WO1998028005A1 - Vaccins contre la chlamydia - Google Patents

Vaccins contre la chlamydia Download PDF

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Publication number
WO1998028005A1
WO1998028005A1 PCT/EP1997/007282 EP9707282W WO9828005A1 WO 1998028005 A1 WO1998028005 A1 WO 1998028005A1 EP 9707282 W EP9707282 W EP 9707282W WO 9828005 A1 WO9828005 A1 WO 9828005A1
Authority
WO
WIPO (PCT)
Prior art keywords
vaccine
momp
chlamydia
outer membrane
mlt
Prior art date
Application number
PCT/EP1997/007282
Other languages
English (en)
Inventor
Jean-Francois Lucien Maisonneuve
Vincent Georges Christian Louis Verlant
Original Assignee
Smithkline Beecham Biologicals S.A.
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 Smithkline Beecham Biologicals S.A. filed Critical Smithkline Beecham Biologicals S.A.
Priority to AU57639/98A priority Critical patent/AU5763998A/en
Priority to JP52842398A priority patent/JP2001507004A/ja
Priority to EP97953919A priority patent/EP0948352A1/fr
Priority to CA002275896A priority patent/CA2275896A1/fr
Publication of WO1998028005A1 publication Critical patent/WO1998028005A1/fr

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Classifications

    • 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
    • A61K39/118—Chlamydiaceae, e.g. Chlamydia trachomatis or Chlamydia psittaci
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • A61K2039/55544—Bacterial toxins

Definitions

  • the present invention relates to a vaccine formulation for the prevention of Chlamydia infections.
  • MOMP major outer membrane protein
  • mLT heat-labile enterotoxin
  • CT cholera toxin
  • Chlamydia trachomatis The gram-negative bacterium Chlamydia trachomatis is a common human pathogen; transmitted from human to human, it causes ocular and genital infections which can result in long term sequelae.
  • Genital Chlamydial infections which are targeted by these vaccine preparations, are the most common bacterial sexually transmitted diseases (STDs) in the US.
  • STDs sexually transmitted diseases
  • the infection exerts its most detrimental consequences in women, the cervix being the most commonly infected site although severe complications like endometritis, pelvic inflammatory diseases (PID) and salpingitis can result from ascending infections leading to infertility and ectopic pregnancy. It has been shown that, whereas a single episode of PID can result in an infertility rate of 6.1 % , three or more episodes have led to an infertility rate of 54% (20).
  • the C. trachomatis species is serotyped into 15 serovars and STDs are caused by serovars D to K which cover 3 different serogroups (19), therefore a vaccine against Chlamydial STD should protect against multiple serovars that are more or less antigenically related.
  • Vaccine trials performed in man and non-human primates using the whole organism as immunogen gave serovar-specific protection but some of the vaccinees developed more severe reactions upon reinfection (6).
  • the MOMP displays 4 variable domains (VD) surrounded by five constant regions that are highly conserved among serovars (15, 22). In vitro and in vivo neutralizing B-cell epitopes have been mapped on these VDs (2, 23) whereas T-cell epitopes have been identified in both variable and constant domains (1, 16).
  • the protein is produced with a signal sequence which is cleaved to produce the mature protein.
  • Immunisations with recombinant or purified MOMP followed by homotypic or heterotypic Chlamydia challenges have been performed in different animal models with variable effects on the parameters of the infection (3, 17, 18). In a heterotypic challenge experiment, Tuffrey et al.
  • the presence of elevated MOMP-specific IgG2a ratios in the serum of immunised mice as well as the secretion of iFN-gamma upon in vitro restimulation of immune spleen cells has confirmed that protection is associated with an antigen-specific Thl -like immune response.
  • others have shown that adoptive transfer of a MoPn-specific Thl clone enables infection to be resolved in nude mice, genitally infected with MoPn.
  • the activation of a predominantly Thl-like subset is consistent also with the protective immune response to other intracellular pathogens such as Leishmania (9) and Mycobacterium (21).
  • the present invention provides a vaccine composition which is effective at the mucosal level in conferring protection against infertility resulting from
  • the vaccine is effective in the mucosa where
  • Chlamydia infections are primarily associated.
  • the vaccine may be administered by any known route, but is advantageously useful as an oral or intranasal vaccine
  • the present invention provides a vaccine formulation comprising a recombinant or purified major outer protein (rMOMP) and a mucosal adjuvant.
  • the vaccine contains MOMP from the serovar L2, F, D or E, but may additionally contain antigens from other serovars.
  • Combination vaccines comprising MOMP from two or more serovars may be utilised.
  • Preferred combination comprise MOMP from D and E serovars.
  • the mucosal adjuvant is a mutated LT (for example LT R192G) from E. coli or the cholera toxin (CT).
  • a mutated LT for example LT R192G
  • CT cholera toxin
  • Mutated LT R192G can be obtained from following the teaching of IPA PCT/US95/09005 published under No. 96/06627]. Cholera Toxin is available commercially from Swiss Serum, Bern.
  • each vaccine is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Generally it is expected that each dose will comprise 1-1000 ⁇ g of protein, preferably 2-100 ⁇ g, typically between 4-40 ⁇ g. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects.
  • compositions of the present invention may be used for both prophylactic and therapeutic purposes.
  • the invention provides a method of treatment comprising administering an effective amount of a vaccine of the present invention to a patient.
  • the vaccine may be administered intra nasally.
  • Doses of vaccine devoted to intra-nasal immunisation were prepared by mixing 10 ⁇ g mLT (obtained from SmithKline Beecham Biologicals) or CT (Swiss Serum, Bern) with 10 ⁇ g of rMOMP serovar F (rMOMPF) or L2 (rMOMPL2) in a final volume of 20 ⁇ l PBS.
  • mice Groups of ten female C3H mice (6 weeks, Iffa Credo) were immunised at week 0 and 2 by intra-nasal administration of 20 ⁇ l of the vaccine formulation containing CT or mLT under Hypnorm (Janssen-Cilag) and Dormicum (Roche) anesthesia.
  • the experimental challenge was carried out as following: at week 5, mice were given 2.5 mg progesterone intra peritoneally (Depo-Provera, Upjohn) and at week 6, they were infected by bilateral intrauterine inoculation with 5 xlO ⁇ inclusion forming units (IFU) C. trachomatis Nil (serovar F) in 100 ⁇ l sucrose phospate glutamate buffer (SPG) or with 100 ⁇ l of a Mc Coy cell extract for the fertility positive control group.
  • IFU inclusion forming units
  • mice were cagged with males for 3 months for fertility assessment (1 male for 2 females per cage with weekly rotation of the males within each group); the parameters used for estimating group's fertility were : F (number of mice which littered one time or more divided by the total number of mice), M (number of newborn mice (dead or alive) divided by the number of litters) and N (number of newborn mice (dead of alive) divided by the total number of mice).
  • CT-specific IgA and IgG were also determined in the samples from the first experiment. Titers were determined arbitrarly as the reciprocal of the sample dilution corresponding to an optical density of 1 at 492 nm and mice that displayed at least once a titer higher or equivalent to 4 were considered to be positive for antigen-specific IgA .
  • triplicates cultures were set up in round bottom 96-well culture plates using 5x10 ⁇ responder cells per well in 200 ⁇ l of RPMI 1640 with 10% foetal calf serum (FCS, Gibco-BRL); after 72 hours of incubation at 37°C in 7% CO2, supematants (SN) were Centered for cells.
  • FCS foetal calf serum
  • SN supematants
  • SI stimulation index
  • IFN-gamma was determined in culture SN using a commercial ELISA kit (Duoset, Genzyme). For cells obtained at day 9 after boosting, 72 h culture SN of the lymphoproliferative assay pooled per triplicate were used while for those obtained at day 19, 48 h culture SN from 24-well plates especially established for that purpose (5xl0 6 cells per ml of RPMI 1640 containing 10% FCS) were used. RESULTS
  • a third experiment was set up in order to characterize the cellular activation evoked by rMOMP adjuvanted with mLT wherein the negative control group consisted in mice intra nasally sham-immunised with mLT alone.
  • mice were intra-nasally immunised either with rMOMPF combined with CT, or with rMOMPL2 combined with CT or mLT; in addition to the negative and positive control groups described above, a sham-immunised control group, intra-nasally treated with CT alone, was included in the experiment.
  • intra-nasal administration of rMOMPF+CT did not induce any detectable humoral rMOMPF- specific response, neither in the sera collected just before challenge (IgG response), nor in the vaginal secretions collected weekly from boosting immunisation to challenge (IgA response).
  • intra-nasal administration of rMOMPL2 combined with CT or mLT induced an antigen-specific humoral response in some of the animals: 1 and 3 out of 10 mice, respectively, were found to be IgG positive when analyzing sera collected just before challenge, while 5 and 7 out of 10 mice, respectively, were found to be IgA positive at least in one of the vaginal washes collected every weeks from boosting immunisation to challenge. Infection did not boost the MOMP-specific IgA response as shown by analysis performed one week after challenge.
  • the cellular activation induced by the antigen formulated with mLT was analysed through cell proliferation and IFN-gamma secretion upon antigen-specific restimulation.
  • spleen cells from groups immunised with the antigen developed strong specific proliferative immune response (38% and 108% of d e positive control respectively) while those from control animals that were sham-immunised with mLT alone did not respond to in vitro restimulation (table 4 and 5).
  • Spleen cells collected at both timepoints and restimulated with the antigen displayed rFN-gamma concentrations in their culture supematants which were in the range of those restimulated during the same period with 4 ⁇ g/ml of Con A.
  • cells isolated from sham-vaccinated animals and cultured with the antigen produced relatively low levels of IFN-gamma when compared with their counterpart cultured with ConA (table 4 and 5).
  • mice Tuffrey, M., F. Alexander, W. Conlan, C. Woods and M. Ward. 1992. Heterotypic protection of mice against chlamydial salpingitis and colonization of me lower genital tract with a human serovar F isolate of Chlamydia trachomatis by prior immunization with recombinant LI major outer-membrane protein. J. Gen. Microbiol. 138: 1707-1715.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des préparations de vaccins comportant une protéine majeure de membrane externe de la Chlamydia et un adjuvant muqueux tel que la toxine cholérique ou l'entérotoxine thermolabile. De telles préparations apportent une protection contre la stérilité provoquée par la Chlamydia.
PCT/EP1997/007282 1996-12-24 1997-12-22 Vaccins contre la chlamydia WO1998028005A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU57639/98A AU5763998A (en) 1996-12-24 1997-12-22 Chlamydia vaccines
JP52842398A JP2001507004A (ja) 1996-12-24 1997-12-22 クラミジア ワクチン
EP97953919A EP0948352A1 (fr) 1996-12-24 1997-12-22 Vaccins contre la chlamydia
CA002275896A CA2275896A1 (fr) 1996-12-24 1997-12-22 Vaccins contre la chlamydia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9626864.4A GB9626864D0 (en) 1996-12-24 1996-12-24 Vaccine
GB9626864.4 1996-12-24

Publications (1)

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WO1998028005A1 true WO1998028005A1 (fr) 1998-07-02

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PCT/EP1997/007282 WO1998028005A1 (fr) 1996-12-24 1997-12-22 Vaccins contre la chlamydia

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EP (1) EP0948352A1 (fr)
JP (1) JP2001507004A (fr)
AR (1) AR011047A1 (fr)
AU (1) AU5763998A (fr)
CA (1) CA2275896A1 (fr)
CO (1) CO4650187A1 (fr)
GB (1) GB9626864D0 (fr)
WO (1) WO1998028005A1 (fr)
ZA (1) ZA9711565B (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962636A (en) * 1998-08-12 1999-10-05 Amgen Canada Inc. Peptides capable of modulating inflammatory heart disease
WO2001019998A1 (fr) * 1999-09-15 2001-03-22 Mogam Biotechnology Research Institute Nouveaux mutants detoxiques de l'enterotoxine instable a la chaleur de escherichia coli
EP1486215A2 (fr) * 1997-03-21 2004-12-15 Chiron Corporation Mutants détoxifies de toxines bactériennes ribolysant l'ADP utilisés comme adjuvants parentéraux
WO2006104890A2 (fr) * 2005-03-31 2006-10-05 Glaxosmithkline Biologicals Sa Vaccins destines a lutter contre une infection a chlamydia
US8052975B2 (en) 1998-12-08 2011-11-08 Corixa Corporation Compounds and methods for treatment and diagnosis of chlamydial infection
US8541007B2 (en) 2005-03-31 2013-09-24 Glaxosmithkline Biologicals S.A. Vaccines against chlamydial infection
US8735543B2 (en) 2010-05-28 2014-05-27 Spixia Biotechnology Ab Chimeric MOMP antigen
US8889142B2 (en) * 2004-10-25 2014-11-18 Statens Serum Institut Chlamydia trachomatis antigens for vaccine and diagnostic use
WO2017083337A1 (fr) * 2015-11-10 2017-05-18 Ohio State Innovation Foundation Méthodes et compositions associées à une affinité humorale accélérée
US11253582B2 (en) 2015-02-10 2022-02-22 Ohio State Innovation Foundation Chlamydia-activated B cell platforms and methods thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006627A1 (fr) * 1994-08-26 1996-03-07 The Administrators Of The Tulane Educational Fund Enterotoxine mutante efficace comme adjuvant oral non toxique
WO1996016178A1 (fr) * 1994-11-17 1996-05-30 Maxim Pharmaceuticals, Inc. Immunogenes pour stimuler l'immunite des muqueuses
WO1996031236A1 (fr) * 1995-04-03 1996-10-10 Smithkline Beecham Biologicals S.A. Vaccins contre les infections a chlamydia
WO1996031235A1 (fr) * 1995-04-07 1996-10-10 Pasteur-Merieux Serums & Vaccins Composition destinee a l'induction d'une reponse immunitaire mucosale
WO1997002836A1 (fr) * 1995-07-07 1997-01-30 Oravax, Inc. Toxines de clostridium difficile utilisees comme adjuvants agissant sur les muqueuses

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006627A1 (fr) * 1994-08-26 1996-03-07 The Administrators Of The Tulane Educational Fund Enterotoxine mutante efficace comme adjuvant oral non toxique
WO1996016178A1 (fr) * 1994-11-17 1996-05-30 Maxim Pharmaceuticals, Inc. Immunogenes pour stimuler l'immunite des muqueuses
WO1996031236A1 (fr) * 1995-04-03 1996-10-10 Smithkline Beecham Biologicals S.A. Vaccins contre les infections a chlamydia
WO1996031235A1 (fr) * 1995-04-07 1996-10-10 Pasteur-Merieux Serums & Vaccins Composition destinee a l'induction d'une reponse immunitaire mucosale
WO1997002836A1 (fr) * 1995-07-07 1997-01-30 Oravax, Inc. Toxines de clostridium difficile utilisees comme adjuvants agissant sur les muqueuses

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VILLENEUVE A ET AL: "Cholera toxin B subunit overcome the H-2 restriction for neutralizable epitopes of the major outer membrane protein of Chlamydia trachomatis.", THE 9TH INTERNATIONAL CONGRESS OF IMMUNOLOGY;MEETING SPONSORED BY THE AMERICAN ASSOCIATION OF IMMUNOLOGISTS AND THE INTERNATIONAL UNION OF IMMUNOLOGICAL SOCIETIES, SAN FRANCISCO, CALIFORNIA, USA, JULY 23-29, (1995) 585, XP002063817 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1486215A3 (fr) * 1997-03-21 2006-04-12 Chiron Corporation Mutants détoxifies de toxines bactériennes ribolysant l'ADP utilisés comme adjuvants parentéraux
EP1486215A2 (fr) * 1997-03-21 2004-12-15 Chiron Corporation Mutants détoxifies de toxines bactériennes ribolysant l'ADP utilisés comme adjuvants parentéraux
US6034230A (en) * 1998-08-12 2000-03-07 Amgen Canada Inc. Nucleic acids encoding myocardial peptides
US5962636A (en) * 1998-08-12 1999-10-05 Amgen Canada Inc. Peptides capable of modulating inflammatory heart disease
US8052975B2 (en) 1998-12-08 2011-11-08 Corixa Corporation Compounds and methods for treatment and diagnosis of chlamydial infection
US8263089B2 (en) 1998-12-08 2012-09-11 Corixa Corporation Compounds and methods for treatment and diagnosis of chlamydial infection
WO2001019998A1 (fr) * 1999-09-15 2001-03-22 Mogam Biotechnology Research Institute Nouveaux mutants detoxiques de l'enterotoxine instable a la chaleur de escherichia coli
US8889142B2 (en) * 2004-10-25 2014-11-18 Statens Serum Institut Chlamydia trachomatis antigens for vaccine and diagnostic use
WO2006104890A2 (fr) * 2005-03-31 2006-10-05 Glaxosmithkline Biologicals Sa Vaccins destines a lutter contre une infection a chlamydia
WO2006104890A3 (fr) * 2005-03-31 2007-03-29 Glaxosmithkline Biolog Sa Vaccins destines a lutter contre une infection a chlamydia
EA014527B1 (ru) * 2005-03-31 2010-12-30 Глаксосмитклайн Байолоджикалс С.А. Вакцины против хламидиоза
US8541007B2 (en) 2005-03-31 2013-09-24 Glaxosmithkline Biologicals S.A. Vaccines against chlamydial infection
US8735543B2 (en) 2010-05-28 2014-05-27 Spixia Biotechnology Ab Chimeric MOMP antigen
US11253582B2 (en) 2015-02-10 2022-02-22 Ohio State Innovation Foundation Chlamydia-activated B cell platforms and methods thereof
WO2017083337A1 (fr) * 2015-11-10 2017-05-18 Ohio State Innovation Foundation Méthodes et compositions associées à une affinité humorale accélérée
US10835601B2 (en) 2015-11-10 2020-11-17 Ohio State Innovation Foundation Methods and compositions related to accelerated humoral affinity

Also Published As

Publication number Publication date
JP2001507004A (ja) 2001-05-29
CA2275896A1 (fr) 1998-07-02
ZA9711565B (en) 1998-08-27
EP0948352A1 (fr) 1999-10-13
AU5763998A (en) 1998-07-17
GB9626864D0 (en) 1997-02-12
CO4650187A1 (es) 1998-09-03
AR011047A1 (es) 2000-08-02

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