WO2001021152A1 - Adjuvant comprenant un ether ou ester d'alkyle polyethylene et au moins un tensioactif non ionique - Google Patents

Adjuvant comprenant un ether ou ester d'alkyle polyethylene et au moins un tensioactif non ionique Download PDF

Info

Publication number
WO2001021152A1
WO2001021152A1 PCT/EP2000/009368 EP0009368W WO0121152A1 WO 2001021152 A1 WO2001021152 A1 WO 2001021152A1 EP 0009368 W EP0009368 W EP 0009368W WO 0121152 A1 WO0121152 A1 WO 0121152A1
Authority
WO
WIPO (PCT)
Prior art keywords
polyoxyethylene
vaccine
adjuvant
ester
ether
Prior art date
Application number
PCT/EP2000/009368
Other languages
English (en)
Inventor
Martin Friede
Philippe Hermand
Veronique Henderickx
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
Priority claimed from GBGB9922700.1A external-priority patent/GB9922700D0/en
Priority claimed from GB0016647A external-priority patent/GB0016647D0/en
Priority to JP2001524578A priority Critical patent/JP2003509452A/ja
Priority to NZ517901A priority patent/NZ517901A/en
Priority to IL14867100A priority patent/IL148671A0/xx
Priority to KR1020027003856A priority patent/KR20020048942A/ko
Priority to MXPA02003068A priority patent/MXPA02003068A/es
Priority to EP00964232A priority patent/EP1214053A1/fr
Application filed by Smithkline Beecham Biologicals S.A. filed Critical Smithkline Beecham Biologicals S.A.
Priority to AU75226/00A priority patent/AU766635B2/en
Priority to HU0203817A priority patent/HUP0203817A3/hu
Priority to BR0014285-9A priority patent/BR0014285A/pt
Priority to CA002383110A priority patent/CA2383110A1/fr
Publication of WO2001021152A1 publication Critical patent/WO2001021152A1/fr
Priority to NO20021432A priority patent/NO20021432L/no
Priority to HK02108461.1A priority patent/HK1046861A1/zh

Links

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
    • A61K39/39—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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61P33/00—Antiparasitic agents
    • 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
    • A61P37/08—Antiallergic 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel adjuvant system comprising a polyoxyethylene alkyl ether or ester surfactant in combination with at least one additional non-ionic surfactant.
  • said additional non-ionic surfactant is an Octoxynol.
  • the present invention provides said novel adjuvants, vaccines comprising them, and methods of their manufacture and their formulation into vaccines.
  • the use of the adjuvants or vaccines of the present invention in the prophylaxis or therapy of disease are also provided.
  • a method to enhance an immune response in a host using the adjuvant and vaccines of the present invention is also provided.
  • the adjuvants are particularly useful as a mucosal adjuvant, but are also effective systemically.
  • mucosal vaccination is attractive since it has been shown in animals that mucosal administration of antigens has a greater efficiency of inducing protective responses at mucosal surfaces, which is the route of entry of many pathogens.
  • mucosal vaccination such as intranasal vaccination, may induce 0 mucosal immunity not only in the nasal mucosa, but also in distant mucosal sites such as the genital mucosa (Mestecky, 1987, Journal of Clinical Immunology, 7, 265-276; McGhee and Kiyono, Infectious Agents and Disease, 1993, 2, 55-73).
  • safe and effective mucosal adjuvants which are suitable for use in humans, remains to be identified.
  • the present invention provides 5 a solution to this problem.
  • vaccine preparations comprising an admixture of either polyoxyethylene castor oil or caprylic/capric acid glycerides, with polyoxyethylene sorbitan monoesters, and an antigen, are capable of inducing systemic immune responses after topical administration to a mucosal membrane (WO 94/17827).
  • This patent application discloses the combination of the non-ionic surfactant TWEEN20TM (polyoxyethylene sorbitan monoester) and Imwitor742TM (caprylic/capric acid glycerides), or a combination of TWEEN20TM and polyoxyethylene castor oil are able to enhance the systemic immune response following intranasal immunisation. Details of the effect of this formulation on the enhancement of the immune response towards intranasally administered antigens have also been described in the literature (Gizurarson et al. 1996. Vaccine Research, 5, 69-75; Aggerbeck et al. 1997, Vaccine, 15, 307-316; Tebbey et al.,Viral Immunol 1999;12(l):41-5).
  • Non-ionic surfactants have also been formulated in such a way as to form non-ionic surfactant vesicles (commonly known as NISV, US 5,679,355). Such formulations of non-ionic surfactants, often in the presence of cholesterol, form lipid-bilayer vesicles which entrapp antigen within the inner aqueous phase or within the bilayer itself.
  • Surfactants are commonly used in the formulation of oil emulsion adjuvants for systemic administration, and function to stabilise the oil droplets.
  • polyoxyethylene sorbitan esters TWEENTM
  • SPANTM sorbitan fatty acid esters
  • TWEENTM polyoxyethylene sorbitan esters
  • SPANTM sorbitan fatty acid esters
  • the applicant presents here the surprising finding that polyoxyethylene alkyl ethers or esters, in combination with at least one additional non-ionic surfactant, together act as a potent adjuvants for vaccines.
  • such compositions may be administered systemically, but are also potent in the induction of systemic immune responses when the vaccine compositions are administered mucosally.
  • the immune responses induced by mucosal administration of vaccines of the present invention may be at least as high as those observed after a systemic injection of conventional vaccine.
  • the present invention provides safe and potent adjuvants which are easily manufactured, and comprise at least one polyoxyethylene alkyl ether or ester and at least one additional non-ionic surfactant.
  • the surfactants employed in the invention may be in aqueous solution or may form suspensions of particulate structures such as vesicles or micelles.
  • Preferably the surfactants are in the form of an aqueous solution or a micelle.
  • one embodiment of the present invention consists of a vaccine formulation comprising a polyoxyethylene alkyl ether of general formula (I), wherein n is between 1 and 50, preferably 4-24, more preferably 6-12, and most preferably 9; the R component is C,. 50 , preferably C 4 -C 20 alkyl and most preferably C 12 alkyl.
  • concentration of the polyoxyethylene ethers should be in the range 0.1-20% , preferably from 0.1-10% , and most preferably in the range 0.1-1 % .
  • Suitable polyoxyethylene ethers are selected from the following group: polyoxyethylene-9- lauryl ether, polyoxyethylene-9-stearyl ether, polyoxyethylene-8-stearyl ether, polyoxyethylene-4-lauryl ether, polyoxyethylene-35-lauryl ether, and polyoxyethylene-23-lauryl ether.
  • said polyoxyethylene alkyl ether is polyoxyethylene-9-lauryl ether (laureth 9).
  • Alternative terms or names for polyoxyethylene lauryl ether are disclosed in the CAS registry.
  • the CAS registry number of polyoxyethylene-9 lauryl ether is: 9002-92-0.
  • Polyoxyethylene ethers such as polyoxyethylene lauryl ether are described in the Merck index (12 th ed: entry 7717, Merck & Co. Inc. , Whitehouse Station, N.J., USA; ISBN 0911910-12-3), where therapeutic uses are stated to include: topical anesthetic; anti-pruritic; and sclerosing agent activities.
  • polyoxyethylene ethers, or esters are non- ionic surfactants.
  • Laureth 9 is formed by reacting ethylene oxide with dodecyl alcohol, and has an average of nine ethylene oxide units.
  • n the average number of ethylene oxide units present in all of the surfactants in the mixture.
  • the ratio of the length of the polyoxyethylene section to the length of the alkyl chain in the surfactant affects the solubility of this class of detergent in an aqueous medium.
  • the adjuvants of the present invention may be in solution or may form paniculate structures such as micelles or vesicles.
  • the adjuvants of the present invention safe, easily sterilisable by for example passing through a 0.22 ⁇ m membrane, simple to administer, and may be manufactured in a simple fashion without the GMP and QC issues associated with the formation of uniform paniculate structures.
  • Some polyoxyethylene ethers, such as laureth 9, are capable of forming non-vesicular solutions.
  • polyoxyethylene-8 palmitoyl ether (C Ig E g ) is capable of forming vesicles. Accordingly, the use of vesicles of polyoxyethylene-8 palmitoyl ether in combination with at least one additional non-ionic surfactant, to form adjuvants of the present invention is specifically contemplated.
  • the polyoxyethylene alkyl ether element present in the adjuvant combinations of the present invention has haemolytic activity.
  • the haemolytic activity of a polyoxyethylene alkyl ether may be measured in vitro, with reference to the following assay, and is as expressed as the highest concentration of the detergent which fails to cause lysis of the red blood cells:
  • the polyoxyethylene alkyl ethers, or surfactants of general formula (I), of the present invention preferably have a haemolytic activity, of approximately between 0.5- 0.0001 % , more preferably between 0.05-0.0001 % , even more preferably between 0.005-0.0001 %, and most preferably between 0.003-0.0004% .
  • said polyoxyethylene ethers or esters should have a haemolytic activity similar (i.e. within a ten-fold difference) to that of either polyoxyethylene-9 lauryl ether or polyoxyethylene-8 stearyl ether.
  • At least one additional non-ionic surfactant which may be any detergent with suitable surface active properties.
  • Preferred non-ionic surfactants are not ones that fall within the general formula (I), e.g. Octoxynols and Polyoxyethylene sorbitan esters. Particularly preferred
  • Octoxynols include Triton X-45, t-octylphenoxy polyethoxyethanol (Triton X-100),
  • Triton X-100 is particularly preferred.
  • the Octoxynol series, including t-octylphenoxypolyethoxyethanol (TRITON XI 00TM) is described in Merck Index Entry 6858 (Page 1162, 12 th Edition, Merck & Co. Inc. , Whitehouse Station, N.J., USA; ISBN 0911910-12-3).
  • polyoxyethylene sorbitan esters are polyoxyethylene sorbitan esters.
  • the polyoxyethylene sorbitan esters including polyoxyethylene sorbitan monooleate (TWEEN80TM) are described in Merck Index Entry 7742 (Page 1308, 12 th Edition, Merck & Co. Inc., Whitehouse Station, N.J., USA; ISBN 0911910-12-3). Both Octoxynols and polyoxyethylene sorbitan esters may be purchased from Sigma Inc.
  • the preferred polyoxyethylene sorbitan ester is polyoxyethylene sorbitan monooleate (Tween 80TM).
  • the most prefered adjuvants of the present invention comprise a polyoxyethylene alkyl ether and an Octoxynol, such as t-octylphenoxypolyethoxyethanol (TRITON XI 00TM).
  • said combination may further comprise a polyoxyethylene sorbitan ester, such as polyoxyethylene sorbitan monooleate (TWEEN80TM).
  • said polyoxyethylene alkyl ether is polyoxyethylene-9-lauryl ether
  • said Octoxynol is t-octylphenoxypolyethoxyethanol (TRITON XI 00TM).
  • an ionic detergent may be added such as a bile salt or derivative of cholic acid.
  • the adjuvant formulation may comprise a polyoxyethylene alkyl ether or ester (formula I), an octoxynol, optionally comprising a polyoxyethylene sorbitan ester, and optionally comprising a bile salt or cholic acid derivative.
  • the preferred embodiment of this formulation comprises a combination of polyoxyethylene-9 lauryl ether, t-octylphenoxypolyethoxyethanol (TRITON XI 00TM), polyoxyethylene sorbitan monooleate and sodium deoxycholate.
  • the concentration of polyoxyethylene alkyl ether or ester, such as polyoxyethylene- 9 lauryl ether, in the adjuvants of the present invention will typically be in the range of 0.001 to 20 % , preferably 0.001 to 10 % and more preferably 0.001 to 1 % , and most preferably between 0.001 and 0.8% or about 0.5% (w/v).
  • the additional non-ionic surfactant which is not a polyoxyethylene ether or ester.
  • the or each of the additional non-ionic surfactants will typically be present in the final vaccine formulation at a concentration of between 0.001 to 20%, more preferably 0.01 to 10% , and most preferably up to about 2% (w/v).
  • additional non-ionic surfactants are present, these are preferably present in the final formulation at a concentration of up to about 2% each, typically at a concentration of up to about 0.6% each. If three or more additional non-ionic surfactants are present, they are generally present at up to a concentration of about 1 % each and typically in traces up to about 0.2% or 0.1 % each. Any mixture of surfactants may be present in the vaccine formulations according to the invention.
  • Non-ionic surfactants such as those discussed above have preferred concentrations in the final vaccine composition as follows: octyl- or nonylphenoxy polyoxyethanols such as Triton X-100TM or other detergents in the Triton series: from 0.001 % to 20% , preferably 0.001 % to 10% , more preferably from 0.001 to 1 % , and most preferably 0.005 to 0.1 % (w/v); and if present polyoxyethylene sorbitan esters such as Tween 80TM: 0.01 to 1 %, most preferably about 0.1 % (w/v).
  • octyl- or nonylphenoxy polyoxyethanols such as Triton X-100TM or other detergents in the Triton series: from 0.001 % to 20% , preferably 0.001 % to 10% , more preferably from 0.001 to 1 % , and most preferably 0.005 to 0.1 % (w/v); and if present polyoxyethylene sorb
  • the total concentration of detergent in the vaccine or adjuvant formulations of the present invention is typically in the range of 0.001 to 40%, preferably between 0.001 and 20%, more preferably between 0.001 and 10%, more preferably still between 0.001 and 1 %, and most preferably between 0.001 to 0.-7%. (w/v).
  • the vaccine preparations of the present invention may be used to protect or treat a mammal susceptible to, or suffering from disease, by means of administering said vaccine via a mucosal route, such as the oral/bucal/intestinal/vaginal/rectal or nasal route. Such administration may be in a droplet, spray, or dry powdered form. Nebulised or aerosolised vaccine formulations also form part of this invention. Enteric formulations such as gastro resistant capsules and granules for oral administration, suppositories for rectal or vaginal administration also form part of this invention. The present invention may also be used to enhance the immunogenicity of antigens applied to the skin (transdermal or transcutaneous delivery). In addition, the adjuvants of the present invention may be parentally delivered, for example intramuscular, or subcutaneous administration. When used for intranasal vaccination, the vaccines of the present invention are preferably haemolytic in nature.
  • a variety of administration devices may be used.
  • a spray device such as the commercially available AccusprayTM (Becton Dickinson) may be used.
  • Preferred spray devices for intranasal use are devices for which the performance of the device is not dependent upon the pressure applied by the user. These devices are known as pressure threshold devices. Liquid is released from the nozzle only when a threshold pressure is attained. These devices make it easier to achieve a spray with a regular droplet size. Pressure threshold devices suitable for use with the present invention are known in the art and are described for example in WO 91/13281 and EP 311 863 B. Such devices are commercially available from Pfeiffer GmbH.
  • Preferred intranasal devices produce droplets (measured using water as the liquid) in the range 1 to 200 ⁇ m, preferably 10 to 120 ⁇ m. Below lO ⁇ m there is a risk of inhalation, therefore it is desirable to have no more than about 5 % of droplets below lO ⁇ m. Droplets above 120 ⁇ m do not spread as well as smaller droplets, so it is desirable to have no more than about 5% of droplets exceeding 120 ⁇ m.
  • Bi-dose delivery is a further preferred feature of an intranasal delivery device for use with the vaccines according to the invention.
  • Bi-dose devices contain two subdoses of a single vaccine dose, one sub-dose for administration to each nostril.
  • the invention provides in a further aspect a kit comprising an intranasal administration device as described herein containing a vaccine formulation according to the invention.
  • the adjuvant formulations of the present invention may also comprise a bile acid or derivative of cholic acid.
  • the derivative of cholic acid is a salt thereof, and more preferably a sodium salt thereof.
  • bile acids and derivatives thereof include cholic acid itself, deoxy cholic acid, taurodeoxycholate, chenodeoxy colic acid, lithocholic acid ursodeoxycholic acid, hyodeoxy cholic acid and derivatives like glyco-, tauro-, amidopropyl-1- propanesulfonic-, amidopropyl-2-hydroxy-l-propanesulfonic derivatives of the aforementioned bile acids, or N,N-bis (3DGluconoamidopropyl) deoxy cholamide.
  • NaDOC sodium deoxycholate
  • the adjuvant formulation of the present invention are advantageous when in the form of an aqueous solution or a suspension of non-vesicular forms.
  • Such formulations are easy to manufacture reproducibly, and also to sterilise (terminal filtration through a 450 or 220 nm pore membrane) and are also easy to administer to the nasal mucosa in the form of a spray without degradation of complex physical structure of the adjuvant.
  • Polyoxyethylene-9 lauryl ether in combination with TRITON-X 100TM forms an aqueous solution (small micelles may also be present).
  • a method of inducing or enhancing an immune response in a host comprising admixing the antigen and the adjuvants of the present invention, and administering said admixture to the host.
  • the route of administration to said host is via a mucosal surface, and more preferably via the nasal mucosa.
  • the admixture is preferably administered as a spray.
  • systemic immune response is induced by a nasal administration of the vaccines of the present invention.
  • the methods to enhance an immune response may be either a priming or boosting dose of the vaccine, and that the vaccine comprises an influenza antigen or antigenic preparation.
  • the prefered adjuvant formulation for administering to the nasal mucosa in these methods are combinations of polyoxyethylene alkyl ether and an octoxynol, such as a preferred combination of polyoxyethylene-9 lauryl ether and t- octylphenoxypolyethoxyethanol (TRITON XI 00TM), optionally said adjuvant combination additionally comprising a polyoxyethylene sorbitan ester (such as the monooleate, TWEEN 80TM) and/or a bile salt or cholic acid derivative such as sodium deoxycholate.
  • a polyoxyethylene sorbitan ester such as the monooleate, TWEEN 80TM
  • a bile salt or cholic acid derivative such as sodium deoxycholate.
  • compositions of the present invention will be used to formulate vaccines containing antigens derived from a wide variety of sources.
  • antigens may include human, bacterial, or viral nucleic acid, pathogen derived antigen or antigenic preparations, tumour derived antigen or antigenic preparations, host-derived antigens, including GnRH and IgE peptides, recombinantiy produced protein or peptides, and chimeric fusion proteins.
  • the vaccine formulations of the present invention contain an antigen or antigenic composition capable of eliciting an immune response against a human pathogen, which antigen or antigenic composition is derived from HIV-1, (such as tat, nef, gpl 20 or gpl 60), human herpes viruses, such as gD or derivatives thereof or Immediate Early protein such as ICP27 from HSV1 or HSV2, cytomegalovirus ((esp Human)(such as gB or derivatives thereof), Rotavirus (including live- attenuated viruses), Epstein Barr virus (such as gp350 or derivatives thereof), Varicella Zoster Virus (such as gpl, II and IE63), or from a hepatitis virus such as hepatitis B virus (for example Hepatitis B Surface antigen or a derivative thereof), hepatitis A virus, hepatitis C virus and hepatitis E virus, or from other viral pathogens, such as paramyxo
  • Encephalitis Virus or Influenza virus (whole live or inactivated virus, split influenza virus, grown in eggs or MDCK cells, or Vero cells or whole flu virosomes (as described by R. Gluck, Vaccine, 1992, 10, 915-920) or purified or recombinant proteins thereof, such as HA, NP, NA, or M proteins, or combinations thereof), or derived from bacterial pathogens such as Neisseria spp, including N. gonorrhea and N. meningitidis (for example capsular polysaccharides and conjugates thereof, transferrin-binding proteins, lactoferrin binding proteins, PilC, adhesins); S.
  • Influenza virus whole live or inactivated virus, split influenza virus, grown in eggs or MDCK cells, or Vero cells or whole flu virosomes (as described by R. Gluck, Vaccine, 1992, 10, 915-920) or purified or recombinant proteins thereof, such as HA, NP,
  • M catarrhalis also known as Branhamella catarrhalis
  • Branhamella catarrhalis for example high and low molecular weight adhesins and invasinsj
  • Bordetella spp including B. pertussis (for example pertactin, pertussis toxin or derivatives thereof, filamente
  • Mycobacterium spp. including M. tuberculosis (for example ESAT6, Antigen 85 A, -B or -C), M. bovis, M. leprae, M. avium, M. paratuberculosis, M. smegmatis; Legionella spp, including L. pneumophila;
  • M. tuberculosis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • M. bovis for example ESAT6, Antigen 85 A, -B or -C
  • Escherichia spp including enter otoxic E. coli (for example colonization factors, heat-labile toxin or derivatives thereof, heat-stable toxin or derivatives thereof), enterohemorragic E. coli, enteropathogenic E. coli (for example shiga toxin-like toxin or derivatives thereof); Vibrio spp, including V. cholera (for example cholera toxin or derivatives thereof j; Shigella spp, including S. sonnei, S. dysenteriae, S. flexnerii; Yersinia spp, including Y. enterocolitica (for example a Yop protein) , Y. pestis, Y.
  • enterotoxic E. coli for example colonization factors, heat-labile toxin or derivatives thereof, heat-stable toxin or derivatives thereof
  • enterohemorragic E. coli enteropathogenic E. coli (for example shiga toxin-like toxin or derivative
  • pseudotuberculosis Campy lobacter spp, including C. jejuni (for example toxins, adhesins and invasins) and C. coli; Salmonella spp, including S. typhi, S. paratyphi, S. choleraesuis, S. enteritidis; Listeria spp., including L. monocytogenes; Helicobacter spp, including H. pylori (for example urease, catalase, vacuolating toxin); Pseudomonas spp, including P. aeruginosa; Staphylococcus spp., including S. aureus, S.
  • C. jejuni for example toxins, adhesins and invasins
  • Salmonella spp including S. typhi, S. paratyphi, S. choleraesuis, S. enteritidis
  • Listeria spp. including L. monocytogenes
  • Clostridium spp. including C. tetani (for example tetanus toxin and derivative thereof), C. botulinum (for example botulinum toxin and derivative thereof), C. difficile (for example clostridium toxins A or B and derivatives thereof); Bacillus spp., including B. anthracis (for example botulinum toxin and derivatives thereof);
  • Corynebacterium spp. including C. diphtheriae (for example diphtheria toxin and derivatives thereof); Borrelia spp., including B. burgdorferi (for example OspA,
  • Chlamydia spp. including C. trachomatis (for example MOMP, heparin-binding proteins), C. pneumoniae (for example MOMP, heparin-binding proteins), C. psittaci; Leptospira spp., including L. interrogans; Treponema spp., including T. pallidum (for example the rare outer membrane proteins), T. denticola, T. hyodysenteriae; or derived from parasites such as Plasmodium spp., including P. falciparum; Toxoplasma spp . , including T. gondii (for example SAG2, SAG3, Tg34);
  • C. trachomatis for example MOMP, heparin-binding proteins
  • C. pneumoniae for example MOMP, heparin-binding proteins
  • C. psittaci Leptospira spp., including L. interrogans
  • Entamoeba spp. including E. histolytica
  • Babesia spp. including B. microti
  • Trypanosoma spp. including T. cruzi; Giardia spp., including G. lamblia;
  • Leshmania spp. including L. major; Pneumocystis spp., including P. carinii; Trichomonas spp., including T. vaginalis; Schisostoma spp., including S. mansoni, or derived from yeast such as Candida spp., including C. albicans; Cryptococcus spp., including C. neoformans.
  • Preferred bacterial vaccines comprise antigens derived from Streptococcus spp, including S. pneumoniae (for example capsular polysaccharides and conjugates thereof, PsaA, PspA, streptolysin, choline-binding proteins)and the protein antigen
  • H. influenzae type B for example PRP and conjugates thereof
  • non typeable H. influenzae for example OMP26
  • high molecular weight adhesins P5, P6, protein D and lipoprotein D
  • fimbrin and fimbrin derived peptides US 5,843,464
  • Other preferred bacterial vaccines comprise antigens derived from Morexella Catarrhalis (including outer membrane vesicles thereof, and OMP106
  • the vaccine formulation of the invention comprises the HIV-1 antigen, gpl20, especially when expressed in CHO cells.
  • the vaccine formulation of the invention comprises gD2t as hereinabove defined.
  • vaccines containing the claimed adjuvant comprise antigen derived from the Human Papilloma Virus (HPV) considered to be responsible for genital warts, (HPV 6 or HPV 11 and others), and the HPV viruses responsible for cervical cancer (HPV 16, HPV 18 and others).
  • HPV Human Papilloma Virus
  • Particularly preferred forms of genital wart prophylactic, or therapeutic, vaccine comprise LI particles or capsomers, and fusion protein? comprising one or more antigens selected from the HPV 6 and HPV 11 proteins E6, E7, LI, and L2.
  • fusion protein L2E7 as disclosed in WO 96/26277, and proteinD(l/3)-E7 disclosed in GB 9717953.5 (PCT/EP98/05285).
  • a preferred HPV cervical infection or cancer, prophylaxis or therapeutic vaccine, composition may comprise HPV 16 or 18 antigens.
  • HPV 16 or 18 antigens For example, LI or L2 antigen monomers, or LI or L2 antigens presented together as a virus like particle (VLP) or the LI alone protein presented alone in a VLP or capsomer structure.
  • VLP virus like particle
  • antigens, virus like particles and capsomer are per se known. See for example WO94/00152, WO94/20137, WO94/05792, and WO93/02184.
  • Additional early proteins may be included alone or as fusion proteins such as preferably E7, E2 or E5 for example; particularly preferred embodiments of this includes a VLP comprising L1E7 fusion proteins (WO 96/11272) .
  • Particularly preferred HPV 16 antigens comprise the early proteins E6 or E7 in fusion with a protein D carrier to form Protein D - E6 or E7 fusions from HPV 16, or combinations thereof; or combinations of E6 or E7 with L2 (WO 96/26277).
  • HPV 16 or 18 early proteins E6 and E7 may be presented in a single molecule, preferably a Protein D- E6/E7 fusion.
  • Such vaccine may optionally contain either or both E6 and E7 proteins from HPV 18, preferably in the form of a Protein D - E6 or Protein D - E7 fusion protein or Protein D E6/E7 fusion protein.
  • the vaccine of the present invention may additionally comprise antigens from other HPV strains, preferably from strains HPV 6, 11, 31, 33, or 45.
  • Vaccines of the present invention further comprise antigens derived from parasites that cause Malaria.
  • preferred antigens from Plasmodia falciparum include RTS,S and TRAP.
  • RTS is a hybrid protein comprising substantially all the C-terminal portion of the circumsporozoite (CS) protein of P. falciparum linked via four amino acids of the preS2 portion of Hepatitis B surface antigen to the surface (S) antigen of hepatitis B virus. It's full structure is disclosed in the International Patent Application No. PCT/EP92/02591 , published under Number WO 93/ 10152 claiming priority from UK patent application No.9124390.7.
  • RTS When expressed in yeast RTS is produced as a lipoprotein particle, and when it is co-expressed with the S antigen from HBV it produces a mixed particle known as RTS,S.
  • TRAP antigens are described in the International Patent Application No. PCT/GB89/00895, published under WO 90/01496.
  • a preferred embodiment of the present invention is a Malaria vaccine wherein the antigenic preparation comprises a combination of the RTS,S and TRAP antigens.
  • Other plasmodia antigens that are likely candidates to be components of a multistage Malaria vaccine are P.
  • the formulations may also contain an anti-tumour antigen and be useful for the immunotherapeutic treatment cancers.
  • the adjuvant formulation finds utility with tumour rejection antigens such as those for prostrate, breast, colorectal, lung, pancreatic, renal or melanoma cancers.
  • Exemplary antigens include MAGE 1 and MAGE 3 or other MAGE antigens for the treatment of melanoma, PRAME, BAGE or GAGE (Robbins and Kawakami, 1996, Current Opinions in Immunology 8, pps 628-636; Van den Eynde et al., International Journal of Clinical & Laboratory Research (submitted 1997); Correale et al. (1997), Journal of the National Cancer Institute 89, p293. Indeed these antigens are expressed in a wide range of tumour types such as melanoma, lung carcinoma, sarcoma and bladder carcinoma.
  • Tumor-Specific antigens are suitable for use with adjuvant of the present invention and include, but are not restricted to Prostate specific antigen (PSA) or Her-2/neu, KSA (GA733), MUC-1 and carcinoembryonic antigen (CEA). Accordingly in one aspect of the present invention there is provided a vaccine comprising an adjuvant composition according to the invention and a tumour rejection antigen.
  • PSA Prostate specific antigen
  • KSA Her-2/neu
  • CEA carcinoembryonic antigen
  • said antigen may be a self peptide hormone such as whole length Gonadotrophin hormone releasing hormone (GnRH, WO 95/20600), a short 10 amino acid long peptide, in the treatment of many cancers, or in immunocastration.
  • GnRH Gonadotrophin hormone releasing hormone
  • a short 10 amino acid long peptide in the treatment of many cancers, or in immunocastration.
  • compositions of the present invention will be used to formulate vaccines containing antigens derived from Borrelia sp.
  • antigens may include nucleic acid, pathogen derived antigen or antigenic preparations, recombinantiy produced protein or peptides, and chimeric fusion proteins.
  • the antigen is OspA.
  • the OspA may be a full mature protein in a lipidated form virtue of the host cell (E.Coli) termed (Lipo-OspA) or a non-lipidated derivative.
  • non-lipidated derivatives include the non-lipidated NSl -OspA fusion protein which has the first 81 N-terminal amino acids of the non-structural protein (NSl) of the influenza virus, and the complete OspA protein, and another, MDP-OspA is a non-lipidated form of OspA carrying 3 additional N-terminal amino acids.
  • Vaccines of the present invention may be used for the prophylaxis or therapy of allergy.
  • Such vaccines would comprise allergen specific (for example Der pi) and allergen non-specific antigens (for example peptides derived from human IgE, including but not restricted to the stanworth decapeptide (EP 0 477 231 Bl)).
  • Non-live influenza virus preparations may be derived from the conventional embryonated egg method, or they may be derived from any of the new generation methods using tissue culture to grow the virus.
  • Suitable cell substrates for growing the virus include for example dog kidney cells such as MDCK or cells from a clone of MDCK, MDCK-like cells, monkey kidney cells such as AGMK cells including Vero cells, or any other cell type suitable for the production of influenza virus for vaccine purposes.
  • Suitable cell substrates include human cells e.g. MRC-5 cells. Suitable cell substrates are not limited to cell lines; for example primary cells such as chicken embryo fibroblasts are also included.
  • the influenza virus antigen preparation may be produced by any of a number of commercially applicable processes, for example the split flu process described in patent no. DD 300 833.
  • Commercially available split influenza includes FluarixTM which is sold by SmithKline Beecham, as such Fluarix in combination with the adjuvant of the present invention constitute a preferred vaccine of the present invention.
  • the influenza vaccine according to the invention is preferably a multivalent influenza vaccine comprising two or more strains of influenza. Most preferably it is a trivalent vaccine comprising three strains.
  • Conventional influenza vaccine generally comprise three strains of influenza, two A strains and one B strain.
  • monovalent vaccines which may be useful for example in a pandemic situation, are not excluded from the invention.
  • a monovalent, pandemic flu vaccine will most likely contain influenza antigen from a single A strain.
  • a preferred vaccine formulation comprises egg or tissue culture influenza antigen, preferably split influenza antigen, a polyoxyethylene alkyl ether and at least one additional non-ionic surfactant, optionally comprising a bile salt or derivative of cholic acid.
  • this vaccine comprises split influenza virus antigen, polyoxyethylene-9 lauryl ether and TRITON-X 100TM.
  • this most preferred vaccine may further comprise a polyoxyethylene sorbitan ester, such as TWEEN80TM, and/or sodium deoxy cholate.
  • each vaccine dose is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Such amount will vary depending upon which specific immunogen is employed and how it is presented. Generally, it is expected that each dose will comprise 1-1000 ⁇ g of protein, preferably 1-500 ⁇ g, preferably l-100 ⁇ g, most preferably 1 to 50 ⁇ g. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of appropriate immune responses in subjects. Following an initial vaccination, subjects may receive one or several booster immunisation adequately spaced.
  • the adjuvant affect of the polyoxyethylene alkyl ether is enhanced synergistically by the additional non-ionic surfactant.
  • the synergy may be observed in the magnitude of the immune response from the combined adjuvant formulation being greater than the sum of the immune responses generated by each individual component when used alone.
  • synergism may also be observed when low doses of polyoxyethylene ether and additional non-ionic surfactant generate significant immune responses, even when one or each component may not generate significant or detectable immune responses when used alone.
  • One aspect of the present invention is adjuvant and vaccine formulations comprising a polyoxyethylene alkyl ether or ester and at least one additional non-ionic surfactant, wherein the antigen present in the vaccine is not entrapped within a non- ionic surfactant vesicle.
  • the vaccines of the present invention may also be administered via the oral route.
  • the pharmaceutically acceptible excipient may also include alkaline buffers, or enteric capsules or microgranules.
  • the vaccines of the present invention may also be administered by the vaginal route.
  • the pharmaceutically acceptable excipients may also include emulsifiers, polymers such as CARBOPOL ® , and other known stablilisers of vaginal creams and suppositories.
  • the vaccines of the present invention may also be administered by the rectal route.
  • the excipients may also include waxes and polymers known in the art for forming rectal suppositories.
  • the formulations of the present invention may be used for both prophylactic and therapeutic purposes. Accordingly, the present invention provides for a method of treating a mammal susceptible to or suffering from an infectious disease or cancer, or allergy, or auto-immune disease. In a further aspect of the present invention there is provided an adjuvant combination and a vaccine as herein described for use in medicine. Vaccine preparation is generally described in New Trends and Developments in Vaccines, edited by Voller et al., University Park Press, Baltimore, Maryland, U.S.A. 1978.
  • One embodiment of the present invention relates to the use of non-ionic surfactants such as a polyoxyethylene alkyl ether or ester of general formula (I), and an octoxynol, in the manufacture of an adjuvant formulation.
  • non-ionic surfactants such as a polyoxyethylene alkyl ether or ester of general formula (I), and an octoxynol
  • the present invention also relates to the use of a polyoxyethylene alkyl ether or ester of general formula (I), an octoxynol, and an antigen, in the manufacture of vaccine formulations.
  • said adjuvant and vaccines manufactured as described may further comprise an polyoxyethylene sorbitan ester.
  • the preferred polyoxyethylene alkyl ether is polyoxyethylene-9 lauryl ether
  • the preferred Octoxynol is t-octylphenoxy polyethoxyethanol (Triton X- 100TM).
  • the adjuvants of the present invention may further be combined with other adjuvants including Cholera toxin and its B subunit, E.Coli heat labile enterotoxin LT, its B subunit LTB and detoxified versions thereof such as mLT; Monophosphoryl Lipid A and its non-toxic derivative 3-O-deacylated monophosphoryl lipid A (3D-MPL, as described in UK patent no.
  • immunologically active saponin fractions e.g. Quil A derived from the bark of the South American tree Quillaja Saponaria Molina and derivatives thereof (for example QS21, US Patent No.5, 057, 540), and the oligonucleotide adjuvant system CpG (as described in WO 96/02555), especially 5 TCG TCG TTT TGT CGT TTT GTC GTT 3' (SEQ ID NO. 1).
  • an adjuvant combination of a polyoxyethylene alkyl ether such as polyoxyethylene-9 lauryl ether
  • additional non-ionic surfactant such as t- octylphenoxy polyethoxyethanol (Triton X-100TM)
  • 3-O-deacylated monophosphoryl lipid A (3D-MPL)
  • This preferred embodiment may optionally further comprise a polyoxyethylene sorbitan ester such as TWEEN80TM, and/or a bile salt or cholic acid derivative such as sodium deoxy cholate.
  • Vaccines comprising this adjuvant formulation and influenza antigens, especially split influenza antigens are particularly preferred.
  • ELISA for the measurement of influenza-specific serum Ig Abs in monkeys Maxisorp Nunc immunoplates are coated overnight at 4°C with 50 ⁇ l/well of 1 ⁇ g/ml HA of ⁇ -propiolactone (BPL) inactivated influenza virus (supplied by SSD GmBH manufacturer, Dresden, Germany) diluted in PBS. Free sites on the plates are blocked (1 hour, 37°C) using saturation buffer : PBS containing 1 %BSA, 0.1 % polyoxyethylene sorbitan monolaurate (TWEEN 20).
  • saturation buffer PBS containing 1 %BSA, 0.1 % polyoxyethylene sorbitan monolaurate (TWEEN 20).
  • serial 2-fold dilutions in saturation buffer, 50 ⁇ l per well
  • a reference serum added as a standard curve (serum having a mid-point titer expressed as ELISA Unit/ml, and put in row A ) and serum samples (starting at a 1/100 dilution and put in rows B to H) are incubated for lhr 30mins at 37°C.
  • the plates are then washed ( ⁇ 3) with washing buffer (PBS, 0.1 % polyoxyethylene sorbitan monolaurate (TWEEN 20)).
  • biotinylated goat anti-human Ig (Amersham) diluted 1/3000 in saturation buffer are incubated (50 ⁇ l/well) for lhr 30mins, at 37°C. After 3 washings, and subsequent addition of streptavidin-horseradish peroxidase conjugate (Amersham), plates are washed 5 times and incubated for 20 min at room temperature with 50 ⁇ l/well of revelation buffer (OPDA 0.4 mg/ml (Sigma) and H 2 O 2 0.03 % in 50mM pH 4.5 citrate buffer). Revelation is stopped by adding 50 ⁇ l/well H 2 SO 4 2N. Optical densities are read at 492 and 630 nm by using Biorad 3550 immunoreader. Antibody titre are calculated by the 4 parameter mathematical method using Sof MaxPro software.
  • HAL Hemagglutination Inhibition
  • BPL inactivated whole virus is added (25 ⁇ l / well) at a concentration of 4 Hemagglutination Units (i.e. at a dilution which is 4-fold lower than the last one provoking an agglutination of red blood cells) for 30 minutes at room temperature (RT) under agitation.
  • Chicken red blood cells are then added (25 ⁇ l / well) for 1 hour at RT. Plates are finally kept overnight at 4°C before to be read.
  • the HAI titer corresponds to the inverse of the last serum dilution inhibiting the virus-induced hemagglutination.
  • TT tetanus toxoid
  • mice Maxisorp Nunc immunoplates were coated overnight at 4°C with 50 ⁇ l/well of 1 ⁇ g/ml antigen (TT provided by Behring) diluted in PBS (in rows B to H of plate), or with 50 ⁇ l of 5 ⁇ g/ml purified goat anti-mouse Ig (Boerhinger), in PBS (row A). Free sites on the plates were blocked (1 hour, 37°C) using saturation buffer : PBS containing 1%BSA, 0.1% polyoxyethylene sorbitan monolaurate (TWEEN 20), and 4% Normal Bovine Serum (NBS).
  • saturation buffer PBS containing 1%BSA, 0.1% polyoxyethylene sorbitan monolaurate (TWEEN 20), and 4% Normal Bovine Serum (NBS).
  • IgG isotype mixture added as a standard curve (mixture of mouse monoclonal antibodies IgGl, IgG2a and IgG2b from Sigma, starting at 200 ng ml and put in row A) and serum samples (starting at a 1/100 dilution and put in rows B to H) were incubated for lhr 30mins at 37°C. The plates were then washed ( ⁇ 3) with washing buffer (PBS, 0.1 % polyoxyethylene sorbitan monolaurate (TWEEN 20)).
  • PBS washing buffer
  • TWEEN 20 polyoxyethylene sorbitan monolaurate
  • biotinylated goat anti-mouse IgG (Amersham) diluted 1/5000 in saturation buffer were incubated (50 ⁇ l/well) for lhr 30mins, at 37°C. After 3 washings, and subsequent addition of strep tavidin-horseradish peroxidase conjugate (Amersham), plates were washed 5 times and incubated for 20 min at room temperature with 50 ⁇ l well of revelation buffer (OPDA 0.4 mg/ml (Sigma) and H 2 O 2 0.03% in 50mM pH 4.5 citrate buffer). Revelation was stopped by adding 50 ⁇ l/well H 2 SO 4 2N. Optical densities were read at 492 and 630 nm by using Biorad 3550 immunoreader. Antibody titre were calculated by the 4 parameter mathematical method using SoftMaxPro software.
  • Example 2 Effect of Laureth 9 together with a combination ofTWEEN80 and TritonXlOO on the immunogenicity of an intranasal influenza vaccine in primed Rhesus monkeys
  • the priming was done in Rhesus monkeys by administering with a spray device (under anesthesia) in each nostril 25 ⁇ g HA per strain of ⁇ -propiolactone-inactivated A/Beijing/262/95 and B/Harbin 7/94 influenza virus contained in 100 ⁇ l PBS.
  • monkeys (4 or 5 animals/group) were boosted intranasally (under anesthesia) with 200 ⁇ l of solution (100 ⁇ l per nostril, delivered with a spray device) containing 30 ⁇ g HA strain of BPL-inactivated A/Beijing/262/95 and B/Harbin/7/94 influenza virus in either A: polyoxyethylene-9-lauryl ether 0.5% (L9); B: polyoxyethylene-9- lauryl ether 0.5% + TWEEN80 (0.11%) + triton-X-100 (0.074%); or by C: intramuscular injection of 15 ⁇ g HA strain of an influenza vaccine containing the same strains as in A and B. Viral antigens were grown in eggs from seed stocks by the supplier (SSD GmBH, Dresden, Germany). HAI and Ig Ab responses were measured in sera as described in example 1. Results are expressed as percentages of animals having experienced a 4-fold Ab rise upon boosting.
  • polyoxyethylene-9-lauryl ether is added to the induction of anti-influenza systemic immune responses.
  • this level of adjuvanticity is significantly improved by the addition of additional non-ionic surfactants.
  • polyoxyethylene-9-lauryl ether is supplemented with TWEEN80 and triton-X-100, this formulation is capable of boosting pre-established systemic Ig Ab responses as efficiently as the classical parenteral influenza vaccine.
  • HAI haemagluttination inhibition
  • Example 3 A comparison of the immunogenicity of an intranasal split influenza vaccine formulated with laureth 9 with TWEEN80 and triton-X-100, with the immunogenicity of a licensed conventional parenteral vaccine (FluarixTM) in healthy adult subjects.
  • FluarixTM a licensed conventional parenteral vaccine
  • the formulations contained three inactivated split virion antigens prepared from the WHO recommended strains of the 1998/1999 season.
  • the device used for administration of the vaccines was the AccusprayTM intranasal syringe from Becton Dickinson. The device works on a similar basis to a conventional syringe, but has a special tip containing spiral channels which result in the production of a spray when even pressure is exerted on the plunger. lOO ⁇ l of the formulation was sprayed in each nostril.
  • composition of the formulation contained the following inactivated split virions:
  • the volume of one dose was 200 ⁇ l (lOO ⁇ l sub-doses for each nostril).
  • Formulation A was adjuvanted with laureth 9 to obtain a final concentration of 0.5 % (w/v).
  • the comparator FluarixTM/ ⁇ -Rix® (B) is SmithKlineBeecham Biologicals' commercial inactivated trivalent split influenza vaccine, which is administered intramuscularly in a dose of 500 ⁇ l.
  • TWEEN80 and triton-X-100 compared to the conventional parenteral vaccine i.e.
  • the immunogenicity of the vaccines was examined by assessing the serum haemagglutination inhibition (HI) titres to determine seroconversion rate (defined as the percentage of vaccinees who have at least a 4-fold increase in serum HI titres on day 21 compared to day 0, for each vaccine strain), conversion factor (defined as the fold increase in serum HI Geometric Mean Titres (GMTs) on day 21 compared to day 0, for each vaccine strain) and seroprotection rate (defined as the percentage of vaccinees with a serum HI titre >40 after vaccination (for each vaccine strain) that is accepted as indicating protection ).
  • HI serum haemagglutination inhibition
  • ELISA Enzyme Linked Immunosorbent Assay
  • HI seropositivity, serconversion and seroprotection rates twenty-one days after one dose of FluarixTM or the intranasal formulation can be seen in Table 3.
  • Table 3 HI seropositivity, serconversion and seroprotection rates at 21 days post dose 1 :
  • Seroprotection (n,%) number and percentage of subjects with titer > 40 Seroconversion (n,%) : number and percentage of subjects with at least a 4-fold increase in titres from day 0 to day 21
  • Table 4 Percentages of subjects with a two-fold or a four-fold increase in the specific/total IgA ratio between day 21 and day 0 (1 dose).
  • the immunogenicity results tabulated above show that the intranasal formulation produced similar levels of seropositivity, seroconversion and seroprotection to the conventional parenteral vaccine (FluarixTM) twenty-one days after one dose.
  • the intranasal formulation generally produced a better mucosal IgA response after one dose than the conventional parenteral vaccine (FluarixTM).
  • Example 4 Effect of Laureth-9 together with Triton X100 on the immunogenicity of an intranasal tetanus toxoid vaccine in primed mice
  • mice Tetanus, acellular Pertussis vaccine: ⁇ SIPANRIXTM SmithKline Beecham, Belgium).
  • mice were boosted intranasally (5 ⁇ l in each nostril, under anesthesia) with 5 ⁇ g TT in A: PBS; B: 0.5% polyoxyethylene-9 lauryl ether; C: 0.1% polyoxyethylene-9 lauryl ether; D: 0.1 % polyoxyethylene-9 lauryl ether + 0.02% Triton X100 or; E: by intramuscular injection of the DTPa vaccine (2x50 ⁇ l).
  • D 0.1 % polyoxyethylene-9 lauryl ether + 0.02% Triton X100 or
  • E by intramuscular injection of the DTPa vaccine (2x50 ⁇ l).
  • Two weeks after the boosting the sera were analyzed for their TT-specific IgG.
  • Laureth-9 low dose (0.1 %>) was ineffective in enhancing the boosting response to TT, contrary to the 0.5% dose.
  • the adjuvanticity of that formulation was strongly improved by supplementing it with Triton XI 00 (pO.OOOl).
  • the antibody response elicited was similar to the one induced by the commercial DTPa vaccine.

Abstract

La présente invention concerne un nouveau système adjuvant comprenant un tensioactif à base d'éther ou d'ester d'alkyle polyoxyéthylène combiné à au moins un tensioactif non ionique supplémentaire. Ce tensioactif non ionique est de préférence un octoxinol (série TRITONTM). La présente invention concerne également ces nouveaux adjuvants, des vaccins les comprenant et des procédés destinés à leur préparation et leur formulation en vaccins. L'invention concerne en outre l'utilisation des ces adjuvants ou de ces vaccins dans la prophylaxie ou la thérapie de maladies.
PCT/EP2000/009368 1999-09-24 2000-09-22 Adjuvant comprenant un ether ou ester d'alkyle polyethylene et au moins un tensioactif non ionique WO2001021152A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BR0014285-9A BR0014285A (pt) 1999-09-24 2000-09-22 Adjuvantes compreendendo um éster ou éter de alquila de polioxietileno e pelo menos um tensoativo não-iÈnico
CA002383110A CA2383110A1 (fr) 1999-09-24 2000-09-22 Adjuvant comprenant un ether ou ester d'alkyle polyethylene et au moins un tensioactif non ionique
AU75226/00A AU766635B2 (en) 1999-09-24 2000-09-22 Adjuvant comprising a polyxyethylene alkyl ether or ester and at least one nonionic surfactant
IL14867100A IL148671A0 (en) 1999-09-24 2000-09-22 Adjuvant comprising a polyxyethylene alkyl ether or ester and at least one nonionic surfactant
KR1020027003856A KR20020048942A (ko) 1999-09-24 2000-09-22 폴리옥시에틸렌 알킬 에테르 또는 에스테르 및 하나이상의 비이온성 계면활성제를 포함하는 애쥬번트
MXPA02003068A MXPA02003068A (es) 1999-09-24 2000-09-22 Adyuvante que comprende un eter o ester alquilo de polioxietileno y al menos un tensioactivo no ionico..
EP00964232A EP1214053A1 (fr) 1999-09-24 2000-09-22 Adjuvant comprenant un ether ou ester d'alkyle polyethylene et au moins un tensioactif non ionique
JP2001524578A JP2003509452A (ja) 1999-09-24 2000-09-22 ポリオキシエチレンアルキルエーテル又はエステル及び少なくとも一つのノニオン界面活性剤を含有するアジュバント
NZ517901A NZ517901A (en) 1999-09-24 2000-09-22 Adjuvant comprising a polyxyethylene alkyl ether or ester and at least one non-ionic surfactant
HU0203817A HUP0203817A3 (en) 1999-09-24 2000-09-22 Adjuvant comprising a polyxyethylene alkyl ether or ester and at least one nonionic surfactant
NO20021432A NO20021432L (no) 1999-09-24 2002-03-21 Adjuvans som omfatter en polyxyetylenalkyleter eller ester og minst en ikke-ionisk surfaktant
HK02108461.1A HK1046861A1 (zh) 1999-09-24 2002-11-21 包括聚氧乙烯烷基酯或者醚以及至少一種非離子表面活性劑的佐劑

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9922700.1A GB9922700D0 (en) 1999-09-24 1999-09-24 Vaccine
GB9922700.1 1999-09-24
GB0016647.0 2000-07-06
GB0016647A GB0016647D0 (en) 2000-07-06 2000-07-06 Novel compounds

Publications (1)

Publication Number Publication Date
WO2001021152A1 true WO2001021152A1 (fr) 2001-03-29

Family

ID=26244608

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/009368 WO2001021152A1 (fr) 1999-09-24 2000-09-22 Adjuvant comprenant un ether ou ester d'alkyle polyethylene et au moins un tensioactif non ionique

Country Status (19)

Country Link
EP (1) EP1214053A1 (fr)
JP (1) JP2003509452A (fr)
KR (1) KR20020048942A (fr)
CN (1) CN1399539A (fr)
AR (1) AR025749A1 (fr)
AU (1) AU766635B2 (fr)
BR (1) BR0014285A (fr)
CA (1) CA2383110A1 (fr)
CO (1) CO5200838A1 (fr)
CZ (1) CZ20021045A3 (fr)
HK (1) HK1046861A1 (fr)
HU (1) HUP0203817A3 (fr)
IL (1) IL148671A0 (fr)
MX (1) MXPA02003068A (fr)
NO (1) NO20021432L (fr)
NZ (1) NZ517901A (fr)
PL (1) PL355232A1 (fr)
TR (1) TR200200777T2 (fr)
WO (1) WO2001021152A1 (fr)

Cited By (150)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10125731A1 (de) * 2001-05-17 2003-03-06 A I D Autoimmun Diagnostika Gm Darreichungsform von immunologischen Wirkstoffen
WO2003028656A2 (fr) 2001-10-03 2003-04-10 Chiron Corporation Compositions d'adjuvants
WO2002074336A3 (fr) * 2001-02-23 2003-08-14 Glaxosmithkline Biolog Sa Vaccin
WO2003070909A2 (fr) 2002-02-20 2003-08-28 Chiron Corporation Microparticules comprenant des molecules adsorbees qui contiennent polypeptides
WO2004092360A2 (fr) 2003-04-10 2004-10-28 Chiron Corporation Le coronavirus du syndrome respiratoire aigu grave
WO2006086799A2 (fr) 2005-02-11 2006-08-17 Novartis Vaccines And Diagnostics Inc. Reactifs de peptide specifiques au prion
WO2008020335A2 (fr) 2006-06-09 2008-02-21 Novartis Ag Compositions immunogènes pour streptococcus agalactiae
EP2039761A1 (fr) * 2001-05-30 2009-03-25 Saechsisches Serumwerk Dresden Composition de vaccin contre la grippe
EP2108374A1 (fr) 2004-04-30 2009-10-14 Novartis Vaccines and Diagnostics S.r.l. Conjugués meningococciques combinés presentant une protéine porteuse commune
EP2168597A1 (fr) 2001-07-26 2010-03-31 Novartis Vaccines and Diagnostics S.r.l. Vaccins comportant des adjuvants d'aluminium et de l'histidine
EP2179729A1 (fr) 2003-06-02 2010-04-28 Novartis Vaccines and Diagnostics, Inc. Compositions immunogene sur la base de microparticules contenant un toxoide adsorbant et un antigene contenant un polysaccharide
EP2193810A1 (fr) 2005-01-14 2010-06-09 Novartis Vaccines and Diagnostics S.r.l. Vaccin conjugué contre le meningocoque
WO2010067286A2 (fr) 2008-12-09 2010-06-17 Pfizer Vaccines Llc Vaccin peptidique ige ch3
US7749518B2 (en) 2004-05-14 2010-07-06 Novartis Vaccines And Diagnostics Srl Polypeptides from non-typeable Haemophilus influenzae
WO2010079464A1 (fr) 2009-01-12 2010-07-15 Novartis Ag Antigènes à domaines cna_b dans des vaccins contre des bactéries à gram positif
US7776523B2 (en) 2000-12-07 2010-08-17 Novartis Vaccines And Diagnostics, Inc. Endogenous retroviruses up-regulated in prostate cancer
WO2010100632A2 (fr) 2009-03-06 2010-09-10 Novartis Ag Antigènes de chlamydia
EP2258388A1 (fr) 2002-08-30 2010-12-08 Novartis Vaccines and Diagnostics S.r.l. Vésicules de membrane externe bactérienne améliorées
EP2258717A2 (fr) 2002-11-22 2010-12-08 Novartis Vaccines and Diagnostics S.r.l. Formes variantes du NadA de la méningococcie
EP2258365A1 (fr) 2003-03-28 2010-12-08 Novartis Vaccines and Diagnostics, Inc. Utilisation de composés organiques pour potentialiser l'immunité
EP2263688A1 (fr) 2001-06-20 2010-12-22 Novartis AG Vaccins combinés contre Neisseria meningitidis
EP2263687A1 (fr) 2002-12-27 2010-12-22 Novartis Vaccines&Diagnostics, Inc. Compositions immunogènes contenant des phospholipides
EP2267036A1 (fr) 2003-10-02 2010-12-29 Novartis Vaccines and Diagnostics S.r.l. Saccharides capsulaires de méningococcie hypo et hyperacétylés
EP2267005A1 (fr) 2003-04-09 2010-12-29 Novartis Vaccines and Diagnostics S.r.l. Toxine ADP-ribosylante de Listeria monocytogenes
EP2272531A2 (fr) 2004-04-30 2011-01-12 Novartis Vaccines and Diagnostics S.r.l. Intégration du vaccin conjugué de méningococcus
WO2011004263A2 (fr) 2009-07-07 2011-01-13 Novartis Ag Immunogènes d' escherichia coli conservés
WO2011007257A1 (fr) 2009-07-16 2011-01-20 Novartis Ag Immunogènes d'escherichia coli détoxifiés
WO2011008974A2 (fr) 2009-07-15 2011-01-20 Novartis Ag Compositions à base de protéine f du vrs et procédés de fabrication associés
EP2277895A1 (fr) 2000-10-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Acides nucléiques et protéines dérivés des groupes de streptocoques A et B
EP2277538A1 (fr) 2003-10-02 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Vaccins combinés contre la méningite
EP2277595A2 (fr) 2004-06-24 2011-01-26 Novartis Vaccines and Diagnostics, Inc. Composés pour potentialiser l'immunité
EP2279747A1 (fr) 2004-10-29 2011-02-02 Novartis Vaccines and Diagnostics S.r.l. Vésicules bactériennes immunogènes dotées de protéines de membrane externe
EP2279746A2 (fr) 2002-11-15 2011-02-02 Novartis Vaccines and Diagnostics S.r.l. Proteines de surface de neisseria meningitidis
WO2011013034A1 (fr) 2009-07-30 2011-02-03 Pfizer Vaccines Llc Peptides tau antigéniques et leurs utilisations
EP2289546A2 (fr) 2003-01-30 2011-03-02 Novartis Vaccines and Diagnostics S.r.l. Vaccins injectables contre les multiples serogroupes du meningocoque
WO2011024072A2 (fr) 2009-08-27 2011-03-03 Novartis Ag Polypeptides hybrides contenant des séquences fhbp à méningocoques
US7901907B2 (en) 1996-01-04 2011-03-08 The Provost Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Near Dublin Process for production of Helicobacter pylori bacterioferritin
WO2011027257A2 (fr) 2009-09-03 2011-03-10 Pfizer Vaccines Llc Vaccin pcsk9
EP2298795A1 (fr) 2005-02-18 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Immunogènes d'E. coli uropathogène
EP2302039A1 (fr) 2002-06-13 2011-03-30 Novartis Vaccines and Diagnostics, Inc. Particules de type virus comprenant le polypeptide gag de HML-2
WO2011048561A1 (fr) 2009-10-20 2011-04-28 Novartis Ag Procédés diagnostiques et thérapeutiques pour une maladie cardiaque rhumatismale basés sur des marqueurs de streptocoque de groupe a
WO2011051893A1 (fr) 2009-10-27 2011-05-05 Novartis Ag Polypeptides fhbp méningococciques modifiés
WO2011058302A1 (fr) 2009-11-10 2011-05-19 Guy's And St Thomas's Nhs Foundation Trust Antigène associé à la bactériémie à partir de staphylococcus aureus
EP2327719A1 (fr) 2001-09-06 2011-06-01 Novartis Vaccines and Diagnostics S.r.l. Adhésines de Meningococcus
WO2011077309A2 (fr) 2009-12-22 2011-06-30 Pfizer Vaccines Llc Compositions de vaccin
EP2351579A1 (fr) 2002-10-11 2011-08-03 Novartis Vaccines and Diagnostics S.r.l. Vaccins incluant du NadA oligomère de la méningococcie pour une protection élargie contre des lignées hypervirulentes
EP2351772A1 (fr) 2005-02-18 2011-08-03 Novartis Vaccines and Diagnostics, Inc. Protéines et acides nucléiques d'Escherichia coli associé à la méningite/sepsie
EP2357000A1 (fr) 2005-10-18 2011-08-17 Novartis Vaccines and Diagnostics, Inc. Immunisations mucosiques et systémiques avec des particules de réplicon à alpha-virus
EP2357184A1 (fr) 2006-03-23 2011-08-17 Novartis AG Composés d'imidazoquinoxaline en tant qu'immunomodulateurs
EP2360175A2 (fr) 2005-11-22 2011-08-24 Novartis Vaccines and Diagnostics, Inc. Particules de type virus (VLPs) de norovirus et de sapovirus
WO2011104632A1 (fr) 2010-02-26 2011-09-01 Novartis Ag Protéines et compositions immunogènes
EP2368572A2 (fr) 2005-11-04 2011-09-28 Novartis Vaccines and Diagnostics S.r.l. Vaccins avec adjuvants dotés d'antigènes non virions préparés à partir de virus de la grippe cultivés dans une culture cellulaire
WO2011121576A2 (fr) 2010-04-01 2011-10-06 Novartis Ag Protéines et compositions immunogènes
WO2011127316A1 (fr) 2010-04-07 2011-10-13 Novartis Ag Procédé de génération de pseudo-particules virales de parvovirus b19
WO2011130379A1 (fr) 2010-04-13 2011-10-20 Novartis Ag Compositions de benzonapthyridine et leurs utilisations
EP2382987A1 (fr) 2006-03-24 2011-11-02 Novartis Vaccines and Diagnostics GmbH Stockage de vaccins contre la grippe sans réfrigération
EP2382988A1 (fr) 2006-03-31 2011-11-02 Novartis AG Immunisation mucosique et parentérale contre le VIH
EP2385127A1 (fr) 2005-11-25 2011-11-09 Novartis Vaccines and Diagnostics S.r.l. Polypeptides tandem, hybrides et chimères de NMB1870 de méningocoque
WO2011138636A1 (fr) 2009-09-30 2011-11-10 Novartis Ag Conjugaison de polysaccharides capsulaires de staphylococcus aureus de type 5 et de type 8
WO2011149564A1 (fr) 2010-05-28 2011-12-01 Tetris Online, Inc. Infrastructure de jeu informatique asynchrone hybride interactif
WO2011154863A1 (fr) 2010-06-07 2011-12-15 Pfizer Inc. Peptides her-2 et vaccins
WO2011154878A1 (fr) 2010-06-07 2011-12-15 Pfizer Vaccines Llc Vaccin peptidique ige ch3
WO2011161551A2 (fr) 2010-06-11 2011-12-29 Novartis Ag Vaccins à base de vésicules membranaires
WO2012006293A1 (fr) 2010-07-06 2012-01-12 Novartis Ag Compositions immunogènes dérivées d'un norovirus et méthodes
WO2012006359A1 (fr) 2010-07-06 2012-01-12 Novartis Ag Délivrance d'arn auto-répliquant en utilisant des particules polymères biodégradables
WO2012035519A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Compositions immunogènes
EP2433647A2 (fr) 2005-01-27 2012-03-28 Children's Hospital & Research Center at Oakland Vaccins à vésicule à base de GNA1870 pour protection spectrale élargie contre les maladies causées par Neisseria Meningitidis
WO2012072769A1 (fr) 2010-12-01 2012-06-07 Novartis Ag Epitopes rrgb de pneumocoque et combinaisons de variantes
WO2012085668A2 (fr) 2010-12-24 2012-06-28 Novartis Ag Composés
EP2478916A1 (fr) 2006-01-27 2012-07-25 Novartis Vaccines and Diagnostics GmbH Vaccins contre la grippe contenant de l'hémagglutinine et des protéines de matrice
EP2484377A1 (fr) 2007-06-27 2012-08-08 Novartis AG Vaccins contre la grippe pauvre en additifs
EP2497495A2 (fr) 2006-09-11 2012-09-12 Novartis AG Fabrication de vaccins contre la grippe sans utiliser d'oeufs
WO2012131504A1 (fr) 2011-03-02 2012-10-04 Pfizer Inc. Vaccin à base de pcsk9
EP2510947A1 (fr) 2009-04-14 2012-10-17 Novartis AG Compositions pour l'immunisation contre le staphylococcus aureus
EP2514437A1 (fr) 2006-07-20 2012-10-24 Novartis AG Stockage congelé de vaccins contre la grippe
WO2012158613A1 (fr) 2011-05-13 2012-11-22 Novartis Ag Antigènes de pré-fusion f du vrs
EP2532362A1 (fr) 2006-12-06 2012-12-12 Novartis AG Vaccins comprenant un antigène issu de quatre souches du virus grippal
EP2537857A2 (fr) 2007-12-21 2012-12-26 Novartis AG Formes mutantes de streptolysine O
WO2013006838A1 (fr) 2011-07-06 2013-01-10 Novartis Ag Compositions de combinaisons immunogènes et utilisations de celles-ci
WO2013006842A2 (fr) 2011-07-06 2013-01-10 Novartis Ag Compositions immunogènes et leurs utilisations
EP2548895A1 (fr) 2007-01-11 2013-01-23 Novartis AG Saccharides modifiés
WO2013016460A1 (fr) 2011-07-25 2013-01-31 Novartis Ag Compositions et procédés d'évaluation de l'immunogénicité fonctionnelle de vaccins contre un parvovirus
EP2572726A1 (fr) 2007-08-01 2013-03-27 Novartis AG Compositions comprenant des antigènes pneumocoques
EP2586790A2 (fr) 2006-08-16 2013-05-01 Novartis AG Immunogènes d'Escherischia coli pathogènes des voies urinaires
US8481043B2 (en) 2001-06-22 2013-07-09 Cpex Pharmaceuticals, Inc. Nasal immunization
EP2612679A1 (fr) 2004-07-29 2013-07-10 Novartis Vaccines and Diagnostics, Inc. Compositions immunogènes pour une bactérie à gram positif telle que streptococcus agalactiae
EP2614835A1 (fr) 2007-11-26 2013-07-17 Novartis AG Vaccination par de multiples clades du virus de la grippe A h5
WO2013108272A2 (fr) 2012-01-20 2013-07-25 International Centre For Genetic Engineering And Biotechnology Vaccin antipaludique ciblant le stade sanguin
EP2631245A1 (fr) 2008-03-10 2013-08-28 Children's Hospital & Research Center at Oakland Protéines chimères de liaison du facteur H contenant un domaine B hétérologue, et procédés d utilisation associés
US8535683B2 (en) 2006-03-22 2013-09-17 Abbott Biologicals B.V. Intranasal or inhalational administration of virosomes
US8562943B2 (en) 2006-11-08 2013-10-22 Novartis Ag Quality control methods for oil-in-water emulsions containing squalene
EP2659912A2 (fr) 2007-07-17 2013-11-06 Novartis AG Purification de conjugué
EP2659907A1 (fr) 2012-05-01 2013-11-06 Affiris AG Compositions
EP2659908A1 (fr) 2012-05-01 2013-11-06 Affiris AG Compositions
EP2659906A1 (fr) 2012-05-01 2013-11-06 Affiris AG Compositions
WO2013164754A2 (fr) 2012-05-04 2013-11-07 Pfizer Inc. Régimes immunothérapeutiques basés sur des antigènes associés à la prostate et un vaccin
DE202005022108U1 (de) 2004-03-09 2013-11-12 Novartis Vaccines And Diagnostics, Inc. Influenza-Virus-Impfstoffe
WO2013174832A1 (fr) 2012-05-22 2013-11-28 Novartis Ag Conjugué de sérogroupe x de méningocoque
WO2014005958A1 (fr) 2012-07-06 2014-01-09 Novartis Ag Compositions immunogéniques et leurs utilisations
WO2014053612A1 (fr) 2012-10-03 2014-04-10 Novartis Ag Composition immunogène
WO2014053521A2 (fr) 2012-10-02 2014-04-10 Novartis Ag Conjugués saccharidiques non linéaires
EP2811027A1 (fr) 2004-05-21 2014-12-10 Novartis Vaccines and Diagnostics, Inc. Vecteurs alphavirus pour vaccins contre le VRS et le PIV
EP2886551A2 (fr) 2008-02-21 2015-06-24 Novartis AG Polypeptides fHbp méningococciques
EP2891498A1 (fr) 2007-12-20 2015-07-08 Novartis AG Procédés de fermentation pour cultiver des streptocoques et procédés de purification pour obtenir des CPS à partir de ceux-ci
WO2015110941A2 (fr) 2014-01-21 2015-07-30 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
WO2015123291A1 (fr) 2014-02-11 2015-08-20 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Vaccin à base de pcsk9 et méthodes d'utilisation dudit vaccin
EP2944320A1 (fr) 2009-06-15 2015-11-18 National University of Singapore Vaccin contre la grippe, composition et procédés d'utilisation
WO2016113644A1 (fr) 2015-01-15 2016-07-21 Pfizer Inc. Compositions immunogènes destinées à être utilisées dans des vaccins antipneumococciques
EP3067048A1 (fr) 2007-12-07 2016-09-14 Novartis Ag Compositions d'induction des réponses immunitaires
WO2016193405A1 (fr) 2015-06-03 2016-12-08 Affiris Ag Vaccins d'il-23-p19
WO2017005851A1 (fr) 2015-07-07 2017-01-12 Affiris Ag Vaccins pour le traitement et la prévention de maladies médiées par ige
WO2017013548A1 (fr) 2015-07-21 2017-01-26 Pfizer Inc. Compositions immunogènes contenant des antigènes saccharidiques capsulaires conjugués, kits comprenant ces compositions et leurs utilisations
WO2017085586A1 (fr) 2015-11-20 2017-05-26 Pfizer Inc. Compositions immunogènes destinées à être utilisées dans des vaccins pneumococciques
WO2017125844A1 (fr) 2016-01-19 2017-07-27 Pfizer Inc. Vaccins anticancéreux
EP3075393A4 (fr) * 2013-11-29 2017-08-16 Terumo Kabushiki Kaisha Composition adjuvante, composition vaccinale la contenant et procédé de production associé
EP3327028A1 (fr) 2010-03-30 2018-05-30 Children's Hospital & Research Center at Oakland Protéines de liaison du facteur h (fhbp) avec des propriétés altérées et leurs procédés d'utilisation
EP3345617A1 (fr) 2012-11-30 2018-07-11 GlaxoSmithKline Biologicals S.A. Antigènes de pseudomonas et combinaisons d'antigènes
WO2018134693A1 (fr) 2017-01-20 2018-07-26 Pfizer Inc. Compositions immunogènes destinées à être utilisées dans des vaccins pneumococciques
US10149901B2 (en) 2009-02-10 2018-12-11 Seqirus UK Limited Influenza vaccines with reduced amounts of squalene
EP3498302A1 (fr) 2005-02-01 2019-06-19 Novartis Vaccines and Diagnostics S.r.l. Conjugaison de saccharides capsulaires streptococciques
WO2020039359A2 (fr) 2018-08-24 2020-02-27 Pfizer Inc. Compositions d'escherichia coli et méthodes associées
WO2020121159A1 (fr) 2018-12-12 2020-06-18 Pfizer Inc. Conjugués polysaccharide-protéine immunogènes à hétéroantigènes multiples et leurs utilisations
EP3689375A1 (fr) 2013-05-15 2020-08-05 The Governors Of The University Of Alberta Vaccins contre le vhc e1e2 et procédés d'utilisation desdits vaccins
WO2020170190A1 (fr) 2019-02-22 2020-08-27 Pfizer Inc. Procédés de purification de polysaccharides bactériens
WO2020208502A1 (fr) 2019-04-10 2020-10-15 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués, kits les comprenant et leurs utilisations
WO2021084429A1 (fr) 2019-11-01 2021-05-06 Pfizer Inc. Compositions d'escherichia coli et méthodes associées
WO2021165928A2 (fr) 2020-02-23 2021-08-26 Pfizer Inc. Compositions d'escherichia coli et méthodes associées
WO2021165847A1 (fr) 2020-02-21 2021-08-26 Pfizer Inc. Purification de saccharides
NL2027383A (en) 2020-01-24 2021-09-01 Aim Immunotech Inc Methods, compositions, and vaccines for treating a virus infection
US11160855B2 (en) 2014-01-21 2021-11-02 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
WO2022090893A2 (fr) 2020-10-27 2022-05-05 Pfizer Inc. Compositions d'escherichia coli et procédés associés
WO2022097010A1 (fr) 2020-11-04 2022-05-12 Pfizer Inc. Compositions immunogènes destinées à être utilisées dans des vaccins pneumococciques
WO2022101745A2 (fr) 2020-11-10 2022-05-19 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
WO2022137078A1 (fr) 2020-12-23 2022-06-30 Pfizer Inc. Mutants fimh e. coli et leurs utilisations
WO2022147373A1 (fr) 2020-12-31 2022-07-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Immunogènes imitant la pcsk9 guidés par des anticorps et ne présentant pas de chevauchement de séquence de 9 résidus avec des protéines humaines
WO2022178196A1 (fr) 2021-02-19 2022-08-25 Sanofi Pasteur Inc. Vaccin recombinant méningococcique b
EP4074726A2 (fr) 2014-07-23 2022-10-19 Children's Hospital & Research Center at Oakland Variants de protéines de liaison au facteur h et leurs procédés d'utilisation
WO2022234483A1 (fr) 2021-05-04 2022-11-10 King Abdullah University Of Science And Technology Compositions immuogéniques de protéine n mutante de sars-cov-2 et gène et procédés d'utilisation associés
WO2022249107A2 (fr) 2021-05-28 2022-12-01 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
WO2022249106A2 (fr) 2021-05-28 2022-12-01 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
US11633471B2 (en) 2018-03-06 2023-04-25 Unm Rainforest Innovations Compositions and methods for reducing serum triglycerides
WO2023079528A1 (fr) 2021-11-05 2023-05-11 King Abdullah University Of Science And Technology Compositions appropriées pour une utilisation dans un procédé pour déclencher une immunité protectrice croisée contre des coronavirus
WO2023079529A1 (fr) 2021-11-05 2023-05-11 King Abdullah University Of Science And Technology Compositions d'immunisation de rappel de protéine de refocalisation et leurs méthodes d'utilisation
WO2023062170A3 (fr) * 2021-10-15 2023-05-25 Glaxosmithkline Biologicals Sa Adjuvants
WO2023092090A1 (fr) 2021-11-18 2023-05-25 Matrivax, Inc. Compositions de protéines de fusion immunogènes et leurs procédés d'utilisation
WO2023135515A1 (fr) 2022-01-13 2023-07-20 Pfizer Inc. Compositions immunogènes à base d'antigènes saccharidiques capsulaires conjugués et leurs utilisations
US11707520B2 (en) 2005-11-03 2023-07-25 Seqirus UK Limited Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture
WO2023161817A1 (fr) 2022-02-25 2023-08-31 Pfizer Inc. Procédés d'incorporation de groupes azido dans des polysaccharides capsulaires bactériens
WO2023218322A1 (fr) 2022-05-11 2023-11-16 Pfizer Inc. Procédé de production de formulations de vaccin avec des conservateurs
WO2024018061A1 (fr) 2022-07-22 2024-01-25 Institut National de la Santé et de la Recherche Médicale Utilisation de souches de bordetella pour le traitement de la bronchopneumopathie chronique obstructive

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100438964C (zh) * 2003-05-15 2008-12-03 广州市白云化工实业有限公司 一种非离子型活性硅表面活性剂及其制备方法
EP3027025B1 (fr) * 2013-10-03 2017-06-28 Dow Global Technologies LLC Composition microbicide comprenant un sel de benzoate ou de sorbate
KR102631297B1 (ko) * 2021-11-09 2024-01-30 주식회사에이치엔비랩스 표면처리를 통해 안정성이 향상된 나노좀의 제조방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996036352A1 (fr) * 1995-05-16 1996-11-21 Pankaj Modi Formulations liquides pour produits pharmaceutiques proteiniques comprenant au moins deux agents d'amelioration de l'absorption
WO1999052549A1 (fr) * 1998-04-09 1999-10-21 Smithkline Beecham Biologicals S.A. Compositions adjuvantes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA929945B (en) * 1991-12-23 1993-08-02 Hem Pharma Corp Method of diagnosing combined cognitive/debilatory disorders.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996036352A1 (fr) * 1995-05-16 1996-11-21 Pankaj Modi Formulations liquides pour produits pharmaceutiques proteiniques comprenant au moins deux agents d'amelioration de l'absorption
WO1999052549A1 (fr) * 1998-04-09 1999-10-21 Smithkline Beecham Biologicals S.A. Compositions adjuvantes

Cited By (239)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7901907B2 (en) 1996-01-04 2011-03-08 The Provost Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Near Dublin Process for production of Helicobacter pylori bacterioferritin
EP2284183A1 (fr) 2000-10-27 2011-02-16 Novartis Vaccines and Diagnostics S.r.l. Acides nucléiques et protéines dérivés des groupes de streptocoques A et B
EP2277895A1 (fr) 2000-10-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Acides nucléiques et protéines dérivés des groupes de streptocoques A et B
EP2277894A1 (fr) 2000-10-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Acides nucléiques et protéines dérivés des groupes de streptocoques A et B
EP2284182A1 (fr) 2000-10-27 2011-02-16 Novartis Vaccines and Diagnostics S.r.l. Acides nucléiques et protéines dérivés des groupes de streptocoques A et B
EP2284181A1 (fr) 2000-10-27 2011-02-16 Novartis Vaccines and Diagnostics S.r.l. Acides nucléiques et protéines dérivés des groupes de streptocoques A et B
EP2277896A1 (fr) 2000-10-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Acides nucléiques et protéines dérivés des groupes de streptocoques A et B
EP2896629A1 (fr) 2000-10-27 2015-07-22 Novartis Vaccines and Diagnostics S.r.l. Acides nucléiques et protéines de streptocoques des groupes A et B
US7776523B2 (en) 2000-12-07 2010-08-17 Novartis Vaccines And Diagnostics, Inc. Endogenous retroviruses up-regulated in prostate cancer
EP2339035A1 (fr) 2000-12-07 2011-06-29 Novartis Vaccines and Diagnostics, Inc. Rétrovirus endogène régulé en hausse dans le cancer de la prostate
EP2336368A1 (fr) 2000-12-07 2011-06-22 Novartis Vaccines and Diagnostics, Inc. Rétrovirus endogène à régulation positive dans le cancer de la prostate
EP2269639A3 (fr) * 2001-02-23 2011-12-07 GlaxoSmithKline Biologicals s.a. Formulations de vaccins contre la grippe dispositif pour administration intradermique
WO2002074336A3 (fr) * 2001-02-23 2003-08-14 Glaxosmithkline Biolog Sa Vaccin
US8557251B2 (en) 2001-02-23 2013-10-15 Glaxosmithkline Biologicals, Sa Non-live trivalent influenza vaccine for one-dose intradermal delivery
EP2281573A3 (fr) * 2001-02-23 2011-12-07 GlaxoSmithKline Biologicals s.a. Formulations de vaccins contre la grippe dispositif pour administration intradermique
DE10125731A1 (de) * 2001-05-17 2003-03-06 A I D Autoimmun Diagnostika Gm Darreichungsform von immunologischen Wirkstoffen
EP2039761A1 (fr) * 2001-05-30 2009-03-25 Saechsisches Serumwerk Dresden Composition de vaccin contre la grippe
EP2495314A1 (fr) * 2001-05-30 2012-09-05 GlaxoSmithKline Biologicals, Niederlassung der SmithKline Beecham Pharma GmbH & Co. KG Nouvelle composition de vaccin
EP2277536A2 (fr) 2001-06-20 2011-01-26 Novartis AG Purification de polysaccharides capsulaires bactériens
EP2277539A2 (fr) 2001-06-20 2011-01-26 Novartis AG Vaccin conjugué combiné contre Neisseria meningitidis
EP2277537A2 (fr) 2001-06-20 2011-01-26 Novartis AG Vaccin conjugué combiné contre Neisseria meningitidis
EP2263688A1 (fr) 2001-06-20 2010-12-22 Novartis AG Vaccins combinés contre Neisseria meningitidis
US8481043B2 (en) 2001-06-22 2013-07-09 Cpex Pharmaceuticals, Inc. Nasal immunization
EP2266605A1 (fr) 2001-07-26 2010-12-29 Novartis Vaccines and Diagnostics S.r.l. Vaccins comportant des adjuvants d'aluminium et de l'histidine
EP2168597A1 (fr) 2001-07-26 2010-03-31 Novartis Vaccines and Diagnostics S.r.l. Vaccins comportant des adjuvants d'aluminium et de l'histidine
EP2360176A2 (fr) 2001-09-06 2011-08-24 Novartis Vaccines and Diagnostics S.r.l. Hybride et tandem l'expression des protéines de Neisseria
EP2327719A1 (fr) 2001-09-06 2011-06-01 Novartis Vaccines and Diagnostics S.r.l. Adhésines de Meningococcus
EP2829549A2 (fr) 2001-09-06 2015-01-28 Novartis Vaccines and Diagnostics S.r.l. Expression tandem et hybride de protéines de Neisserial
WO2003028656A2 (fr) 2001-10-03 2003-04-10 Chiron Corporation Compositions d'adjuvants
EP2572707A2 (fr) 2002-02-20 2013-03-27 Novartis Vaccines and Diagnostics, Inc. Microparticules avec des molécules contenant un polypeptide adsorbé
WO2003070909A2 (fr) 2002-02-20 2003-08-28 Chiron Corporation Microparticules comprenant des molecules adsorbees qui contiennent polypeptides
EP2302039A1 (fr) 2002-06-13 2011-03-30 Novartis Vaccines and Diagnostics, Inc. Particules de type virus comprenant le polypeptide gag de HML-2
US8518694B2 (en) 2002-06-13 2013-08-27 Novartis Vaccines And Diagnostics, Inc. Nucleic acid vector comprising a promoter and a sequence encoding a polypeptide from the endogenous retrovirus PCAV
EP2258390A1 (fr) 2002-08-30 2010-12-08 Novartis Vaccines and Diagnostics S.r.l. Vésicules de membrane externe bactérienne améliorées
EP2258388A1 (fr) 2002-08-30 2010-12-08 Novartis Vaccines and Diagnostics S.r.l. Vésicules de membrane externe bactérienne améliorées
EP2258389A1 (fr) 2002-08-30 2010-12-08 Novartis Vaccines and Diagnostics S.r.l. Vésicules de membrane externe bactérienne améliorées
EP2351579A1 (fr) 2002-10-11 2011-08-03 Novartis Vaccines and Diagnostics S.r.l. Vaccins incluant du NadA oligomère de la méningococcie pour une protection élargie contre des lignées hypervirulentes
EP2353608A1 (fr) 2002-10-11 2011-08-10 Novartis Vaccines and Diagnostics S.r.l. Vaccins incluant du NadA oligomère de la méningococcie pour une protection élargie contre des lignées hypervirulentes
EP2279746A2 (fr) 2002-11-15 2011-02-02 Novartis Vaccines and Diagnostics S.r.l. Proteines de surface de neisseria meningitidis
EP2258717A2 (fr) 2002-11-22 2010-12-08 Novartis Vaccines and Diagnostics S.r.l. Formes variantes du NadA de la méningococcie
EP2258716A2 (fr) 2002-11-22 2010-12-08 Novartis Vaccines and Diagnostics S.r.l. Variantes multiples de protéine NMB1870 de la méningococcie
EP2261239A2 (fr) 2002-11-22 2010-12-15 Novartis Vaccines and Diagnostics S.r.l. Variants multiples de la protéine NMB1870 meningococcique
EP2263687A1 (fr) 2002-12-27 2010-12-22 Novartis Vaccines&Diagnostics, Inc. Compositions immunogènes contenant des phospholipides
EP2289546A2 (fr) 2003-01-30 2011-03-02 Novartis Vaccines and Diagnostics S.r.l. Vaccins injectables contre les multiples serogroupes du meningocoque
EP2258365A1 (fr) 2003-03-28 2010-12-08 Novartis Vaccines and Diagnostics, Inc. Utilisation de composés organiques pour potentialiser l'immunité
EP2267005A1 (fr) 2003-04-09 2010-12-29 Novartis Vaccines and Diagnostics S.r.l. Toxine ADP-ribosylante de Listeria monocytogenes
WO2004092360A2 (fr) 2003-04-10 2004-10-28 Chiron Corporation Le coronavirus du syndrome respiratoire aigu grave
EP2179729A1 (fr) 2003-06-02 2010-04-28 Novartis Vaccines and Diagnostics, Inc. Compositions immunogene sur la base de microparticules contenant un toxoide adsorbant et un antigene contenant un polysaccharide
EP2277538A1 (fr) 2003-10-02 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Vaccins combinés contre la méningite
EP2267036A1 (fr) 2003-10-02 2010-12-29 Novartis Vaccines and Diagnostics S.r.l. Saccharides capsulaires de méningococcie hypo et hyperacétylés
DE202005022108U1 (de) 2004-03-09 2013-11-12 Novartis Vaccines And Diagnostics, Inc. Influenza-Virus-Impfstoffe
EP2108374A1 (fr) 2004-04-30 2009-10-14 Novartis Vaccines and Diagnostics S.r.l. Conjugués meningococciques combinés presentant une protéine porteuse commune
EP2272531A2 (fr) 2004-04-30 2011-01-12 Novartis Vaccines and Diagnostics S.r.l. Intégration du vaccin conjugué de méningococcus
EP2341069A1 (fr) 2004-05-14 2011-07-06 Novartis Vaccines and Diagnostics S.r.l. Polypeptides de haemophilus influenzae non typable
EP2351773A1 (fr) 2004-05-14 2011-08-03 Novartis Vaccines and Diagnostics S.r.l. Polypeptides de haemophilus influenzae non typable
US7749518B2 (en) 2004-05-14 2010-07-06 Novartis Vaccines And Diagnostics Srl Polypeptides from non-typeable Haemophilus influenzae
US8124098B2 (en) 2004-05-14 2012-02-28 Novartis Vaccines And Diagnostics Srl Polypeptides from non-typeable Haemophilus influenzae
US9102729B2 (en) 2004-05-14 2015-08-11 Novartis Vaccines And Diagnostics Srl Polypeptides from non-typeable Haemophilus influenzae
EP2351774A1 (fr) 2004-05-14 2011-08-03 Novartis Vaccines and Diagnostics S.r.l. Polypeptides de hamophilus influenzae non typable
EP2343313A1 (fr) 2004-05-14 2011-07-13 Novartis Vaccines and Diagnostics S.r.l. Polypeptides de hamophilus influenzae non typable
EP2811027A1 (fr) 2004-05-21 2014-12-10 Novartis Vaccines and Diagnostics, Inc. Vecteurs alphavirus pour vaccins contre le VRS et le PIV
EP2848692A1 (fr) 2004-05-21 2015-03-18 Novartis Vaccines and Diagnostics, Inc. Vecteurs d'alphavirus de vaccins contre le virus de la grippe
EP2277595A2 (fr) 2004-06-24 2011-01-26 Novartis Vaccines and Diagnostics, Inc. Composés pour potentialiser l'immunité
EP2612679A1 (fr) 2004-07-29 2013-07-10 Novartis Vaccines and Diagnostics, Inc. Compositions immunogènes pour une bactérie à gram positif telle que streptococcus agalactiae
EP2279747A1 (fr) 2004-10-29 2011-02-02 Novartis Vaccines and Diagnostics S.r.l. Vésicules bactériennes immunogènes dotées de protéines de membrane externe
EP2193810A1 (fr) 2005-01-14 2010-06-09 Novartis Vaccines and Diagnostics S.r.l. Vaccin conjugué contre le meningocoque
EP2433647A2 (fr) 2005-01-27 2012-03-28 Children's Hospital & Research Center at Oakland Vaccins à vésicule à base de GNA1870 pour protection spectrale élargie contre les maladies causées par Neisseria Meningitidis
EP3498302A1 (fr) 2005-02-01 2019-06-19 Novartis Vaccines and Diagnostics S.r.l. Conjugaison de saccharides capsulaires streptococciques
WO2006086799A2 (fr) 2005-02-11 2006-08-17 Novartis Vaccines And Diagnostics Inc. Reactifs de peptide specifiques au prion
EP2351772A1 (fr) 2005-02-18 2011-08-03 Novartis Vaccines and Diagnostics, Inc. Protéines et acides nucléiques d'Escherichia coli associé à la méningite/sepsie
EP2298795A1 (fr) 2005-02-18 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Immunogènes d'E. coli uropathogène
EP2357000A1 (fr) 2005-10-18 2011-08-17 Novartis Vaccines and Diagnostics, Inc. Immunisations mucosiques et systémiques avec des particules de réplicon à alpha-virus
US11707520B2 (en) 2005-11-03 2023-07-25 Seqirus UK Limited Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture
EP2368572A2 (fr) 2005-11-04 2011-09-28 Novartis Vaccines and Diagnostics S.r.l. Vaccins avec adjuvants dotés d'antigènes non virions préparés à partir de virus de la grippe cultivés dans une culture cellulaire
US10842867B2 (en) 2005-11-04 2020-11-24 Seqirus UK Limited Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture
EP3714900A1 (fr) 2005-11-04 2020-09-30 Seqirus UK Limited Vaccins avec adjuvants dotés d'antigènes non virions préparés à partir de virus de la grippe cultivés dans une culture cellulaire
EP2360175A2 (fr) 2005-11-22 2011-08-24 Novartis Vaccines and Diagnostics, Inc. Particules de type virus (VLPs) de norovirus et de sapovirus
EP2385127A1 (fr) 2005-11-25 2011-11-09 Novartis Vaccines and Diagnostics S.r.l. Polypeptides tandem, hybrides et chimères de NMB1870 de méningocoque
EP2385126A1 (fr) 2005-11-25 2011-11-09 Novartis Vaccines and Diagnostics S.r.l. Polypeptides tandem, hybrides et chimères de NMB1870 de méningocoque
EP3346009A1 (fr) 2005-11-25 2018-07-11 GlaxoSmithKline Biologicals S.A. Polypeptides tandem, hybrides et chimères de nmb1870 de méningocoque
EP3753574A1 (fr) 2006-01-27 2020-12-23 Seqirus UK Limited Vaccins contre la grippe contenant de l'hémagglutinine et des protéines de matrice
EP2478916A1 (fr) 2006-01-27 2012-07-25 Novartis Vaccines and Diagnostics GmbH Vaccins contre la grippe contenant de l'hémagglutinine et des protéines de matrice
US8535683B2 (en) 2006-03-22 2013-09-17 Abbott Biologicals B.V. Intranasal or inhalational administration of virosomes
EP2357184A1 (fr) 2006-03-23 2011-08-17 Novartis AG Composés d'imidazoquinoxaline en tant qu'immunomodulateurs
EP2382987A1 (fr) 2006-03-24 2011-11-02 Novartis Vaccines and Diagnostics GmbH Stockage de vaccins contre la grippe sans réfrigération
EP2382988A1 (fr) 2006-03-31 2011-11-02 Novartis AG Immunisation mucosique et parentérale contre le VIH
WO2008020335A2 (fr) 2006-06-09 2008-02-21 Novartis Ag Compositions immunogènes pour streptococcus agalactiae
EP2514437A1 (fr) 2006-07-20 2012-10-24 Novartis AG Stockage congelé de vaccins contre la grippe
EP2586790A2 (fr) 2006-08-16 2013-05-01 Novartis AG Immunogènes d'Escherischia coli pathogènes des voies urinaires
EP2497495A2 (fr) 2006-09-11 2012-09-12 Novartis AG Fabrication de vaccins contre la grippe sans utiliser d'oeufs
EP3456348A1 (fr) 2006-09-11 2019-03-20 Seqirus UK Limited Fabrication de vaccins contre le virus de la grippe sans utiliser d' ufs
US8562943B2 (en) 2006-11-08 2013-10-22 Novartis Ag Quality control methods for oil-in-water emulsions containing squalene
US9744231B2 (en) 2006-11-08 2017-08-29 Novartis Ag Quality control methods for oil-in-water emulsions containing squalene
EP2679240A1 (fr) 2006-12-06 2014-01-01 Novartis AG Vaccins comprenant un antigène issu de quatre souches du virus grippal
EP2532362A1 (fr) 2006-12-06 2012-12-12 Novartis AG Vaccins comprenant un antigène issu de quatre souches du virus grippal
EP2548895A1 (fr) 2007-01-11 2013-01-23 Novartis AG Saccharides modifiés
EP2484377A1 (fr) 2007-06-27 2012-08-08 Novartis AG Vaccins contre la grippe pauvre en additifs
US9463250B2 (en) 2007-07-17 2016-10-11 Glaxosmithkline Biologicals Sa Conjugate purification
EP2659912A2 (fr) 2007-07-17 2013-11-06 Novartis AG Purification de conjugué
EP2572726A1 (fr) 2007-08-01 2013-03-27 Novartis AG Compositions comprenant des antigènes pneumocoques
EP2614835A1 (fr) 2007-11-26 2013-07-17 Novartis AG Vaccination par de multiples clades du virus de la grippe A h5
EP3067048A1 (fr) 2007-12-07 2016-09-14 Novartis Ag Compositions d'induction des réponses immunitaires
EP2891498A1 (fr) 2007-12-20 2015-07-08 Novartis AG Procédés de fermentation pour cultiver des streptocoques et procédés de purification pour obtenir des CPS à partir de ceux-ci
EP2537857A2 (fr) 2007-12-21 2012-12-26 Novartis AG Formes mutantes de streptolysine O
EP2886551A2 (fr) 2008-02-21 2015-06-24 Novartis AG Polypeptides fHbp méningococciques
EP2631245A1 (fr) 2008-03-10 2013-08-28 Children's Hospital & Research Center at Oakland Protéines chimères de liaison du facteur H contenant un domaine B hétérologue, et procédés d utilisation associés
US9216229B2 (en) 2008-12-09 2015-12-22 Pfizer Vaccines Llc IgE CH3 peptide vaccine
US8475801B2 (en) 2008-12-09 2013-07-02 Pfizer Vaccines, LCC IgE CH3 peptide vaccine
EP2865389A1 (fr) 2008-12-09 2015-04-29 Pfizer Vaccines LLC Vaccin peptidique IgE CH3
US8298547B2 (en) 2008-12-09 2012-10-30 Pfizer Vaccines, LLC IgE CH3 peptide vaccine
WO2010067286A2 (fr) 2008-12-09 2010-06-17 Pfizer Vaccines Llc Vaccin peptidique ige ch3
WO2010079464A1 (fr) 2009-01-12 2010-07-15 Novartis Ag Antigènes à domaines cna_b dans des vaccins contre des bactéries à gram positif
US11246921B2 (en) 2009-02-10 2022-02-15 Seqirus UK Limited Influenza vaccines with reduced amounts of squalene
US10149901B2 (en) 2009-02-10 2018-12-11 Seqirus UK Limited Influenza vaccines with reduced amounts of squalene
WO2010100632A2 (fr) 2009-03-06 2010-09-10 Novartis Ag Antigènes de chlamydia
EP3549602A1 (fr) 2009-03-06 2019-10-09 GlaxoSmithKline Biologicals S.A. Antigènes de chlamydia
EP3263128A2 (fr) 2009-04-14 2018-01-03 GlaxoSmithKline Biologicals S.A. Compositions pour l'immunisation contre staphylococcus aureus
EP2510947A1 (fr) 2009-04-14 2012-10-17 Novartis AG Compositions pour l'immunisation contre le staphylococcus aureus
EP2944320A1 (fr) 2009-06-15 2015-11-18 National University of Singapore Vaccin contre la grippe, composition et procédés d'utilisation
WO2011004263A2 (fr) 2009-07-07 2011-01-13 Novartis Ag Immunogènes d' escherichia coli conservés
EP4183412A1 (fr) 2009-07-15 2023-05-24 GlaxoSmithKline Biologicals S.A. Compositions à base de protéine f du vrs et procédés de fabrication associés
WO2011008974A2 (fr) 2009-07-15 2011-01-20 Novartis Ag Compositions à base de protéine f du vrs et procédés de fabrication associés
EP3988115A2 (fr) 2009-07-15 2022-04-27 GlaxoSmithKline Biologicals S.A. Compositions à base de protéine f du vrs et procédés de fabrication associés
EP3178490A2 (fr) 2009-07-15 2017-06-14 GlaxoSmithKline Biologicals S.A. Compositions à base de protéine f du vrs et procédés de fabrication associés
EP4218799A1 (fr) 2009-07-15 2023-08-02 GlaxoSmithKline Biologicals S.A. Compositions de protéine f rsv et leurs procédés de fabrication
EP4218800A1 (fr) 2009-07-15 2023-08-02 GlaxoSmithKline Biologicals S.A. Compositions de protéine f rsv et leurs procédés de fabrication
WO2011007257A1 (fr) 2009-07-16 2011-01-20 Novartis Ag Immunogènes d'escherichia coli détoxifiés
EP2837386A1 (fr) 2009-07-16 2015-02-18 Novartis AG Immunogènes d'escherichia coli détoxifiés
WO2011013034A1 (fr) 2009-07-30 2011-02-03 Pfizer Vaccines Llc Peptides tau antigéniques et leurs utilisations
WO2011024072A2 (fr) 2009-08-27 2011-03-03 Novartis Ag Polypeptides hybrides contenant des séquences fhbp à méningocoques
EP3017828A1 (fr) 2009-08-27 2016-05-11 GlaxoSmithKline Biologicals SA Polypeptides hybrides contenant des séquences fhbp à méningocoques
WO2011027257A2 (fr) 2009-09-03 2011-03-10 Pfizer Vaccines Llc Vaccin pcsk9
EP3358008A1 (fr) 2009-09-03 2018-08-08 Pfizer Vaccines LLC Vaccin pcsk9
EP2865752A1 (fr) 2009-09-03 2015-04-29 Pfizer Vaccines LLC Vaccin PCSK9
WO2011138636A1 (fr) 2009-09-30 2011-11-10 Novartis Ag Conjugaison de polysaccharides capsulaires de staphylococcus aureus de type 5 et de type 8
WO2011048561A1 (fr) 2009-10-20 2011-04-28 Novartis Ag Procédés diagnostiques et thérapeutiques pour une maladie cardiaque rhumatismale basés sur des marqueurs de streptocoque de groupe a
WO2011051893A1 (fr) 2009-10-27 2011-05-05 Novartis Ag Polypeptides fhbp méningococciques modifiés
WO2011058302A1 (fr) 2009-11-10 2011-05-19 Guy's And St Thomas's Nhs Foundation Trust Antigène associé à la bactériémie à partir de staphylococcus aureus
EP3257525A2 (fr) 2009-12-22 2017-12-20 Celldex Therapeutics, Inc. Compositions vaccinales
WO2011077309A2 (fr) 2009-12-22 2011-06-30 Pfizer Vaccines Llc Compositions de vaccin
WO2011104632A1 (fr) 2010-02-26 2011-09-01 Novartis Ag Protéines et compositions immunogènes
EP3327028A1 (fr) 2010-03-30 2018-05-30 Children's Hospital & Research Center at Oakland Protéines de liaison du facteur h (fhbp) avec des propriétés altérées et leurs procédés d'utilisation
EP4036104A1 (fr) 2010-03-30 2022-08-03 Children's Hospital & Research Center at Oakland Protéines de liaison de facteur h (fhbp) avec propriétés altérées et leurs procédés d'utilisation
WO2011121576A2 (fr) 2010-04-01 2011-10-06 Novartis Ag Protéines et compositions immunogènes
WO2011127316A1 (fr) 2010-04-07 2011-10-13 Novartis Ag Procédé de génération de pseudo-particules virales de parvovirus b19
WO2011130379A1 (fr) 2010-04-13 2011-10-20 Novartis Ag Compositions de benzonapthyridine et leurs utilisations
WO2011149564A1 (fr) 2010-05-28 2011-12-01 Tetris Online, Inc. Infrastructure de jeu informatique asynchrone hybride interactif
EP2942061A2 (fr) 2010-06-07 2015-11-11 Pfizer Vaccines LLC Vaccin peptidique ige ch3
WO2011154878A1 (fr) 2010-06-07 2011-12-15 Pfizer Vaccines Llc Vaccin peptidique ige ch3
US9249233B2 (en) 2010-06-07 2016-02-02 Pfizer Vaccines Llc IgE CH3 peptide vaccine
WO2011154863A1 (fr) 2010-06-07 2011-12-15 Pfizer Inc. Peptides her-2 et vaccins
US8722053B2 (en) 2010-06-07 2014-05-13 Pfizer Vaccines Llc IgE CH3 peptide vaccine
EP3399021A1 (fr) 2010-06-11 2018-11-07 GlaxoSmithKline Biologicals S.A. Vaccins d'omv
WO2011161551A2 (fr) 2010-06-11 2011-12-29 Novartis Ag Vaccins à base de vésicules membranaires
EP3611269A1 (fr) 2010-07-06 2020-02-19 GlaxoSmithKline Biologicals SA Administration d' arn autoreplicatif en utilisant des particules de polymères biodégradables
WO2012006359A1 (fr) 2010-07-06 2012-01-12 Novartis Ag Délivrance d'arn auto-répliquant en utilisant des particules polymères biodégradables
WO2012006293A1 (fr) 2010-07-06 2012-01-12 Novartis Ag Compositions immunogènes dérivées d'un norovirus et méthodes
EP3153578A1 (fr) 2010-07-06 2017-04-12 Novartis Ag Compositions immunogènes dérivées de norovirus et procédés
WO2012035519A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Compositions immunogènes
WO2012072769A1 (fr) 2010-12-01 2012-06-07 Novartis Ag Epitopes rrgb de pneumocoque et combinaisons de variantes
WO2012085668A2 (fr) 2010-12-24 2012-06-28 Novartis Ag Composés
WO2012131504A1 (fr) 2011-03-02 2012-10-04 Pfizer Inc. Vaccin à base de pcsk9
WO2012158613A1 (fr) 2011-05-13 2012-11-22 Novartis Ag Antigènes de pré-fusion f du vrs
EP3275892A2 (fr) 2011-05-13 2018-01-31 GlaxoSmithKline Biologicals S.A. Antigènes f de rsv pré-fusion
WO2013006838A1 (fr) 2011-07-06 2013-01-10 Novartis Ag Compositions de combinaisons immunogènes et utilisations de celles-ci
EP3854413A1 (fr) 2011-07-06 2021-07-28 GlaxoSmithKline Biologicals SA Compositions de combinaisons immunogènes et utilisations de celles-ci
WO2013006842A2 (fr) 2011-07-06 2013-01-10 Novartis Ag Compositions immunogènes et leurs utilisations
EP3332802A1 (fr) 2011-07-06 2018-06-13 GlaxoSmithKline Biologicals SA Compositions de combinaisons immunogènes et utilisations de celles-ci
WO2013016460A1 (fr) 2011-07-25 2013-01-31 Novartis Ag Compositions et procédés d'évaluation de l'immunogénicité fonctionnelle de vaccins contre un parvovirus
WO2013108272A2 (fr) 2012-01-20 2013-07-25 International Centre For Genetic Engineering And Biotechnology Vaccin antipaludique ciblant le stade sanguin
EP2659906A1 (fr) 2012-05-01 2013-11-06 Affiris AG Compositions
EP2659908A1 (fr) 2012-05-01 2013-11-06 Affiris AG Compositions
EP2659907A1 (fr) 2012-05-01 2013-11-06 Affiris AG Compositions
WO2013164754A2 (fr) 2012-05-04 2013-11-07 Pfizer Inc. Régimes immunothérapeutiques basés sur des antigènes associés à la prostate et un vaccin
EP3563865A2 (fr) 2012-05-04 2019-11-06 Pfizer Inc Régimes immunothérapeutiques basés sur des antigènes associés à la prostate et un vaccin
US10124051B2 (en) 2012-05-22 2018-11-13 Glaxosmithkline Biologicals Sa Meningococcus serogroup X conjugate
WO2013174832A1 (fr) 2012-05-22 2013-11-28 Novartis Ag Conjugué de sérogroupe x de méningocoque
WO2014005958A1 (fr) 2012-07-06 2014-01-09 Novartis Ag Compositions immunogéniques et leurs utilisations
WO2014053521A2 (fr) 2012-10-02 2014-04-10 Novartis Ag Conjugués saccharidiques non linéaires
WO2014053612A1 (fr) 2012-10-03 2014-04-10 Novartis Ag Composition immunogène
WO2014053607A1 (fr) 2012-10-03 2014-04-10 Novartis Ag Compositions immunogènes
US9855324B2 (en) 2012-10-03 2018-01-02 Glaxosmithkline Biologicals Sa Immunogenic compositions
EP3482770A1 (fr) 2012-10-03 2019-05-15 GlaxoSmithKline Biologicals S.A. Compositions immunogènes
EP3345617A1 (fr) 2012-11-30 2018-07-11 GlaxoSmithKline Biologicals S.A. Antigènes de pseudomonas et combinaisons d'antigènes
EP3689375A1 (fr) 2013-05-15 2020-08-05 The Governors Of The University Of Alberta Vaccins contre le vhc e1e2 et procédés d'utilisation desdits vaccins
EP3075393A4 (fr) * 2013-11-29 2017-08-16 Terumo Kabushiki Kaisha Composition adjuvante, composition vaccinale la contenant et procédé de production associé
US11000586B2 (en) 2013-11-29 2021-05-11 Terumo Kabushiki Kaisha Adjuvant composition, vaccine composition containing the same, and method for producing both of them
US10179169B2 (en) 2013-11-29 2019-01-15 Terumo Kabushiki Kaisha Adjuvant composition, vaccine composition containing the same, and method for producing both of them
EP3607966A1 (fr) 2014-01-21 2020-02-12 Pfizer Inc Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
US11872274B2 (en) 2014-01-21 2024-01-16 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
EP3616716A2 (fr) 2014-01-21 2020-03-04 Pfizer Inc Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
US9492559B2 (en) 2014-01-21 2016-11-15 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
US11160855B2 (en) 2014-01-21 2021-11-02 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens and uses thereof
WO2015110941A2 (fr) 2014-01-21 2015-07-30 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
US10925938B2 (en) 2014-02-11 2021-02-23 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Composition comprising PCSK9 peptide conjugated to a Qbeta carrier and methods of using the same
US10279019B2 (en) 2014-02-11 2019-05-07 Stc.Unm PCSK9 peptide vaccine conjugated to a Qbeta carrier and methods of using the same
WO2015123291A1 (fr) 2014-02-11 2015-08-20 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Vaccin à base de pcsk9 et méthodes d'utilisation dudit vaccin
US11696941B2 (en) 2014-02-11 2023-07-11 The Usa, As Represented By The Secretary, Dept. Of Health And Human Services Compositions comprising a PCSK9 peptide conjugated to a qbeta carrier and methods of using the same
EP4074726A2 (fr) 2014-07-23 2022-10-19 Children's Hospital & Research Center at Oakland Variants de protéines de liaison au facteur h et leurs procédés d'utilisation
US10653764B2 (en) 2015-01-15 2020-05-19 Pfizer Inc. Immunogenic compositions for use in pneumococcal vaccines
WO2016113644A1 (fr) 2015-01-15 2016-07-21 Pfizer Inc. Compositions immunogènes destinées à être utilisées dans des vaccins antipneumococciques
US11135279B2 (en) 2015-01-15 2021-10-05 Pfizer Inc. Immunogenic compositions for use in pneumococcal vaccines
WO2016193405A1 (fr) 2015-06-03 2016-12-08 Affiris Ag Vaccins d'il-23-p19
WO2017005851A1 (fr) 2015-07-07 2017-01-12 Affiris Ag Vaccins pour le traitement et la prévention de maladies médiées par ige
US10124050B2 (en) 2015-07-21 2018-11-13 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof
WO2017013548A1 (fr) 2015-07-21 2017-01-26 Pfizer Inc. Compositions immunogènes contenant des antigènes saccharidiques capsulaires conjugués, kits comprenant ces compositions et leurs utilisations
US11020469B2 (en) 2015-07-21 2021-06-01 Pfizer Inc. Immunogenic compositions comprising conjugated capsular saccharide antigens, kits comprising the same and uses thereof
WO2017085586A1 (fr) 2015-11-20 2017-05-26 Pfizer Inc. Compositions immunogènes destinées à être utilisées dans des vaccins pneumococciques
US10786561B2 (en) 2015-11-20 2020-09-29 Pfizer Inc. Immunogenic compositions for use in pneumococcal vaccines
WO2017125844A1 (fr) 2016-01-19 2017-07-27 Pfizer Inc. Vaccins anticancéreux
EP3733201A1 (fr) 2016-01-19 2020-11-04 Pfizer Inc Vaccins contre le cancer
WO2018134693A1 (fr) 2017-01-20 2018-07-26 Pfizer Inc. Compositions immunogènes destinées à être utilisées dans des vaccins pneumococciques
US11413344B2 (en) 2017-01-20 2022-08-16 Pfizer Inc. Immunogenic compositions for use in pneumococcal vaccines
US11633471B2 (en) 2018-03-06 2023-04-25 Unm Rainforest Innovations Compositions and methods for reducing serum triglycerides
WO2020039359A2 (fr) 2018-08-24 2020-02-27 Pfizer Inc. Compositions d'escherichia coli et méthodes associées
WO2020121159A1 (fr) 2018-12-12 2020-06-18 Pfizer Inc. Conjugués polysaccharide-protéine immunogènes à hétéroantigènes multiples et leurs utilisations
WO2020170190A1 (fr) 2019-02-22 2020-08-27 Pfizer Inc. Procédés de purification de polysaccharides bactériens
WO2020208502A1 (fr) 2019-04-10 2020-10-15 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués, kits les comprenant et leurs utilisations
WO2021084429A1 (fr) 2019-11-01 2021-05-06 Pfizer Inc. Compositions d'escherichia coli et méthodes associées
NL2027383A (en) 2020-01-24 2021-09-01 Aim Immunotech Inc Methods, compositions, and vaccines for treating a virus infection
WO2021165847A1 (fr) 2020-02-21 2021-08-26 Pfizer Inc. Purification de saccharides
WO2021165928A2 (fr) 2020-02-23 2021-08-26 Pfizer Inc. Compositions d'escherichia coli et méthodes associées
WO2022090893A2 (fr) 2020-10-27 2022-05-05 Pfizer Inc. Compositions d'escherichia coli et procédés associés
WO2022097010A1 (fr) 2020-11-04 2022-05-12 Pfizer Inc. Compositions immunogènes destinées à être utilisées dans des vaccins pneumococciques
WO2022101745A2 (fr) 2020-11-10 2022-05-19 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
WO2022137078A1 (fr) 2020-12-23 2022-06-30 Pfizer Inc. Mutants fimh e. coli et leurs utilisations
WO2022147373A1 (fr) 2020-12-31 2022-07-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Immunogènes imitant la pcsk9 guidés par des anticorps et ne présentant pas de chevauchement de séquence de 9 résidus avec des protéines humaines
WO2022178196A1 (fr) 2021-02-19 2022-08-25 Sanofi Pasteur Inc. Vaccin recombinant méningococcique b
WO2022234483A1 (fr) 2021-05-04 2022-11-10 King Abdullah University Of Science And Technology Compositions immuogéniques de protéine n mutante de sars-cov-2 et gène et procédés d'utilisation associés
WO2022249107A2 (fr) 2021-05-28 2022-12-01 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
WO2022249106A2 (fr) 2021-05-28 2022-12-01 Pfizer Inc. Compositions immunogènes comprenant des antigènes saccharidiques capsulaires conjugués et leurs utilisations
WO2023062170A3 (fr) * 2021-10-15 2023-05-25 Glaxosmithkline Biologicals Sa Adjuvants
WO2023079528A1 (fr) 2021-11-05 2023-05-11 King Abdullah University Of Science And Technology Compositions appropriées pour une utilisation dans un procédé pour déclencher une immunité protectrice croisée contre des coronavirus
WO2023079529A1 (fr) 2021-11-05 2023-05-11 King Abdullah University Of Science And Technology Compositions d'immunisation de rappel de protéine de refocalisation et leurs méthodes d'utilisation
WO2023092090A1 (fr) 2021-11-18 2023-05-25 Matrivax, Inc. Compositions de protéines de fusion immunogènes et leurs procédés d'utilisation
WO2023135515A1 (fr) 2022-01-13 2023-07-20 Pfizer Inc. Compositions immunogènes à base d'antigènes saccharidiques capsulaires conjugués et leurs utilisations
WO2023161817A1 (fr) 2022-02-25 2023-08-31 Pfizer Inc. Procédés d'incorporation de groupes azido dans des polysaccharides capsulaires bactériens
WO2023218322A1 (fr) 2022-05-11 2023-11-16 Pfizer Inc. Procédé de production de formulations de vaccin avec des conservateurs
WO2024018061A1 (fr) 2022-07-22 2024-01-25 Institut National de la Santé et de la Recherche Médicale Utilisation de souches de bordetella pour le traitement de la bronchopneumopathie chronique obstructive

Also Published As

Publication number Publication date
AR025749A1 (es) 2002-12-11
PL355232A1 (en) 2004-04-05
MXPA02003068A (es) 2002-09-30
HK1046861A1 (zh) 2003-01-30
HUP0203817A3 (en) 2004-07-28
TR200200777T2 (tr) 2002-09-23
JP2003509452A (ja) 2003-03-11
EP1214053A1 (fr) 2002-06-19
HUP0203817A2 (hu) 2003-03-28
NZ517901A (en) 2003-08-29
KR20020048942A (ko) 2002-06-24
CO5200838A1 (es) 2002-09-27
CN1399539A (zh) 2003-02-26
AU766635B2 (en) 2003-10-23
BR0014285A (pt) 2002-05-21
NO20021432D0 (no) 2002-03-21
CA2383110A1 (fr) 2001-03-29
AU7522600A (en) 2001-04-24
IL148671A0 (en) 2002-09-12
NO20021432L (no) 2002-05-21
CZ20021045A3 (cs) 2002-08-14

Similar Documents

Publication Publication Date Title
AU766635B2 (en) Adjuvant comprising a polyxyethylene alkyl ether or ester and at least one nonionic surfactant
AU765824B2 (en) Vaccines
AU746163B2 (en) Adjuvant compositions
ES2397714T3 (es) Vacuna que comprende un adyuvante de emulsión de aceite en agua
AU728759B2 (en) Oil in water vaccine compositions
JP4805242B2 (ja) ワクチン
ES2298316T3 (es) Emulsiones de aceite en agua que contienen saponinas.
US6558670B1 (en) Vaccine adjuvants
US20020058047A1 (en) Vaccines
JP5307859B2 (ja) ワクチン
ZA200202268B (en) Adjuvant comprising a polyxyethylene alkyl ether or ester and at least one non-ionic surfactant.
ZA200202270B (en) Use of combination of polyxyethylene sorbitan ester and octoxynol as adjuvant and its use in vaccines.
CZ20003732A3 (cs) Pomocný prostředek
MXPA00009887A (en) Adjuvant compositions
CZ447699A3 (cs) Vakcína typu olej ve vodě

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 148671

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 75226/00

Country of ref document: AU

Ref document number: IN/PCT/2002/412/CHE

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2002/02268

Country of ref document: ZA

Ref document number: 517901

Country of ref document: NZ

Ref document number: 200202268

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2002/003068

Country of ref document: MX

Ref document number: PV2002-1045

Country of ref document: CZ

Ref document number: 2383110

Country of ref document: CA

Ref document number: 2002/00777

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 1020027003834

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2001 524578

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020027003856

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1020027003834

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2000964232

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 008162638

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2000964232

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020027003856

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV2002-1045

Country of ref document: CZ

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 517901

Country of ref document: NZ

WWR Wipo information: refused in national office

Ref document number: PV2002-1045

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 517901

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 75226/00

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 2000964232

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1020027003856

Country of ref document: KR