Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1997-10-27
1999-10-26
Woodward, Michael P.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4241841, 4242011, 4242021, 4242261, 4242281, 4242781, A61K 3929, A61K 39295, A61K 4500
Patent
active
059723467
DESCRIPTION:
BRIEF SUMMARY
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 the development of effective vaccines is critical and, despite notable successes, is still an on-going task. A review on modern 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 plc) 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 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 L-protein 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 preS1-preS2-S polypeptide described in EP 0 198 474 (Endotronics) or analogues thereof such as those described in EP 0 304 578 (Mc 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 A1, 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 vaccine 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
REFERENCES:
Coursajet, et al., Simultaneous Adminstration of Diphtheriz-Tetanus-Pertussis-Polio and Hepatitis B Vaccines . . . , in Infection and Immunity 51(3) pp. 784-787 (1986).
D'Hondt 1992 Vaccine vol. 10 S1 pp. s48-s52, 1992.
Pellegrini, et al., "Preparation and immunogenicity of an inactivated hepatitis A vaccine", Vaccine, 11, Issue 3, pp. 383-387 (1993).
Ewasyshyn, et al., "Comparative analysis of the immunostimulatory properties of different adjuvants on the immunogenicity of a prototype parainfluenza virus type 3 subunit vaccine", Vaccine, 10, Issue 6, pp. 412-420 (1992).
Desmons Pierre
Garcon Nathalie Marie-Josephe Claude
Hauser Pierre
Kerekes Zoltan
Kinzig Charles M.
SmithKline Beecham Biologicals (S.A.)
Venetianer Stephen
Woodward Michael P.
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