AP766A - A vaccine based on hepatitis B antigen. - Google Patents

A vaccine based on hepatitis B antigen. Download PDF

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AP766A
AP766A APAP/P/1997/001060A AP9701060A AP766A AP 766 A AP766 A AP 766A AP 9701060 A AP9701060 A AP 9701060A AP 766 A AP766 A AP 766A
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hepatitis
vaccine
hbsag
antigen
vaccine composition
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APAP/P/1997/001060A
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AP9701060A0 (en
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Pierre Hauser
Nathalie Marie-Josephe Claude Garcon-Johnson
Pierre Michel Desmons
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Smithkline Biologicals S A
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/29—Hepatitis virus
    • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61K2039/55505—Inorganic adjuvants
    • 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
    • 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
    • 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

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
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Abstract

A novel vaccine formulation is provided, compromising a hepatitis B component, particularly hepatitis B surface antigen combination with aluminum phosphate and 3 de-O-acylated monophosphoryl lipid A.

Description

HEPATITIS B VACCINE
The present invention relates to novel vaccine formulations, methods for preparing them and to their use in therapy. In particular the present invention relates to novel formulations for treating Hepatitis infections and to combination vaccine formulations including a Hepatitis B vaccine component.
Viral hepatitis, caused by the A, B, C, D, and E hepatitis viruses, is a very common viral illness. Via the B and C viruses, in particular, it is also responsible for many cases of liver cancer. Thus ±e development of effective vaccines is critical and, despite notable successes, is still an on-going task. A review on modem hepatitis vaccines, including a number of key references, may be found in the Lancet, May 12th 1990 at page 1142 ff (Prof A.L.W.F. Eddleston). See also 'Viral Hepatitis and Liver Disease' (Vyas, B.N., Dienstag, J.L., and Hoofnagle,
J.H., eds, Grune and Stratton, Inc. (1984) and 'Viral Hepatitis and Liver Disease' (Proceedings of the 1990 International Symposium, eds F.B. Hollinger, S.M. Lemon and H. Margolis, published by Williams and Wilkins).
As used herein the expression 'hepatitis B antigen' is used to refer to any antigenic material derived from a hepatitis B virus which may be used to induce immunity to the virus in humans.
Infection with hepatitis B virus (HBV) is a widespread problem but vaccines which can be used for mass immunisation are now available, for example the product 'Engerix-B' (SmithKline Beecham pic) which is obtained by genetic engineering techniques.
The preparation of Hepatitis B surface antigen (HBsAg) is well documented. See. for example, Harford et al in Develop. Biol. Standard 54, page 125 (1983), Gregg et al in Biotechnology, 5, page 479 (1987), EP-A- 0 226 846, EP-A-0 299 108 and references therein.
As used herein the expression 'Hepatitis B surface antigen' or 'HBsAg' includes any HBsAg antigen or fragment 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. In particular the
- 1 AP/P/ 9 7 / 0 1 0 60
HBsAg may comprise a polypeptide comprising an amino acid sequence comprising residues 12-52 followed by residues 133-145 followed by residues 175-400 of the Lprotein of HBsAg relative to the open reading frame on a Hepatitis B virus of ad serotype (this polypeptide is referred to as L*; see EP 0 414 374). HBsAg within the scope of the invention may also include the preSl-preS2 -S polypeptide described in EP 0 198 474 (Endotronics) or analogues thereof such as those described in EP 0 304 578 (Me Cormick and Jones). HBsAg as herein described can also refer to mutants, for example the ’escape mutant' described in WO 91/14703 or European Patent Application Publication Number 0 511 855 Al, especially HBsAg wherein the amino acid substitution at position 145 is to arginine from glycine.
Normally the HBsAg will be in particle form. The particles may comprise for example S protein alone or may be composite particles, for example (L*,S) where L* is as defined above and S denotes the S-protein of HBsAg. The said particle is advantageously in the form in which it is expressed in yeast.
Whilst experimental and commercially available Hepatitis vaccines, for example Engerix-B, afford excellent results it is an accepted fact that an optimal vacpine needs to stimulate not only neutralising antibody but also needs to stimulate as effectively as possible cellular immunity mediated through T-cells. International Patent Application No. WO 93/19780, discloses combination vaccines with a hepatitis B component based on a hepatitis B surface antigen, aluminium hydroxide and 3-de-O-acylated monophosphoryl Lipid A. A formulation comprising aluminium phosphate was not suggested.
Surprisingly, the present invention provides a formulation up to four times more potent than those described in WO 93/19780.
Accordingly the present invention provides a vaccine comprising a hepatitis B antigen in conjunction with 3-O-deacylated monophosphoryl lipid A (abbreviated herein to MPL) and aluminum phosphate.
3-O-deacylated monophosphoryl lipid A (or 3 De-O-acyiated monophosphoryl lipid A) has formerly been termed 3D-MPL or d3-MPL to indicate that position 3 of the reducing end glucosamine is de-O-acy lated. For preparation, see GB 2 220 211 A Chemically it is a mixture of 3-deacylated monophosphoryl lipid A with 4, 5 or 6 acylated chains. Herein the term 3D-MPL (or d3-MPL) is abbreviated to MPL
AP.00766 since 'MPL' is a Registered Trademark of-Ribi Immunochem., Montana which is used by Ribi to denote unambiguously their 3-O-deacylated monophosphoryl lipid A product.
Preferably in the compositions of the present invention small panicle MPL is used. Small particle MPL has a particle size generally less than 120 nm. Such preparations are described in International Patent Application No. WO 94/21292.
GB 2 220 211A mentions that the endotoxicity of the previously used 10 enterobacterial lipopolysacharides (LPS) is reduced while the immunogenic properties are conserved. However GB 2 220 211 cited these findings merely in connection with bacterial (Gram negative) systems.
Surprisingly, however, it has been found that vaccine compositions according to the 15 invention comprising hepatitis B viral antigens have particularly advantageous properties as described herein.
A particular advantage is that the vaccine formulations of the invention are very effective in inducing protective immunity, even with very low doses of antigen.
The new vaccine formulations allow immunogenicity enhancements equivalent to currently available hepatitis B formulations after two doses. In particular equivalent levels of antibodies were obtained in a human clinical trial after two doses of vaccine compared with three doses of Engerix-B.
They provide excellent protection against primary infection and stimulate advantageously both specific humoral (neutralising antibodies) and also effector cell mediated (DTH) immune responses.
A further important advantage is that vaccine compositions according to the invention may also be used as therapeutic vaccines.
The MPL as defined above will normally be present in the range of 10-100ug, preferably 25-50ug per dose wherein the Hepatitis B antigen will be typically present in a range 2-50ug per dose and the aluminum phosphate will be in the range 500ug (Al 3+) per dose.
AP/P/ 9 7 / 0 1 0 60
An embodiment of the invention is HBsAg S antigen (for example as in Engerix-B) in admixture with MPL and aluminum phosphate as described herein below.
A further specific embodiment of the invention is HBsAg antigen as (L*,S) particles, defined herein above, in admixture with MPL and aluminum phosphate.
The invention in a further aspect provides a vaccine formulation as described herein for use in medical therapy, particularly for use in the treatment or prophylaxis of hepatitis viral infections. In a preferred aspect the vaccine according to the invention is a therapeutic vaccine useful for the treatment of ongoing hepatitis B infections.
In another aspect, the hepatitis vaccine composition of the invention contains other antigens so that it is effective in the treatment or prophylaxis of one or more other bacterial, viral or fungal infections.
Accordingly the hepatitis vaccine formulation according to an embodiment of the invention contains at least one other component selected from other hepatitis antigens, in particular hepatitis A antigen, or non-hepatitis antigens which are known in the art to afford protection against one or more of the following: diphtheria, tetanus, pertussis, Haemophilus influenzae b (Hib), and polio. Antigens against meningitidis A, B, or C may also be included.
Preferably the vaccine according to the invention includes HBsAg as herein above defined.
Particular combination vaccines within the scope of the invention include a DTP (diphtheria-tetanus-pertussis) -hepatitis B combination vaccine formulation, an HibHepatitis-B vaccine formulation, a DTP-Hib-Hepatitis B vaccine formulation and an IPV (inactivated polio vaccine) -DTP-Hib-Hepatitis B vaccine formulation.
The hepatitis vaccine or the above combinations may advantageously include a component which is protective against Hepatitis A, especially the killed attenuated strain derived from the HM-175 strain as is present in Havrix.
Suitable components for use in such vaccines are already commercially available and details may be obtained from the World Health Organisation. For example the IPV component may be the Salk inactivated polio vaccine. The pertussis vaccine
AP.00766 may comprise whole cell or acellular product, formulated with Diphtheria and Tetanus antigen such as Infanrix DTPa, which comprises three B. pertussis antigens :69KDa, pertussis Toxin (inactivated), and FHA.
In one aspect the hepatitis or combination vaccine according to the invention may be a paediatric vaccine.
Vaccine preparation is generally described in New Trends and Developments in Vaccines, edited by Voller et ai., University Park Press, Baltimore, Maryland
U.S.A. 1978’. Encapsulation within liposomes is described, for example, by
Fullerton, US Patent 4,235,877. Conjugation of proteins to macromolecules is disclosed, for example, by Likhite, US Patent 4,372,945 and by Anmor et al., US Patent 4,474,757.
The amount of antigen in 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 on which specific antigens are employed. Generally it is expected that each dose will comprise l-1000ug of total antigen, preferably 2-200ug. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of antibody titres and other responses in subjects. Following an initial vaccination, subjects may receive one or more booster doses, for example after 2 and 6 months.
In a further aspect of the present invention there is provided a method of manufacture of a vaccine effective in preventing or treating hepatitis infection, wherein the method comprises mixing the hepatitis antigen as defined herein with aluminum phosphate and MPL.
Using this method one or more additional components are preferably admixed with
HBsAg to provide a combination vaccine. Several methods of mixing the components may be used. In one method each antigen may be separately absorbed on aluminum phosphate and after a period of time MPL may be added to each before adding the blending solution.
It will be appreciated that the invention also provides a method of inducing neutralising antibody titres in the range of lOmU for hepatitis B in a human susceptible to or suffering from hepatitis B infection by administering a composition as herein defined in no more than two doses.
AP/P/ 9 7 / 0 1 0 6 0
In another aspect, the invention provides the use of a composition as herein defined for the manufacture of a vaccine for the induction of neutralising antibodies in the range of lOmU for hepatitis B in humans preferably after no more than two doses.
The following examples illustrate the invention and its advantages.
AP.00766
Example 1: Hepatitis B vaccine formulation
MPL (3 de-O-acylated monophosphoryl lipid A) was obtained from Ribi Immunochem Research Inc. Aluminum phosphate was obtained from Superphos (Denmark).
MPL was resuspended in water for injection at a concentration varying from 0.2 to 3 mg/ml by sonication until the particles reach a size of between 80 and 200 nm as measured by photo correlation light scattering.
to 20ug of HBsAg (S- antigen as in Engerix B) in phosphate buffer solution at 0.5 to 3mg/ml) is adsorbed on 5 to lOOOug of aluminum phosphate (solution at 3-6 Ai^ + mg/ml) for one hour at room temperature under agitation. The mixture was stored at room temperature for 15 days and then maintained at 4°C before further processing. Then 5 to 200ug of MPL (solution 0.2 to lOmg/ml) were added to the solution. Volume and osmolarity were adjusted to 500 to lOOOul with water for injection and saline. Thiomersal (l%w/v) is added up to a final concentration of 0.005% to give the final product.
«
A similar formulation was prepared by using as the HBsAg component the composite (L*,S) antigen as defined herein above. In this formulation the bacteriostatic agent was 2-phenoxyethanol.
AP/P/ 9 7 / 0 1 0 6 0
Example 2: Clinical studies of Hepatitis B surface antigen formulated with 3 deacylated monophosphoryl lipid A and Aluminium phosphate
In clinical testing, various hepatitis B surface antigen containing vaccines were compared. The following groups are considered:
Group 1 HBsAg (20 pg)/MPL (50pg)/AlPO4 (Al:500 pg)/Thiomersal (5Opg)/15O mM NaCl/pH 6.1 in 1ml, formulated as in example 1.
Group 2 HBsAg (20 pg)/MPL (50pg)/Al(OH)3 (Al:100 pg)/Thiomersal (50pg)/10 mM phosphate buffer + 150 mM NaCl/pH 6.8 in 1ml.
Group 3 HBsAg (20 pg)/MPL (50pg)/Al(OH)3 (Al:500 pg)/Thiomersal (50pg)/10 mM phosphate buffer + 150 mM NaCl/pH 6.8 in 1 ml.
Group 4 Engerix like
HBsAg (20 pg)/MPL (Opg)/A1(OH)3 (Al:500 pg)/Thiomersal (50pg)/10 mM phosphate buffer + 150 mM NaCl/pH 6.8 in 1 ml.
c
Group 5 HBsAg (20 pg)/MPL (0pg)/AlPO4 (Al:500 pg)/Thiomersal (50pg)/150 mM NaCl/pH 6.1 in 1ml.
The Volunteers aged 18 to 40 years old were recruited for participation in the trial. Each group (about 60 adults per group at day 0) was vaccinated intramuscularly in the deltoid region at day 0 and 2 months later. A sample of blood was collected before the first injection, one and two months after the first injection and 1, 2 and 4 months after the second injection. The anti-HBs antibodies were measured using the AUSAB kit (Abbott) and a WHO reference calibrated in mlU/ml. Responders had a titre > 1 ml U/ml. For each time point, the GMT (Geometric Mean Titre) was calculated for seroconverters.
Results
The. GMT’s are given in Table 1 for each vaccine and table 2 gives the ranking of the antibody titres in each group of vaccinees.
The GMT results (table 1) clearly show that after 2 doses of vaccine containing Al PO4 + MPL (group 1), a more than 10 fold increase of the titers is observed after
AP . 0 0 7 6 6 the second dose compared with the titre reached using the commercial Engerix B (group 4). The anti-HBs response is also faster and 51 and 70% of vaccinees have a protective titre (lOml/U/ml) 1 and 2 months after the first dose (compared to 34 and 16% for Engerix B) (table 2). The addition of 3D-MPL to Engerix B (Group 3), the use of A1PO4 only (group 5) slightly improve the anti-HBS response (compared to Engerix B) but the titres are still 4 to 5 fold lower than with the Al PO4 + MPL formulation. Adsorption of HBsAg on a reduced dose of Al (OH)3 + MPL gives titres which are similar to those reached with Engerix B. Together, the results indicate that both Al PO4 and MPL are necessary to have an optimal increase of the anti-HBs response in vaccinees after only 2 doses.
AP/P/ 9 7 / 0 1 0 6 0
Seroconversion rates (%) and geometric mean anti-HBs antibody titre (GMT) of seroconverters: Preliminary analysis
TABLE 1
K
Group Timing N S + % GMT CL 95% lower CL 95% upper Min titre Max titre
1 Pre 59 0 0.0 0 0 0
PI (ml) 53 46 86.8 12 9 8 1 410
PI (m2) 53 50 94.3 18 13 26 1 140
PII (m3) 53 53 100.0 2092 1356 3227 43 60000
PII (m4) 39 39 100.0 1613 1074 2423 40 19620
PII (m6) 25 25 100.0 890 582 ' 1363 42 3900
2 Pre 59 0 0.0 0 0 0
PI (ml) 53 31 58.5. 17 10 32 1 1000
PI (m2) 53 35 66.0 9 6 16 1 860
PII (m3) 53 35 100.0 215 128 360 1 25000
PII (m4) 40 40 100.0 122 74 201 . 2 2808
PII (m6) 22 22 100.0 85 50 145 2 900
3 Pre 59 0 0.0 0 0 0
PI (ml) 53 43 81.1 9 6 15 1 720
PI (m2) 53 44 83.0 7 4 10 1 1040
PII (m3) 53 53 100.0 527 332 838 3 10100
PII (m4) 40 40 100.0 363 225 586 3 5638
PII (m6) 24 24 100.0 177 99 316 9 2196
4 Pre 59 0 0.0 0 0 0
PI (ml) 50 30 60.0 11 6 19 1 290
PI (m2) 50 34 68.0 4 3 6 1 45
PII (m3) 50 50 100.0 187 107 329 1 9500
PII (m4) 42 42 ' 100.0 211 127 350 5 10584
PII (m6) 25 25 100.0 226 132 386 20 2595
5 Pre 59 0 0.0 0 0 0
PI (ml) 52 30 57.7 12 6 25 1 1060
PI (m2) 52 41 78.8 9 6 14 1 420
PII (m3) 52 52 100.0 294 168 515 1 18000
PII (m4) 41 41 100.0 287 158 521 2 15764
PII (m6) 24 22 91.7 353 188 660 10 7701
-10AP.00766
Distribution of individual anti-HBs antibody titres preliminary analysis
TABLE 2
Group Timing N > =10 n % > =100 n % > +1000 n %
1 Pre 59 0 0.0 0 0.0 0 0.0
PI (ml) 53 27 50.9 2 3.8 0 0.0
PI (m2) 53 37 69.8 2 3.8 0 0.0
PII (m3) 53 53 100.0 49 92.5 40 75.5
PII (m4) 39 39 100.0 37 94.9 27 69.2
PII (m6) 25 25 100.0 24 96.0 15 60.0
2 Pre 59 0 0.0 0 0.0 0 0.0
PI (ml) 53 20 37.7 3 5.7 1 1.9
PI (m2) 53 14 26.4 3 5.7 0 0.0
PII (m3) 53 50 94.3 38 71.7 11 20.8
PII (m4) 40 38 95.0 24 60.0 3 7.5
PII (m6) 22 21 95.5 8 36.4 0 0.0
3 Pre 59 0 0.0 0 0.0 0 0.0
PI (ml) 53 17 32.1 7 13.2 0 0.0
PI (m2) 53 17 , 32.1 1 1.9 1 1.9
PII (m3) 53 51 96.2 45 84.9 20 37.7
PII (m4) 40 39 97.5 34 85.0 10 25.0
PII (m6) 24 23 95.8 18 75.0 3 12.5
4 Pre 59 0 0.0 0 0.0 0 0.0
PI (ml) 50 17 34.0 3 6.0 0 0.0
PI (m2) 50 8 16.0 0 0.0 0 0.0
PII (m3) 50 46 92.0 35 70.0 11 22.0
PII (m4) 42 40 95.2 30 71.4 5 11.9
PII (m6) 25 25 100.0 18 72.0 4 16.0
5 Pre 59 0 0.0 0 0.0 0 0.0
PI (ml) 52 15 28.8 5 9.6 1 1.9
PI (m2) 52 20 38.5 3 5.8 0 0.0
PII (m3) 52 48 92.3 39 75.0 14 26.9
PII (m4) 41 39 95.1 31 75.6 9 22.0
PII. (m6) 24 22 91.7 18 75.0 5 20.8
AP/P/ 9 7 / 0 1 0 6 0

Claims (16)

1. A vaccine composition comprising a hepatitis B antigen in conjunction with 3-0deacyiated monophosphoryl lipid A and aluminum phosphate.
Claims partieuUuJy ··
L-erwin^ Slild •v ,,,· -Ur same ’· ,vhat nvanne. -v •ibeil a«ul\ mN *η ‘ u'inecii
2. A vaccine composition as claimed in Claim 1 wherein the antigen comprises Hepatitis B surface antigen (HBsAg) or a variant thereof.
3. A vaccine composition as claimed in Claim 2 wherein the HBsAg comprises the S antigen of HBsAg (226 amino acids).
4. A vaccine composition as claimed in Claim 3 wherein the HBsAg additionally comprises a pre-S sequence.
5. A vaccine composition as claimed in Claim 3 or Claim 4 wherein the HBsAg is the composite particle of the formula (L*,S) wherein L* denotes a modified L protein of hepatitis B virus having an amino acid sequence comprising residues 1252 followed by residues 133-145 followed by residues 175-400 of the L protein and S denotes the S-protein of HBsAg.
6. A vaccine composition as claimed in any preceding claim comprising one or more hepatitis antigens and at least one other component selected from a hepatitis A antigen or a non-hepatitis antigen which affords protection against one or more of the following: diphtheria, tetanus, pertussis, Haemophilus influenzae b (Hib), polio and meningitidis A, B, or C.
7. A vaccine composition according to Claim 6 selected from a DTP (diphtheriatetanus-pertussis) HBsAg combination, an Hib-HBsAg combination, a DTP-HibHBsAg combination and an IPV (inactivated polio vaccine) -DTP-Hib-HBsAg combination.
8. A vaccine composition according to claim 7 additionally comprising a hepatitis A antigen.
9. A vaccine composition as claimed in any preceding claim wherein the 3-0deacylated monophosphoryl lipid A is present in the range lOug-lOOug per dose.
- 12AP . 0 0 7 6 6
10. A vaccine composition as claimed herein for use in medicine.
11. Use of a hepatitis B antigen in conjunction with 3-O-deacylated
5 monophosphoryl lipid A and aluminum phosphate in the manufacture of a medicament for the prophylaxis or treatment of hepatitis infections.
12. A method of inducing neutralising antibody titres in the range of 10mU for hepatitis B in a human susceptible to or suffering from hepatitis B infection by
10 administering a composition according to any one of claims 1 to 10.
13. The use of a composition according to any one of claims 1 to 10 for the manufacture of a vaccine for the induction of neutralising antibodies in the range of lOmU for hepatitis B in humans.
14. A method of treating a human subject suffering from or susceptible to hepatitis B infections comprising administering an effective amount of a vaccine according to any of claims 1 to 10.
20
15. A method of treating a human subject suffering from ongoing hepatitis B infection comprising administering an effective amount of a therapeutic vaccine according to any of claims 1 to 10.
16. A process for the production of a vaccine as claimed in any one of claims 1 to
25 9 comprising absorbing Hepatitis B surface antigen on to aluminium phosphate and then adding 3-O-de acylated monophosphoryl lipid A.
APAP/P/1997/001060A 1995-02-25 1996-02-15 A vaccine based on hepatitis B antigen. AP766A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9503863.4A GB9503863D0 (en) 1995-02-25 1995-02-25 Vaccine compositions
PCT/EP1996/000681 WO1996026741A1 (en) 1995-02-25 1996-02-15 Hepatitis b vaccine

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AP9701060A0 AP9701060A0 (en) 1997-10-31
AP766A true AP766A (en) 1999-09-17

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SK115097A3 (en) 1998-02-04
EP0810877B1 (en) 2001-11-21
DK0810877T3 (en) 2002-02-25
FI118118B (en) 2007-07-13
ES2166879T3 (en) 2002-05-01
CZ267497A3 (en) 1998-02-18
AR002279A1 (en) 1998-03-11
NO973873D0 (en) 1997-08-22
JP3881015B2 (en) 2007-02-14
HUP9801242A1 (en) 1998-08-28
GB9503863D0 (en) 1995-04-19
JPH11501018A (en) 1999-01-26
CZ288417B6 (en) 2001-06-13
KR100365373B1 (en) 2003-07-07
KR19980702480A (en) 1998-07-15
FI973457L (en) 1997-08-22
NO319394B1 (en) 2005-08-08
OA10612A (en) 2002-08-29
EP0810877A1 (en) 1997-12-10
HK1004117A1 (en) 1998-11-20
MY113428A (en) 2002-02-28
WO1996026741A1 (en) 1996-09-06
ZA961460B (en) 1996-08-29
CA2212552A1 (en) 1996-09-06
US5972346A (en) 1999-10-26
NO973873L (en) 1997-08-22
HUP9801242A3 (en) 2000-08-28
EA199700126A1 (en) 1998-02-26
CA2212552C (en) 2006-07-11
HU224832B1 (en) 2006-03-28
PT810877E (en) 2002-04-29
AU695921B2 (en) 1998-08-27
NZ302674A (en) 1999-01-28
AP9701060A0 (en) 1997-10-31
TR199700849T1 (en) 1998-01-21
BG101851A (en) 1998-04-30
CN1101225C (en) 2003-02-12
FI973457A0 (en) 1997-08-22
BR9607458A (en) 1998-06-30
MX9706450A (en) 1998-07-31
PL321966A1 (en) 1998-01-05
DE69617211D1 (en) 2002-01-03
AU4878096A (en) 1996-09-18
ATE209045T1 (en) 2001-12-15
PL182679B1 (en) 2002-02-28
IL117249A0 (en) 1996-06-18
CN1176604A (en) 1998-03-18
IL117249A (en) 2000-11-21
MA23814A1 (en) 1996-10-01
DE69617211T2 (en) 2002-07-25
TW467745B (en) 2001-12-11
SA96160633B1 (en) 2005-10-15

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