WO2000041463A2 - Combination of hepatitis b vaccine with antiviral agents - Google Patents

Combination of hepatitis b vaccine with antiviral agents Download PDF

Info

Publication number
WO2000041463A2
WO2000041463A2 PCT/EP1999/010295 EP9910295W WO0041463A2 WO 2000041463 A2 WO2000041463 A2 WO 2000041463A2 EP 9910295 W EP9910295 W EP 9910295W WO 0041463 A2 WO0041463 A2 WO 0041463A2
Authority
WO
WIPO (PCT)
Prior art keywords
hepatitis
pharmaceutical pack
vaccine
antiviral agent
treatment
Prior art date
Application number
PCT/EP1999/010295
Other languages
English (en)
French (fr)
Other versions
WO2000041463A3 (en
Inventor
Gillian Frances Atkinson
Ronald James Boon
Pierre G. Vandepapeliere
Martine Anne Cecile Wettendorff
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 to EP99965531A priority Critical patent/EP1140163A2/en
Priority to JP2000593088A priority patent/JP2002534438A/ja
Priority to AU21009/00A priority patent/AU760574B2/en
Priority to NZ512890A priority patent/NZ512890A/en
Priority to KR1020017008833A priority patent/KR20010090011A/ko
Priority to BR9916893-6A priority patent/BR9916893A/pt
Priority to CA002359110A priority patent/CA2359110A1/en
Priority to HU0105070A priority patent/HUP0105070A2/hu
Application filed by Smithkline Beecham Biologicals S.A. filed Critical Smithkline Beecham Biologicals S.A.
Priority to PL99349347A priority patent/PL349347A1/xx
Priority to IL14418699A priority patent/IL144186A0/xx
Publication of WO2000041463A2 publication Critical patent/WO2000041463A2/en
Publication of WO2000041463A3 publication Critical patent/WO2000041463A3/en
Priority to NO20013337A priority patent/NO20013337L/no
Priority to HK02101211.9A priority patent/HK1041434A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/29—Hepatitis virus
    • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • 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
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • 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
    • A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
    • 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
    • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • This invention relates to the use of a nucleoside analogue active against hepatitis B virus (HBN). or another class of antiviral active against HBN, such as ⁇ interferon or a nucleotide analogue and an HBN vaccine in the treatment of hepatitis B virus infections.
  • HBN hepatitis B virus
  • Chronic hepatitis B virus (HBV) infection for which there is currently no effective cure, constitutes a global public health problem of enormous dimensions.
  • Chronic carriers of HBN estimated to number more than 300 million world-wide, are at risk for development of chronic active hepatitis, cirrhosis and primary heptocellular carcinoma.
  • EP-A-388049 (Beecham Group p. I.e.), discloses the use of penciclovir/famciclovir in the treatment of hepatitis B virus infection. All references herein to penciclovir/famciclovir include pharmaceutically acceptable salts, such as the hydrochloride, and solvates, such as hydrates.
  • EP-A-494119 discloses the use of 1 ,3-oxathiolane nucleoside analogues, including lamivudine. in treatment of Hepatitis B.
  • the present invention provides a pharmaceutical pack comprising as active ingredients (1) an antiviral agent active against hepatitis B virus and (2) a vaccine for the prophylaxis and/or treatment of hepatitis B infection, the active ingredients being for simultaneous or sequential use.
  • pharmaceutical pack is meant a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration. Where the antiviral agent and the HBN vaccine are intended for administration as two separate compositions these may be presented in the form of, for example, a twin pack.
  • the invention may be used for either the treatment or prophylaxis of hepatitis B infections. The invention is most particularly of value for treatment, for example, of chronic hepatitis B infections.
  • the antiviral agent as used in the pharmaceutical pack is a nucleoside agent.
  • the antiviral agent is a nucleotide agent Suitable agents for use in the invention include penciclovir, famciclovir, lamivudine, ganciclovir, lobucavir, adefovir, ⁇ bavi ⁇ n, BMS200,475, vidarabin or ARA-AMP
  • Preferred nucleoside analogues include penciclovir, famciclovir and lamivudine
  • a further potential antiviral agent is an interferon Alpha - interferon is especially preferred.
  • nucleoside analogues may be obtained from well known pharmaceutical industry references, such as "Pharmaprojects", PJB publications Limited, Richmond, Surrey, U K or from 'R & D Focus', isssued by IMS World publications, 364 Euston Road, London NW1 3BL
  • references to an anti-hepatitis B virus nucleoside analogue include solvates such as hydrates.
  • the anti-hepatitis B virus nucleoside or nucleotide analogue and HBV vaccine of this invention may be administered in combination with other pharmacologically active agents, in particular, other antivirals
  • the vaccine for the prophylaxis and/or treatment of hepatitis B infection includes all vaccines containing HBV antigens (such as surface antigen, core and polymerase) and therapeutic vaccines.
  • the hepatitis B virus antigen is the hepatitis B surface antigen (HbsAg).
  • HbsAg hepatitis B surface antigen
  • Hepatitis B surface antigen' or ⁇ BsAg' includes any HBsAg antigen or immunogenic derivative thereof, particularly fragments thereof, displaying the antigenicity of HBV surface antigen. It will be understood that in addition to the 226 amino acid sequence of the HBsAg S antigen (see Tiollais et. al. Nature, 317, 489 (1985) and references therein) HBsAg as herein described may, if desired, contain all or part of a pre-S sequence as described in the above references and in EP-A- 0 278 940. HBsAg as herein described can also refer to variants, for example the 'escape mutant' described in WO 91/14703.
  • the HBsAg may comprise a protein described as L* in European Patent Application Number 0 414 374, that is to say a protein, the amino acid sequence of which consists of parts of the amino acid sequence of the hepatitis B virus large (L) protein (ad or ay subtype), characterised in that the amino acid sequence of the protein consists of either:
  • HBsAg may also refer to polypeptides described in EP 0 198 474 or EP 0 304 578. Normally the HBsAg will be in particle form. It may comprise S protein alone or may be as composite particles, for example (S, L*) wherein L* is as defined above and S denotes the S-protein of hepatitis B surface antigen. A preferred hepatitis B antigen is this composite particle, defined as S,L*.
  • a further preferred hepatitis B antigen is the 226 amino acid sequence of the HBV surface antigen, in particle form.
  • Such a vaccine may advantageously include a pharmaceutically acceptable excipient such as a suitable adjuvant.
  • suitable adjuvants include an aluminium salt such as aluminium hydroxide gel (alum) or aluminium phosphate (as described in WO93/24148), but may also be a salt of calcium, iron or zinc, or may be an insoluble suspension of acylated tyrosine, or acylated sugars, cationically or anionically derivatised polysaccharides, or polyphosphazenes.
  • the hepatitis B virus may be formulated with strong adjuvant systems.
  • the adjuvant composition induces an immune response comprising THl aspects.
  • Suitable adjuvant systems include, for example a combination of monophosphoryl lipid A, preferably 3- de-O-acylated monophosphoryl lipid A (3D-MPL) together with an aluminium salts.
  • a vaccine comprising hepatitis B surface antigen in conjunction with 3D-MPL was described in European Patent Application 0 633 784.
  • An enhanced system involves the combination of monophosphoryl lipid A and a saponin derivative particularly the combination of QS21 and 3D-MPL as disclosed in WO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol as disclosed in WO 96/33739.
  • CpG containing oligonucleotides see University of Iowa; WO9602555.
  • a vaccine comprising an HBV antigen, adjuvanted with a monophosphoryl lipid A or derivative thereof.
  • the vaccine additional comprises a saponin, more preferably QS21.
  • the formulation additional comprises an oil in water emulsion and tocopherol.
  • the present invention also provides a method of treatment and/or prophylaxis of hepatitis B virus infections, which comprises administering to a human or animal subject, suffering from or susceptible to Hepatitis B virus infection, either either simultaneously or sequentially in any order, a safe and effective amount of 1) an antiviral agent active against hepatitis B virus and 2) a vaccine for the prophylaxis and/or treatment of hepatitis B infection.
  • the antiviral such as penciclovir/famciclovir and the HBV vaccine or a pharmaceutically acceptable salt or ester thereof, may be co-administered in the form of two separate pharmaceutical compositions for simultaneous or sequential use. Normally the active ingredients will be administered separately according to the normal dosage and administration regimen for the ingredients given alone.
  • Commencement of administration may be either with the vaccine or the antiviral.
  • the present invention also provides for the use of an antiviral compound in the manufacture of a medicament for the treatment of patients already primed with a hepatitis B vaccine and suffering from a hepatitis B virus infection.
  • the invention further provides for the use of a hepatitis B vaccine in the manufacture of a medicament for the treatment of patients already primed with an antiviral compound and suffering from a hepatitis B virus infection.
  • the preferred antiviral is a nucleoside analogue, most preferably penciclovir/famciclovir or lamivudine.
  • Preferred hepatitis B vaccines are identified hereinabove.
  • the unit doses of the nucleoside or nucleotide analogue may be administered, for example, 1 to 4 times per day.
  • the exact dose will depend on the route of administration and the severity of the condition being treated, and it will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient and immunocompromised patients may require an increased dosage.
  • Vaccines are administered in multiple doses at various intervals. This is usually 6 - 12 doses at biweekly or monthly intervals.
  • the preferred ingredients in the pharmaceutical pack when administered simultaneously are given as separate preparations, for example, as vaccinations in each arm. It is however possible to consider simultaneous administration by mixing the ingredients before administration.
  • the ingredients may be given enterally, such as orally or parenterally (e.g. intramuscularly or, more particularly, intravenously).
  • compositions for oral use such as tablets and capsules may be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, micro -crystalline cellulose or calcium hydrogen phosphate); lubricant (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agent (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art.
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, micro -crystalline cellulose or calcium hydrogen phosphate
  • lubricant e.g. magnesium stearate, talc or silica
  • disintegrants e.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-g-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of one or both active ingredients.
  • compositions may be presented in a form suitable for bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in syringes, ampoules or in multi-dose containers, with an added preservative.
  • the active antiviral agent may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredients may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the active antiviral agents may be formulated as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active antiviral agents of the invention may be prepared according to conventional techniques well known in the pharmaceutical industry.
  • the lamivudine/penciclovir/famciclovir may be admixed, if desired, with suitable excipients.
  • Tablets may be prepared, for example, by direct compression of such a mixture.
  • Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules, using a suitable filling machine.
  • Controlled release forms for oral or rectal administration may be formulated in a conventional manner associated with controlled release forms.
  • Anti-hepatitis B virus nucleoside analogues may be identified by standard methods, such as tests involving studies in in vitro primary duck hepatocytye cultures infected with the duck hepatitis B virus (DHBV). Changes in the levels of preSl and/or viral
  • analogues may be identified by the ability to interfere with normal acylation of synthetic peptides representing the N-terminal amino acids of DHBV or hepatitis B viruses of man, woodchucks, ground squirrels or other animals.
  • the following vaccine composition was employed.
  • the HBV surface antigen was equivalent to the antigen employed in the commercially available Engerix-B vaccine TM (Smithkline Beecham Biologicals), except that it was lyophilised. Lyophilized Ag:
  • Adjuvant system oil in water emulsion: 250 ⁇ l
  • Lamivudine (Zeffix TM, Glaxo Wellcome) was administered daily by oral capsule to three male and three female dogs at a dose level of 100 mg/dog/day for 6 weeks. On Days 14, 28 and 42 the HBs/adjuvant vaccine as described above was administered by intramuscular injection immediately before administration of Lamivudine. Blood samples were taken at pre-dose, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 hours after dosing of Lamivudine on Days 7, 14, 28 and 42. The separated plasma was frozen at -20°C prior to despatch to Pharma Bio-Research for analysis of plasma concentrations of Lamivudine.
  • Plasma concentrations of Lamivudine in samples taken up to 24 hours post-dose were measured by Pharma Bio-Research.
  • the maximum mean plasma concentrations of Lamivudine occurred at 2 hours post- dose on all the sampling days except for females on Day 7 where the maximum mean plasma Lamivudine concentration occurred at 1 hour post-dose. On Day 28, the maximum mean plasma concentrations of Lamivudine were lower than those values on Day 7, 14 and 42. After the maximum, the mean plasma concentrations of Lamivudine declined in an apparently biexponential manner.
  • Cmax Mean maximum plasma concentrations (Cmax) of Lamivudine and the areas under the plasma Lamivudine concentration-time curves estimated up to 24 hours post-dose (AUC 24 ) on Days 7, 14, 28 and 42 are summarised below with standard deviations in parentheses:
  • Tmax The times at which the maximum plasma concentrations occurred (Tmax) in individual dogs were generally 2 hours, and in the range 0.75 to 4 hours and appeared to be independent of administration of the HBs vaccine.
  • Plasma concentrations of Lamivudine were quantifiable in male animal numbers 71 and 73 and in female animal number 70 at all time points on Days 7, 14, 28 and 42, therefore, these animals were continuously exposed to quantifiable concentrations of Lamivudine during a dosing interval.
  • Lamivudine was generally slightly lower than that in male dogs. However, there was no statistically significant evidence for any sex-related differences in systemic exposure (p > 0.57). On Days 14, 28 and 42 the rate (Cmax) and extent (AUC 24 ) of systemic exposure of dogs to Lamivudine were generally similar to those values on Day 7, however, the
  • the mean accumulation ratios were generally close to or less than one indicating that little or no accumulation of Lamivudine occurred following administration of HBs vaccine.
  • the terminal rate constants, and corresponding terminal half-lives, of Lamivudine on Days 7, 14, 28 and 42 are presented in Tables 5 - 8.
  • the terminal rate constant, where it could be calculated ranged from 0.3239 to 0.1364 hours " ' corresponding to a terminal half-life of Lamivudine of 2.1 to 5.1 hours.
  • HBs Hep 286
  • Antigen and antibody solutions were used at 100 ⁇ l per well.
  • Antigen was diluted at a final concentration of 1 ⁇ g/ml in PBS and was adsorbed overnight at 4°C to the wells of 96 wells microtiter plates (Maxisorb Immuno-plate, Nunc, Denmark). The plates were then incubated for lhr 30 min at 37°C with PBS containing 5% non fat powder milk and 0.1% Tween 20.
  • TMB Tetramethyl benzidine
  • the mid-point average titers at the different timepoint are the respectively 25 on Day 0 (arbitrary 1/2 of first dilution), 383 on day 29 and 5321 on day 43. This clearly indicate the induction of an immune response.
PCT/EP1999/010295 1999-01-12 1999-12-21 Combination of hepatitis b vaccine with antiviral agents WO2000041463A2 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
CA002359110A CA2359110A1 (en) 1999-01-12 1999-12-21 Combination of hepatitis b vaccine with antiviral agents
AU21009/00A AU760574B2 (en) 1999-01-12 1999-12-21 Novel treatment
NZ512890A NZ512890A (en) 1999-01-12 1999-12-21 Antiviral agents including nucleoside analogues active against hepatitis B virus (HBV)
KR1020017008833A KR20010090011A (ko) 1999-01-12 1999-12-21 신규 처리
BR9916893-6A BR9916893A (pt) 1999-01-12 1999-12-21 Tratamento
EP99965531A EP1140163A2 (en) 1999-01-12 1999-12-21 Combination of hepatitis b vaccine with antiviral agents
HU0105070A HUP0105070A2 (hu) 1999-01-12 1999-12-21 Hepatitis B vírus fertőzések megelőzésére és kezelésére szolgáló készlet
JP2000593088A JP2002534438A (ja) 1999-01-12 1999-12-21 新規治療法
PL99349347A PL349347A1 (en) 1999-01-12 1999-12-21 Novel treatment
IL14418699A IL144186A0 (en) 1999-01-12 1999-12-21 Novel treatment
NO20013337A NO20013337L (no) 1999-01-12 2001-07-05 Ny behandling
HK02101211.9A HK1041434A1 (zh) 1999-01-12 2002-02-19 抗病毒藥物和乙型肝炎疫苗的聯合

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9900630 1999-01-12
GB9900630.6 1999-01-12

Publications (2)

Publication Number Publication Date
WO2000041463A2 true WO2000041463A2 (en) 2000-07-20
WO2000041463A3 WO2000041463A3 (en) 2000-11-09

Family

ID=10845878

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/010295 WO2000041463A2 (en) 1999-01-12 1999-12-21 Combination of hepatitis b vaccine with antiviral agents

Country Status (19)

Country Link
EP (1) EP1140163A2 (ko)
JP (1) JP2002534438A (ko)
KR (1) KR20010090011A (ko)
CN (1) CN1391482A (ko)
AR (1) AR022250A1 (ko)
AU (1) AU760574B2 (ko)
BR (1) BR9916893A (ko)
CA (1) CA2359110A1 (ko)
CO (1) CO5241355A1 (ko)
CZ (1) CZ20012544A3 (ko)
HK (1) HK1041434A1 (ko)
HU (1) HUP0105070A2 (ko)
IL (1) IL144186A0 (ko)
NO (1) NO20013337L (ko)
NZ (1) NZ512890A (ko)
PL (1) PL349347A1 (ko)
TR (1) TR200102024T2 (ko)
WO (1) WO2000041463A2 (ko)
ZA (1) ZA200105690B (ko)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003028757A1 (fr) * 2001-09-28 2003-04-10 Haruo Sugiyama Nouvelle methode pour induire des lymphocytes t specifiques d'antigenes
WO2003028758A1 (fr) * 2001-09-28 2003-04-10 Haruo Sugiyama Nouvelle methode d'induction de lymphocytes t specifiques d'un antigene
EP1492510A1 (en) * 2002-04-08 2005-01-05 Bristol-Myers Squibb Company Low dose liquid entecavir formulations and use
WO2005121378A2 (en) * 2004-06-03 2005-12-22 Saint Louis University Methods and compositions for vaccination
US7030212B1 (en) 1998-07-31 2006-04-18 Haruo Sugiyama Tumor antigen based on products of the tumor suppressor gene WT1
WO2008104133A1 (es) * 2007-02-28 2008-09-04 Centro De Ingeniería Genética Y Biotecnología Terapia combinada para el tratamiento de la hepatitis b crónica
US7956043B2 (en) 2002-12-11 2011-06-07 Coley Pharmaceutical Group, Inc. 5′ CpG nucleic acids and methods of use
US7998492B2 (en) 2002-10-29 2011-08-16 Coley Pharmaceutical Group, Inc. Methods and products related to treatment and prevention of hepatitis C virus infection
US8105604B2 (en) 2001-03-22 2012-01-31 International Institute Of Cancer Immunology, Inc. WT1 modified peptide
US8574599B1 (en) 1998-05-22 2013-11-05 Ottawa Hospital Research Institute Methods and products for inducing mucosal immunity

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100443117C (zh) * 2003-05-13 2008-12-17 深圳康泰生物制品股份有限公司 一种治疗性乙型肝炎的疫苗制剂、其制备方法及其用途
WO2020134682A1 (zh) * 2018-12-24 2020-07-02 南京远大赛威信生物医药有限公司 用于治疗乙型肝炎的药物制剂及其制备方法和用途
CN117120088A (zh) * 2021-04-07 2023-11-24 电化株式会社 佐剂活性增强剂和佐剂组合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0414374A2 (en) * 1989-07-25 1991-02-27 Smithkline Biologicals S.A. Novel antigens and methods for their preparation
WO1999045957A2 (en) * 1998-03-09 1999-09-16 Smithkline Beecham Biologicals S.A. Combined vaccine compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0414374A2 (en) * 1989-07-25 1991-02-27 Smithkline Biologicals S.A. Novel antigens and methods for their preparation
WO1999045957A2 (en) * 1998-03-09 1999-09-16 Smithkline Beecham Biologicals S.A. Combined vaccine compositions

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BERENGUER M ET AL: "Hepatitis B and C viruses: Molecular identification and targeted antiviral therapies" PROCEEDINGS ASSOCIATION OF AMERICAN PHYSICIANS, vol. 110, no. 2, March 1998 (1998-03), pages 98-112, XP000909240 *
BONI C ET AL: "Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B Äsee commentsÜ." JOURNAL OF CLINICAL INVESTIGATION, (1998 SEP 1) 102 (5) 968-75., XP000909082 *
GROB P J: "Hepatitis B: virus, pathogenesis and treatment" VACCINE,GB,BUTTERWORTH SCIENTIFIC. GUILDFORD, vol. 16, no. 1001, November 1998 (1998-11), pages S11-S16, XP004150417 ISSN: 0264-410X *
MOLLOY P J ET AL: "Combined interferon, famciclovir and GM-CSF treatment of HBV infection in an individual with periarteritis nodosa." HEPATO-GASTROENTEROLOGY, (1999 JUL-AUG) 46 (28) 2529-31., XP000909277 *
PIANKO S. ET AL: "Chronic hepatitis B: New therapies on the horizon?." LANCET, (13 NOV 1999) 354/9191 (1662-1663)., XP000906960 *
RUDD, JENNIFER N. (1) ET AL: "Possible role for hepatitis B vaccine after lamivudine rescue for severe acute hepatitis B." GASTROENTEROLOGY, (APRIL, 1999) VOL. 116, NO. 4 PART 2, PP. A1268. MEETING INFO.: DIGESTIVE DISEASE WEEK AND THE 100TH ANNUAL MEETING OF THE AMERICAN GASTROENTEROLOGICAL ASSOCIATION ORLANDO, FLORIDA, USA MAY 16-19, 1999 AMERICAN GASTROENTEROLOGICAL A, XP000909262 *
SUK-FONG LOK A.: "Hepatitis B infection: Pathogenesis and management." JOURNAL OF HEPATOLOGY, SUPPLEMENT, (2000) 32/1 (89-97)., XP000909278 *
VALDEZ H ET AL: "Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. ACTG 375 team. AIDS Clinical Trials Group." AIDS, (2000 JAN 7) 14 (1) 11-21., XP000909260 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8574599B1 (en) 1998-05-22 2013-11-05 Ottawa Hospital Research Institute Methods and products for inducing mucosal immunity
US7030212B1 (en) 1998-07-31 2006-04-18 Haruo Sugiyama Tumor antigen based on products of the tumor suppressor gene WT1
US7390871B2 (en) 1998-07-31 2008-06-24 International Institute Of Cancer Immunology, Inc. Tumor antigen based on products of the tumor suppressor gene WT1
US7517950B2 (en) 1998-07-31 2009-04-14 International Institute Of Cancer Immunology, Inc. Tumor antigen based on products of the tumor suppressor gene WT1
US7608685B1 (en) 1998-07-31 2009-10-27 International Institute Of Cancer Immunology, Inc. Tumor antigen based on products of the tumor suppressor gene WT1
US8105604B2 (en) 2001-03-22 2012-01-31 International Institute Of Cancer Immunology, Inc. WT1 modified peptide
WO2003028757A1 (fr) * 2001-09-28 2003-04-10 Haruo Sugiyama Nouvelle methode pour induire des lymphocytes t specifiques d'antigenes
WO2003028758A1 (fr) * 2001-09-28 2003-04-10 Haruo Sugiyama Nouvelle methode d'induction de lymphocytes t specifiques d'un antigene
US8735357B2 (en) 2001-09-28 2014-05-27 International Institute Of Cancer Immunology, Inc. Method of inducing antigen-specific T cells
EP1492510A1 (en) * 2002-04-08 2005-01-05 Bristol-Myers Squibb Company Low dose liquid entecavir formulations and use
EP1492510A4 (en) * 2002-04-08 2006-01-11 Bristol Myers Squibb Co LOW-DOSED LIQUID ENTECAVIR FORMULATIONS AND USE
US7998492B2 (en) 2002-10-29 2011-08-16 Coley Pharmaceutical Group, Inc. Methods and products related to treatment and prevention of hepatitis C virus infection
US7956043B2 (en) 2002-12-11 2011-06-07 Coley Pharmaceutical Group, Inc. 5′ CpG nucleic acids and methods of use
US8541167B2 (en) 2004-06-03 2013-09-24 Saint Louis University Methods and compositions for vaccination
WO2005121378A3 (en) * 2004-06-03 2007-02-15 Univ Saint Louis Methods and compositions for vaccination
WO2005121378A2 (en) * 2004-06-03 2005-12-22 Saint Louis University Methods and compositions for vaccination
WO2008104133A1 (es) * 2007-02-28 2008-09-04 Centro De Ingeniería Genética Y Biotecnología Terapia combinada para el tratamiento de la hepatitis b crónica

Also Published As

Publication number Publication date
IL144186A0 (en) 2002-05-23
HUP0105070A2 (hu) 2002-04-29
WO2000041463A3 (en) 2000-11-09
NO20013337L (no) 2001-08-17
NZ512890A (en) 2003-09-26
CZ20012544A3 (cs) 2002-01-16
KR20010090011A (ko) 2001-10-17
TR200102024T2 (tr) 2001-12-21
PL349347A1 (en) 2002-07-15
JP2002534438A (ja) 2002-10-15
NO20013337D0 (no) 2001-07-05
CN1391482A (zh) 2003-01-15
ZA200105690B (en) 2002-09-25
AU2100900A (en) 2000-08-01
AU760574B2 (en) 2003-05-15
EP1140163A2 (en) 2001-10-10
CO5241355A1 (es) 2003-01-31
AR022250A1 (es) 2002-09-04
CA2359110A1 (en) 2000-07-20
HK1041434A1 (zh) 2002-07-12
BR9916893A (pt) 2001-11-20

Similar Documents

Publication Publication Date Title
AU760574B2 (en) Novel treatment
AU695921B2 (en) Hepatitis B vaccine
Ocama et al. Hepatitis B virus infection: current status
JP3470719B2 (ja) ３−ｏ−脱アシル化モノホスホリル脂質ａ含有の肝炎ワクチン
JP2002506045A (ja) 併合ワクチン組成物
WO2015196935A1 (zh) 含有CpG寡核苷酸的药物组合物
JP2018512428A5 (ko)
WO2014139359A1 (zh) 乙型肝炎疫苗
EP1850871A2 (en) Adjuvant composition comprising aluminium phosphate and 3d-mpl
Fernández et al. Five-year follow-up of chronic hepatitis B patients immunized by nasal route with the therapeutic vaccine HeberNasvac
US20110059132A1 (en) Composition for therapy and/or for prophylaxis of hbv-infections and hbv-mediated diseases
MXPA01007112A (en) Novel treatment
KR100612547B1 (ko) 백신 조성물
Lu et al. Induction of antibodies to the PreS region of surface antigens of woodchuck hepatitis virus (WHV) in chronic carrier woodchucks by immunizations with WHV surface antigens
Huang et al. New advances in hepatitis B vaccination for adults
KR20210151047A (ko) B형 간염 치료를 위한 면역원성 조성물
CN109219449B (zh) 包含乙型肝炎病毒的表面抗原和核衣壳抗原的药用组合物
JP2022516041A (ja) Ｂ型肝炎を治療するための薬物製剤、その製造方法及び用途
US7144703B2 (en) Composition
Yoon Clinical Experience of HBV DNA Vaccine in Korean Patients with Chronic HBV Infection

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99816471.2

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM 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 NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW 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
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM 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 NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW 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

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2000 593088

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 144186

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 1999965531

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2359110

Country of ref document: CA

Ref document number: 2359110

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 21009/00

Country of ref document: AU

Ref document number: IN/PCT/2001/969/CHE

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 512890

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1020017008833

Country of ref document: KR

Ref document number: PA/a/2001/007112

Country of ref document: MX

Ref document number: PV2001-2544

Country of ref document: CZ

Ref document number: 2001/02024

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 09869998

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1999965531

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020017008833

Country of ref document: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2001-2544

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 21009/00

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 1999965531

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1020017008833

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV2001-2544

Country of ref document: CZ