DE69739372D1 - Verfahren und zusammensetzungen zur genetisch schützenden und therapeutischen immunisierung - Google Patents
Verfahren und zusammensetzungen zur genetisch schützenden und therapeutischen immunisierungInfo
- Publication number
- DE69739372D1 DE69739372D1 DE69739372T DE69739372T DE69739372D1 DE 69739372 D1 DE69739372 D1 DE 69739372D1 DE 69739372 T DE69739372 T DE 69739372T DE 69739372 T DE69739372 T DE 69739372T DE 69739372 D1 DE69739372 D1 DE 69739372D1
- Authority
- DE
- Germany
- Prior art keywords
- genetically
- compositions
- protective
- therapeutic immunization
- immunization
- 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.)
- Expired - Lifetime
Links
- 230000003053 immunization Effects 0.000 title 1
- 238000002649 immunization Methods 0.000 title 1
- 238000000034 method Methods 0.000 title 1
- 239000000203 mixture Substances 0.000 title 1
- 230000001681 protective effect Effects 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
Classifications
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- 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
- A61K39/12—Viral antigens
-
- 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
- A61K39/12—Viral antigens
- A61K39/21—Retroviridae, e.g. equine infectious anemia virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/10—Cellular immunotherapy characterised by the cell type used
- A61K40/19—Dendritic cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
- A61K40/24—Antigen-presenting cells [APC]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
- A61K40/34—Antigenic peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
- A61K40/46—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- 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
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- 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
- A61K2039/525—Virus
- A61K2039/5254—Virus avirulent or attenuated
-
- 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
- A61K2039/53—DNA (RNA) vaccination
-
- 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
- A61K2039/55511—Organic adjuvants
- A61K2039/55522—Cytokines; Lymphokines; Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K40/00—Cellular immunotherapy
- A61K40/50—Cellular immunotherapy characterised by the use of allogeneic cells
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
- C12N2740/15034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16041—Use of virus, viral particle or viral elements as a vector
- C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16061—Methods of inactivation or attenuation
- C12N2740/16062—Methods of inactivation or attenuation by genetic engineering
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Zoology (AREA)
- General Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Communicable Diseases (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Mycology (AREA)
- Oncology (AREA)
- Biophysics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Hematology (AREA)
- AIDS & HIV (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60462796A | 1996-02-21 | 1996-02-21 | |
| PCT/US1997/002933 WO1997031119A1 (en) | 1996-02-21 | 1997-02-20 | Methods and compositions for protective and therapeutic genetic immunization |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE69739372D1 true DE69739372D1 (de) | 2009-06-04 |
Family
ID=24420371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69739372T Expired - Lifetime DE69739372D1 (de) | 1996-02-21 | 1997-02-20 | Verfahren und zusammensetzungen zur genetisch schützenden und therapeutischen immunisierung |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0882134B8 (enExample) |
| JP (1) | JP2000517290A (enExample) |
| AP (1) | AP964A (enExample) |
| AT (1) | ATE429505T1 (enExample) |
| AU (1) | AU726623B2 (enExample) |
| CA (1) | CA2246359A1 (enExample) |
| DE (1) | DE69739372D1 (enExample) |
| EA (2) | EA003554B1 (enExample) |
| ES (1) | ES2324745T3 (enExample) |
| NZ (1) | NZ331369A (enExample) |
| OA (1) | OA10842A (enExample) |
| WO (1) | WO1997031119A1 (enExample) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3210997A (en) * | 1996-05-24 | 1997-12-09 | University Of Maryland At Baltimore | Dna vaccines for eliciting a mucosal immune response |
| US5980898A (en) | 1996-11-14 | 1999-11-09 | The United States Of America As Represented By The U.S. Army Medical Research & Material Command | Adjuvant for transcutaneous immunization |
| US6797276B1 (en) | 1996-11-14 | 2004-09-28 | The United States Of America As Represented By The Secretary Of The Army | Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response |
| US20060002949A1 (en) | 1996-11-14 | 2006-01-05 | Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. | Transcutaneous immunization without heterologous adjuvant |
| ES2279580T3 (es) * | 1997-09-15 | 2007-08-16 | Genetic Immunity, Llc | Composiciones para administrar genes a celulas de la piel que presentan antigenos. |
| CA2314683A1 (en) * | 1997-12-12 | 1999-06-24 | Luigi Naldini | Therapeutic use of lentiviral vectors |
| WO1999047146A1 (en) * | 1998-03-17 | 1999-09-23 | Julianna Lisziwiewicz | Anti-hiv combination comprising hydroxyurea, ddi, and a protease inhibitor |
| US6461616B1 (en) * | 2000-09-09 | 2002-10-08 | Akzo Nobel Nv | EIAV p26 deletion vaccine and diagnostic |
| US20070025958A1 (en) | 2000-10-27 | 2007-02-01 | Hadden John W | Vaccine immunotherapy |
| CA2950109C (en) | 2000-10-27 | 2019-02-19 | John W. Hadden | Vaccine immunotherapy for immune suppressed patients |
| US7628980B2 (en) | 2000-11-23 | 2009-12-08 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US7097842B2 (en) | 2000-11-23 | 2006-08-29 | Bavarian Nordic A/S | Modified vaccinia virus ankara for the vaccination of neonates |
| US7445924B2 (en) | 2000-11-23 | 2008-11-04 | Bavarian Nordic A/S | Modified Vaccinia Ankara virus variant and cultivation method |
| DE20122302U1 (de) | 2000-11-23 | 2005-02-24 | Bavarian Nordic A/S | Variante des Modifizierten Vaccinia-Ankara-Virus |
| PT1372708E (pt) | 2001-02-13 | 2008-09-29 | Us Gov Sec Army | Vacina para imunização transcutânea |
| AU2002356690B2 (en) | 2001-12-04 | 2008-07-24 | Bavarian Nordic A/S | Flavivirus NS1 subunit vaccine |
| JP4801880B2 (ja) | 2002-04-19 | 2011-10-26 | バヴァリアン・ノルディック・アクティーゼルスカブ | 新生仔予防接種用変異ワクシニアウイルスアンカラ |
| UA85543C2 (ru) | 2002-09-05 | 2009-02-10 | Бавариан Нордик А/С | Способ культивирования первичных клеток и амплификации вирусов в условиях безсывороточной среды, композиция и ее применение, и способ лечения или вакцинации животных |
| WO2004065575A2 (en) * | 2003-01-15 | 2004-08-05 | Research Institute For Genetic And Human Therapy (Right) | Dna compositon and uses thereof |
| FR2872170B1 (fr) * | 2004-06-25 | 2006-11-10 | Centre Nat Rech Scient Cnrse | Lentivirus non interactif et non replicatif, preparation et utilisations |
| EP1797189A4 (en) * | 2004-09-02 | 2010-05-19 | Qun Chen | ENCAPSIDATION SYSTEM FOR THE PRODUCTION OF RECOMBINANT VIRUSELY PARTICLES |
| GB0526211D0 (en) * | 2005-12-22 | 2006-02-01 | Oxford Biomedica Ltd | Viral vectors |
| ES2654303T3 (es) | 2007-05-04 | 2018-02-13 | University Health Network | Inmunoterapia de IL-12 contra el cáncer |
| AU2008329741B2 (en) | 2007-11-28 | 2013-09-12 | Irx Therapeutics, Inc. | Method of increasing immunological effect |
| WO2010009465A2 (en) * | 2008-07-18 | 2010-01-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Htlv-ii vector and methods of use |
| CA3017298C (en) | 2009-05-15 | 2021-09-28 | Irx Therapeutics, Inc. | Compositions comprising primary cell-derived biologics for enhancing immune responses in patients |
| CN103097543A (zh) | 2009-12-08 | 2013-05-08 | 伊尔克斯治疗有限公司 | 逆转朗格汉斯细胞免疫抑制的方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5342774A (en) * | 1991-05-23 | 1994-08-30 | Ludwig Institute For Cancer Research | Nucleotide sequence encoding the tumor rejection antigen precursor, MAGE-1 |
| JPH08509606A (ja) * | 1993-04-20 | 1996-10-15 | ロビンソン,ウィリアム エス. | 細胞内感染因子に感染した個体を処置する方法および物質 |
| US6080408A (en) * | 1994-08-22 | 2000-06-27 | Connaught Laboratories Limited | Human immunodeficiency virus type 1 nucleic acids devoid of long terminal repeats capable of encoding for non-infectious, immunogenic, retrovirus-like particles |
-
1997
- 1997-02-20 NZ NZ331369A patent/NZ331369A/en not_active IP Right Cessation
- 1997-02-20 EP EP97906764A patent/EP0882134B8/en not_active Expired - Lifetime
- 1997-02-20 JP JP09530399A patent/JP2000517290A/ja not_active Ceased
- 1997-02-20 EA EA200100302A patent/EA003554B1/ru not_active IP Right Cessation
- 1997-02-20 AT AT97906764T patent/ATE429505T1/de not_active IP Right Cessation
- 1997-02-20 AP APAP/P/1998/001320A patent/AP964A/en active
- 1997-02-20 DE DE69739372T patent/DE69739372D1/de not_active Expired - Lifetime
- 1997-02-20 WO PCT/US1997/002933 patent/WO1997031119A1/en not_active Ceased
- 1997-02-20 EA EA199800746A patent/EA002020B1/ru not_active IP Right Cessation
- 1997-02-20 AU AU21369/97A patent/AU726623B2/en not_active Ceased
- 1997-02-20 ES ES97906764T patent/ES2324745T3/es not_active Expired - Lifetime
- 1997-02-20 CA CA002246359A patent/CA2246359A1/en not_active Abandoned
-
1998
- 1998-08-18 OA OA9800147A patent/OA10842A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATE429505T1 (de) | 2009-05-15 |
| EA199800746A1 (ru) | 1999-02-25 |
| AU726623B2 (en) | 2000-11-16 |
| EP0882134B1 (en) | 2009-04-22 |
| EP0882134B8 (en) | 2009-09-02 |
| CA2246359A1 (en) | 1997-08-28 |
| ES2324745T3 (es) | 2009-08-13 |
| NZ331369A (en) | 2001-04-27 |
| WO1997031119A1 (en) | 1997-08-28 |
| EP0882134A1 (en) | 1998-12-09 |
| AU2136997A (en) | 1997-09-10 |
| AP9801320A0 (en) | 1998-09-30 |
| EA003554B1 (ru) | 2003-06-26 |
| EA200100302A1 (ru) | 2001-10-22 |
| OA10842A (en) | 2001-08-14 |
| AP964A (en) | 2001-05-11 |
| EA002020B1 (ru) | 2001-12-24 |
| JP2000517290A (ja) | 2000-12-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition |