ATE205534T1 - Pneumolysin-mutanten und pneumokokken-impfstoffe daraus - Google Patents

Pneumolysin-mutanten und pneumokokken-impfstoffe daraus

Info

Publication number
ATE205534T1
ATE205534T1 AT90900035T AT90900035T ATE205534T1 AT E205534 T1 ATE205534 T1 AT E205534T1 AT 90900035 T AT90900035 T AT 90900035T AT 90900035 T AT90900035 T AT 90900035T AT E205534 T1 ATE205534 T1 AT E205534T1
Authority
AT
Austria
Prior art keywords
mutants
pneumolysine
pneumococcal vaccines
vaccines
pneumolysin
Prior art date
Application number
AT90900035T
Other languages
English (en)
Inventor
James Cleland Paton
Graham John Boulnois
Peter William Andrew
Timothy John Mitchell
Magna
John Arthur Walker
Original Assignee
Nederlanden Staat
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 Nederlanden Staat filed Critical Nederlanden Staat
Application granted granted Critical
Publication of ATE205534T1 publication Critical patent/ATE205534T1/de

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/315Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci
    • C07K14/3156Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci from Streptococcus pneumoniae (Pneumococcus)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Saccharide Compounds (AREA)
  • Exchange Systems With Centralized Control (AREA)
  • Manufacturing Of Steel Electrode Plates (AREA)
  • Current-Collector Devices For Electrically Propelled Vehicles (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
AT90900035T 1988-12-16 1989-12-15 Pneumolysin-mutanten und pneumokokken-impfstoffe daraus ATE205534T1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPJ198988 1988-12-16
PCT/AU1989/000539 WO1990006951A1 (en) 1988-12-16 1989-12-15 Pneumolysin mutants and pneumococcal vaccines made therefrom

Publications (1)

Publication Number Publication Date
ATE205534T1 true ATE205534T1 (de) 2001-09-15

Family

ID=3773589

Family Applications (1)

Application Number Title Priority Date Filing Date
AT90900035T ATE205534T1 (de) 1988-12-16 1989-12-15 Pneumolysin-mutanten und pneumokokken-impfstoffe daraus

Country Status (15)

Country Link
EP (1) EP0449856B1 (de)
JP (1) JP3237842B2 (de)
AT (1) ATE205534T1 (de)
AU (1) AU626961B2 (de)
BG (1) BG51358A3 (de)
CA (1) CA2005704C (de)
DE (1) DE68929323T2 (de)
DK (1) DK173629B1 (de)
ES (1) ES2160570T3 (de)
FI (1) FI103122B1 (de)
HU (1) HUT58804A (de)
MC (1) MC2178A1 (de)
NO (1) NO304317B1 (de)
RU (1) RU2121481C1 (de)
WO (1) WO1990006951A1 (de)

Families Citing this family (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6716432B1 (en) * 1988-12-16 2004-04-06 James Cleland Paton Pneumolysin mutants and pneumococcal vaccines made therefrom
CA2059693C (en) * 1991-01-28 2003-08-19 Peter J. Kniskern Polysaccharide antigens from streptococcus pneumoniae
US5391712A (en) * 1991-08-30 1995-02-21 Beckman Instruments, Inc. Non-hemolytic streptolysin O variants
US5928900A (en) * 1993-09-01 1999-07-27 The Rockefeller University Bacterial exported proteins and acellular vaccines based thereon
EP0687688A1 (de) * 1993-12-17 1995-12-20 Universidad De Oviedo Antikörper gegen neumolysin und ihre verwendung
US8791237B2 (en) 1994-11-08 2014-07-29 The Trustees Of The University Of Pennsylvania Compositions and methods for treatment of non-hodgkins lymphoma
HUP0002475A3 (en) * 1997-07-21 2002-01-28 Baxter Healthcare S A Wallisel Modified immunogenic pneumolysin compositions as vaccines
GB9906437D0 (en) * 1999-03-19 1999-05-12 Smithkline Beecham Biolog Vaccine
BR0009166A (pt) * 1999-03-19 2001-12-26 Smithkline Beecham Biolog Vacina
GB9918319D0 (en) 1999-08-03 1999-10-06 Smithkline Beecham Biolog Vaccine composition
GB0022742D0 (en) * 2000-09-15 2000-11-01 Smithkline Beecham Biolog Vaccine
MXPA03003690A (es) 2000-10-27 2004-05-05 Chiron Spa Acidos nucleicos y proteinas de los grupos a y b de estreptococos.
GB0109297D0 (en) 2001-04-12 2001-05-30 Glaxosmithkline Biolog Sa Vaccine
ES2537737T3 (es) 2002-08-02 2015-06-11 Glaxosmithkline Biologicals S.A. Composiciones de vacuna que comprenden lipooligosacáridos de inmunotipo L2 y/o L3 de Neisseria meningitidis de IgtB
MXPA05004528A (es) 2002-11-01 2005-07-26 Glaxosmithkline Biolog Sa Composicion inmunogenica.
TWI315986B (en) 2002-11-07 2009-10-21 Synergy America Inc Compositions and methods for treating or preventing pneumococcal infection
CA2812817C (en) 2003-03-13 2016-12-20 Glaxosmithkline Biologicals S.A. Method of detoxification of pneumolysin
PT1648500E (pt) 2003-07-31 2014-10-10 Novartis Vaccines & Diagnostic Composições imunogénicas para estreptococos piogenes
US8945589B2 (en) 2003-09-15 2015-02-03 Novartis Vaccines And Diagnostics, Srl Immunogenic compositions for Streptococcus agalactiae
CA2539715C (en) 2003-10-02 2015-02-24 Glaxosmithkline Biologicals S.A. Pertussis antigens and use thereof in vaccination
EP1713917A4 (de) * 2004-02-13 2009-06-17 Sanofi Pasteur Ltd Pneumolysinderivate
WO2005108419A1 (en) * 2004-05-07 2005-11-17 Lea-Ann Kirkham Mutant cholesterol-binding cytolysin proteins
GB0410220D0 (en) * 2004-05-07 2004-06-09 Kirkham Lea Ann Mutant pneumolysin proteins
WO2006078318A2 (en) 2004-07-29 2006-07-27 Novartis Vaccines And Diagnostics Inc. Immunogenic compositions for gram positive bacteria such as streptococcus agalactiae
GB0421083D0 (en) * 2004-09-22 2004-10-27 Glaxosmithkline Biolog Sa Purification process
CA2583803C (en) 2004-10-08 2014-11-25 Giuliano Bensi Immunogenic and therapeutic compositions for streptococcus pyogenes
GB0505996D0 (en) 2005-03-23 2005-04-27 Glaxosmithkline Biolog Sa Fermentation process
TWI457133B (zh) 2005-12-13 2014-10-21 Glaxosmithkline Biolog Sa 新穎組合物
TR201900418T4 (tr) 2005-12-22 2019-02-21 Glaxosmithkline Biologicals Sa Pnömokok polisakkarit konjugat aşısı.
GB0607088D0 (en) 2006-04-07 2006-05-17 Glaxosmithkline Biolog Sa Vaccine
ES2809167T3 (es) 2006-01-17 2021-03-03 Forsgren Arne Una novedosa proteína de Haemophilus influenzae expuesta en la superficie (proteína E; pE)
US20090181078A1 (en) 2006-09-26 2009-07-16 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
EP3403667B1 (de) 2006-09-26 2020-07-22 Infectious Disease Research Institute Impfstoffzusammensetzung mit einem synthetischen adjuvans
PL2086582T3 (pl) 2006-10-12 2013-04-30 Glaxosmithkline Biologicals Sa Kompozycja zawierająca adiuwant w postaci emulsji typu olej w wodzie
ES2397714T3 (es) 2006-10-12 2013-03-08 Glaxosmithkline Biologicals S.A. Vacuna que comprende un adyuvante de emulsión de aceite en agua
MX2009009342A (es) 2007-03-02 2009-09-11 Glaxosmithkline Biolog Sa Metodo novedoso y composiciones.
US9717788B2 (en) 2007-03-02 2017-08-01 Glaxosmithkline Biologicals Sa Method of inducing an immune response against HIV employing HIV immunogens, adenoviral vectors encoding said immunogens, and adjuvant
EP2147015A4 (de) * 2007-04-13 2011-01-26 Univ Oklahoma State Mutanten von cholesterinabhängigen cytolysinen und verwendungen davon
EA020817B1 (ru) 2007-06-26 2015-02-27 Глаксосмитклайн Байолоджикалс С.А. Вакцина, содержащая конъюгаты капсульных полисахаридов streptococcus pneumoniae
GB0714963D0 (en) 2007-08-01 2007-09-12 Novartis Ag Compositions comprising antigens
CA2699513C (en) 2007-09-12 2018-03-13 Novartis Ag Gas57 mutant antigens and gas57 antibodies
PT2235046E (pt) 2007-12-21 2012-10-26 Novartis Ag Formas mutantes de estreptolisina o
AU2009237647A1 (en) 2008-04-16 2009-10-22 Glaxosmithkline Biologicals S.A. Vaccine
GB0815872D0 (en) 2008-09-01 2008-10-08 Pasteur Institut Novel method and compositions
KR101741426B1 (ko) * 2008-12-24 2017-05-30 더 킹덤 오드 더 네덜란드, 레프리젠티드 바이 더 미니스트리 오브 헬스, 웰페어 앤드 스포츠, 온 비하프 오브 더 미니스터, 더 내셔널 인스티튜트 포 퍼블릭 헬스 앤드 디 인바이런먼트 변형된 스트렙토코커스 뉴모니아 뉴몰리신(ply) 폴리펩타이드
CA2756533A1 (en) 2009-03-24 2010-09-30 Novartis Ag Combinations of meningococcal factor h binding protein and pneumococcal saccharide conjugates
SI2437753T1 (sl) 2009-06-05 2016-12-30 Infectious Disease Research Institute Sintetični glukopiranozil-lipidni adjuvansi in cepivni sestavki, ki jih vsebujejo
CA2773637A1 (en) 2009-09-10 2011-03-17 Novartis Ag Combination vaccines against respiratory tract diseases
CA2784447A1 (en) 2009-12-22 2011-06-30 Sanofi Pasteur Limited Adjuvanted immunogenic compositions and related methods
JP5894083B2 (ja) * 2009-12-22 2016-03-23 サノフィ パストゥール リミテッドSanofi Pasteur Limited 免疫原性組成物
EP2544693B1 (de) 2010-03-09 2017-09-13 Biomedical Research Models, Inc. Neuer schleimhautimpfungsansatz für den herpes-simplex-virus vom typ 2
GB201003924D0 (en) 2010-03-09 2010-04-21 Glaxosmithkline Biolog Sa Immunogenic composition
CA2792683A1 (en) 2010-03-10 2011-09-15 Glaxosmithkline Biologicals S.A. Neisserial fhbp vaccine composition
SG184310A1 (en) 2010-04-13 2012-10-30 Celldex Therapeutics Inc Antibodies that bind human cd27 and uses thereof
GB201015132D0 (en) 2010-09-10 2010-10-27 Univ Bristol Vaccine composition
WO2012072769A1 (en) 2010-12-01 2012-06-07 Novartis Ag Pneumococcal rrgb epitopes and clade combinations
GB201022007D0 (en) 2010-12-24 2011-02-02 Imp Innovations Ltd DNA-sensor
WO2012134975A1 (en) 2011-03-28 2012-10-04 St. Jude Children's Research Hospital Methods and compositions employing immunogenic fusion proteins
BR112013025799A2 (pt) 2011-04-08 2016-12-20 Immune Design Corp método para induzir uma resposta imune em um sujeito, e, preparação
CA2834834A1 (en) 2011-05-17 2012-11-22 Glaxosmithkline Biologicals S.A. Vaccine against streptococcus pneumoniae
SI2811981T1 (sl) 2012-02-07 2019-08-30 Infectious Disease Research Institute Izboljšanje adjuvantne formulacije, ki obsegajo TLR4 agoniste in postopki za uporabo le-teh
JP2015510872A (ja) 2012-03-07 2015-04-13 ノバルティス アーゲー Streptococcuspneumoniae抗原の増強された製剤
EP2850431B1 (de) 2012-05-16 2018-04-18 Immune Design Corp. Impfstoffe gegen hsv-2
CA2897398A1 (en) 2013-01-07 2014-07-10 Mucosal Vaccine Technologies Llc Use of vaccines for the treatment of herpes simplex virus type 2 infections
JP6446377B2 (ja) 2013-03-08 2018-12-26 ファイザー・インク 免疫原性融合ポリペプチド
JP6426706B2 (ja) 2013-04-18 2018-11-21 イミューン デザイン コーポレイション がん処置で使用するためのgla単剤療法
WO2014186796A1 (en) 2013-05-17 2014-11-20 The Board Of Regents Of The University Of Texas System Immunization to protect against adverse cardiac events relating to pneumococcal infection
US9463198B2 (en) 2013-06-04 2016-10-11 Infectious Disease Research Institute Compositions and methods for reducing or preventing metastasis
BR112016015422A2 (pt) 2013-12-31 2017-10-24 Infectious Disease Res Inst formulações de vacina de frasco único
US9815886B2 (en) 2014-10-28 2017-11-14 Adma Biologics, Inc. Compositions and methods for the treatment of immunodeficiency
SMT202400482T1 (it) 2014-11-21 2025-01-14 The Board Of Regents Of Theuniversity Of Oklahoma Mutanti della pneumolisina e metodi per relativo uso
WO2016145085A2 (en) 2015-03-09 2016-09-15 Celldex Therapeutics, Inc. Cd27 agonists
GB201518684D0 (en) 2015-10-21 2015-12-02 Glaxosmithkline Biolog Sa Vaccine
WO2017176076A1 (en) 2016-04-06 2017-10-12 Ewha University - Industry Collaboration Foundation A peptide with ability to penetrate cell membrane
AU2017252527A1 (en) 2016-04-18 2018-11-08 Celldex Therapeutics, Inc. Agonistic antibodies that bind human CD40 and uses thereof
IL319503A (en) 2016-05-16 2025-05-01 Access To Advanced Health Inst PEGylated liposomes and methods of use
CN109310773B (zh) 2016-05-16 2022-04-26 传染病研究所 含有tlr激动剂的配制品和使用方法
BR112018074352B1 (pt) 2016-06-01 2021-11-30 Infectious Disease Research Institute Partículas de nanoalume contendo um agente de dimensionamento
GB201610599D0 (en) 2016-06-17 2016-08-03 Glaxosmithkline Biologicals Sa Immunogenic Composition
US10259865B2 (en) 2017-03-15 2019-04-16 Adma Biologics, Inc. Anti-pneumococcal hyperimmune globulin for the treatment and prevention of pneumococcal infection
CN111315362A (zh) 2017-06-15 2020-06-19 传染病研究所 纳米结构脂质载剂和稳定乳剂以及其用途
KR102755593B1 (ko) 2017-09-08 2025-01-20 액세스 투 어드밴스드 헬스 인스티튜트 사포닌을 포함하는 리포솜 제형 및 사용 방법
SG11202010011RA (en) 2018-04-17 2020-11-27 Celldex Therapeutics Inc Anti-cd27 and anti-pd-l1 antibodies and bispecific constructs
WO2020123444A1 (en) 2018-12-11 2020-06-18 Celldex Therapeutics, Inc. Methods of using cd27 antibodies as conditioning treatment for adoptive cell therapy
JP7551618B2 (ja) 2018-12-12 2024-09-17 グラクソスミスクライン バイオロジカルズ ソシエテ アノニム O-結合型グリコシル化のための修飾キャリアタンパク質
EP3976092A1 (de) 2019-05-25 2022-04-06 Infectious Disease Research Institute Zusammensetzung und verfahren zum sprühtrocknen einer adjuvans-impfstoff-emulsion
EP3900739A1 (de) 2020-04-21 2021-10-27 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Synthetische streptococcus-pneumoniae-saccharid-konjugate zum konservierten membranprotein
EP3919076A1 (de) 2020-06-02 2021-12-08 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Synthetische oligosaccharidimpfstoffe gegen streptococcus pneumoniae mit mikropartikel-adjuvans-formulierungen
US20230310323A1 (en) 2020-09-04 2023-10-05 Access To Advanced Health Institute Co-lyophilized rna and nanostructured lipid carrier
KR20240006541A (ko) 2021-04-09 2024-01-15 셀덱스 쎄라퓨틱스, 인크. Ilt4에 대한 항체, 이중특이적 항-ilt4/pd-l1 항체 및 이의 용도
WO2023077521A1 (en) 2021-11-08 2023-05-11 Celldex Therapeutics, Inc Anti-ilt4 and anti-pd-1 bispecific constructs
AU2022391752A1 (en) 2021-11-18 2024-06-13 Matrivax, Inc. Immunogenic fusion protein compositions and methods of use thereof
WO2024052882A1 (en) 2022-09-09 2024-03-14 Access To Advanced Health Institute Immunogenic vaccine composition incorporating a saponin

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2495939B1 (fr) * 1980-12-11 1985-10-11 Merieux Inst Procede de purification de polyosides de streptococcus pneumoniae et vaccin a base de polyosides ainsi purifies
DE69428854T2 (de) * 1993-09-03 2002-04-11 Societe Des Produits Nestle S.A., Vevey Bacteriocine aus Streptococcus thermophilus

Also Published As

Publication number Publication date
FI103122B (fi) 1999-04-30
CA2005704A1 (en) 1990-06-16
AU626961B2 (en) 1992-08-13
WO1990006951A1 (en) 1990-06-28
HUT58804A (en) 1992-03-30
DK173629B1 (da) 2001-05-14
JPH04503948A (ja) 1992-07-16
NO912226D0 (no) 1991-06-11
EP0449856A1 (de) 1991-10-09
DK115591D0 (da) 1991-06-14
BG51358A3 (bg) 1993-04-15
RU2121481C1 (ru) 1998-11-10
CA2005704C (en) 2003-02-11
NO912226L (no) 1991-07-25
FI912878A0 (fi) 1991-06-14
DK115591A (da) 1991-08-14
NO304317B1 (no) 1998-11-30
AU4756490A (en) 1990-07-10
DE68929323T2 (de) 2002-04-18
EP0449856A4 (en) 1992-05-20
JP3237842B2 (ja) 2001-12-10
DE68929323D1 (de) 2001-10-18
FI103122B1 (fi) 1999-04-30
EP0449856B1 (de) 2001-09-12
ES2160570T3 (es) 2001-11-16
MC2178A1 (fr) 1992-05-22

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