lung or gut.
- antigen a wide variety of substances can be selected. Good examples are viral antigens, comprising viral structural or non structural proteins with antigenic properties, such as the E2 protein of classical swine fever virus, gE of pseudorabies virus, SI of Corona viruses.
- bacterial or protozoal or parasitic antigens comprising toxins, or adhesian factors, or constituents of the cell membrane tnat elicit an immune response in a host.
- Mucosal vaccination via food or drinking water or via the aerosal route is widely applicable.
- small animals such as dogs and cats and other pets
- animal friendly treatments are greatly appreciated by the client.
- large animals such as farm animals, such as cows, horses, pigs and poultry, the ease of application of mucosal vaccines according to the invention allows for fast applications on a wide scale.
- Newcastle Disease infectious bronchitis virus
- laryngotracheitis virus infectious bursal disease virus
- tenosynovitisreovirus malabsortion syndrome virus
- Marek ' s disease virus chicken anemia virus, Escherichia coli, Salmonella spp, Pasteurella multocida, or Eimeria spp.
- influenza virus In pigs, influenza virus, classical swine fever virus, pseudorabies virus, Estavirus, Corona virus, Escherichia coli, actinobacillus pleuropneumonia,
- Bordetella bronchisentia, or Pasteurella multocida are, among others, pathogens against which can be vaccinated with the liposomes provided by the invention.
- aerosol vaccination In humans, aerosol vaccination is not widely applied. However, parenteral vaccination is often uncomfortable to the patient to be treated. Especially aerosol and/or oral vaccination of infants and children will be positively received.
- Good examples are viral diseases such as poliomyelitis, rubella, influenza respiratory syncitial virus and various other viral and bacterial diseases .
- Vaccines can be prepared according to the invention by preparing a pharmaceutical composition of a liposome provided by the invention and a suitable carrier and/or stabilizer .
- the local destruction of alveolar macrophages by the liposomes creates enough local penetration of the mucosal surfaces by the antigen provided by the same liposomes that an effective immune response can follow. Therefore, immunization or vaccination of humans or animals with the liposomes according to the invention can be used to obtain an effective mucosal vaccination, without hampering the majority of the alveolar macrophages and thus safeguarding a solid protection of the alveolar mucosae and thus the lung.
- Liposome preparation specifically for elimination phagocytic cells is discussed in Cell Tissue Res (1984) 238:355-3.
- Uni-and multilamellar forms of liposomes exist and size and other characteristics of liposomes depends on the constituents (such as cholesterol, sphingomyeline or other naturally occurring or synthetic phospholipids of the liposomal membranes and the ratios in which these constituents are being used.
- a specific protocol for liposomes containing EDTA and viral antigen is provided herewith, however, this protocol can in no way be seen as limiting the invention.
- the liposomes can be stored or used immediately. Application of immunomodulating liposomes in mucosal vaccination.
- mice Five groups of 4 BALB/C mice each were treated intratracheally with 0.1 ml liposomes prepared as above with 90% phosphadityl choline and 10% cholesterol and containing, respectively, PBS (control), or 0.6 M
- CI2MDP or 0.2, 0.4, or 0.5 M EDTA (experimental groups). After two days the number of macrophages per lung were counted. In the experimental groups, the percentages of alveolar macrophages found were reduced to approximately 20, 40, 30, and 35% of the number in the controls, showing that EDTA can replace the toxic CI2MDP.
- Figure 1 Mean antibody titer directed against NCD in four groups of chickens vaccinated against NCD in preparations of liposomes containing NCD (1), and additionally, PBS (2) CI2MDP (3) or EDTA (4)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98909873A EP0969826A1 (de) | 1997-03-11 | 1998-03-11 | Verwendung von ein chelatierungsmittel und/oder ein fungizid und/oder ein secropin enthaltenden liposomen zur verbesserung der impfung der schleimhaut |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97200729 | 1997-03-11 | ||
| EP97200729 | 1997-03-11 | ||
| PCT/NL1998/000145 WO1998040062A1 (en) | 1997-03-11 | 1998-03-11 | Use of liposomes containing a chelating agent, a fungicide or a secropine for improving mucosal vaccination |
| EP98909873A EP0969826A1 (de) | 1997-03-11 | 1998-03-11 | Verwendung von ein chelatierungsmittel und/oder ein fungizid und/oder ein secropin enthaltenden liposomen zur verbesserung der impfung der schleimhaut |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0969826A1 true EP0969826A1 (de) | 2000-01-12 |
Family
ID=26146231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP98909873A Withdrawn EP0969826A1 (de) | 1997-03-11 | 1998-03-11 | Verwendung von ein chelatierungsmittel und/oder ein fungizid und/oder ein secropin enthaltenden liposomen zur verbesserung der impfung der schleimhaut |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0969826A1 (de) |
| WO (1) | WO1998040062A1 (de) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074403A (zh) * | 2016-07-28 | 2016-11-09 | 浙江美保龙生物技术有限公司 | 一种伪狂犬病毒脂质体稀释液冻干制品及其制备方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5422120A (en) * | 1988-05-30 | 1995-06-06 | Depotech Corporation | Heterovesicular liposomes |
| GB9018690D0 (en) * | 1990-08-24 | 1990-10-10 | Wellcome Found | Vaccines |
| JPH07500813A (ja) * | 1991-05-13 | 1995-01-26 | リージェンツ オブ ザ ユニバーシティー オブ カリフォルニア | リポソーム多糖体ワクチン |
-
1998
- 1998-03-11 EP EP98909873A patent/EP0969826A1/de not_active Withdrawn
- 1998-03-11 WO PCT/NL1998/000145 patent/WO1998040062A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9840062A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998040062A1 (en) | 1998-09-17 |
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