Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
2000-11-30
2003-03-04
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S278100, C424S280100, C424S283100, C514S025000, C514S026000, C514S033000
Reexamination Certificate
active
06528058
ABSTRACT:
TECHNICAL FIELD
This invention relates to adjuvant compositions for stimulating an immune response to an antigenic substance when co-administered to an animal with said antigenic substance, and to vaccines containing said adjuvant composition.
BACKGROUND ART
Vaccination against disease has a long history. In general terms the technique involves injection of an antigenic substance, or antigen, into an animal whereby the presence of the antigenic substance generates an immune response in the animal. Classical vaccination techniques involve the injection of killed organisms but more recently vaccines comprising attenuated live organisms or antigenic components of an organism have been developed. It is frequently found with killed vaccines and, more particularly, with vaccines comprising a component of an organism that the immune response is substantially less than the response to natural infection. However, the effectiveness of such vaccines can be considerably enhanced by the co-administration of a suitable adjuvant composition with the antigenic substance. Adjuvants, while not necessarily being antigenic themselves, potentiate or enhance an animal's immune response to the antigenic substance with which it is challenged. There are many adjuvants known and used but there is an ongoing need to identify new and effective adjuvants which are inexpensive, which produce minimal injection site irritation and discomfort and which are widely applicable and effective.
A common formulation for vaccines is to present the antigen(s) in an aluminium hydroxide gel. While this is effective in some cases and is reasonably benign, in many cases this adjuvant fails to induce a sufficiently protective response. It is also well known that antigens emulsified in a mineral oil vehicle together with whole mycobacterial cells (Freund's complete adjuvant, FCA) can produce a generally effective immune response against a wide range of antigens. However, this formulation is unacceptable for routine use because of the inflammation, granulomas, ulceration and other lesions which can be formed at the injection site. Mineral oils alone (frequently referred to as Freund's Incomplete Adjuvant, FIA or Incomplete Freund's, ICF) are less damaging but are also less effective. Neutral oils (such as miglyol) and vegetable oils (such as arachis oil), ISCOMS and liposomes have also been used. Also effective are adjuvants containing purified mycobacterial component such as N-acetylmuramyl-L-alanyl-D-isogulutamine (MDP) or its analogues in aqueous or oil formulations. Among other adjuvants which have been or are currently used are the saponins, particularly triterpenoid mixtures such as Quil A (a purified extract from the bark of the tree Quillaja saponarioa) in aqueous solution or in the form of a matrix with cholesterol. Polycations such as diethylaminoethyldextran (DEAE dextran) can also be effective as adjuvants in some cases.
There have also been proposals to use a combination of two adjuvants substances in an adjuvant composition. For example, Australian patent no. 602348 describes an immunoadjuvant comprising an immunoadjuvant oil substantially free of mycobacteria and a polycationic polyelectrolyte immunoadjuvant such as DEAE dextran in the form of an emulsion having the polycationic polyelectrolyte dissolved in the aqueous phase. The two-component immunoadjuvant is said to overcome the rapid decline in the immune response associated with polycationic polyelectrolyte adjuvants on the one hand and, on the other, the weak initial response associated with immunoadjuvant oils. Accordingly, the two-component adjuvant is said to fill the gap in the prior art between those adjuvants inducing high peak/short life antibody responses and those inducing low peak/long life responses.
International application no. 88/07547 is primarily concerned with a novel peptide nevertheless, it also discloses the use of a novel adjuvant comprising DEAE dextran and a saponin or aluminium hydroxide and notes an improved antibody titre when the two-component immunoadjuvants are used. In particular, solutions of DEAE dextran and saponin in phosphate buffered saline are used but there is no suggestion of the incorporation of an immunoadjavent oil into such compositions.
Australian patent no. 640414 discloses a solid vaccine composition comprising an antigenic substance capable of inducing the generation of antibodies on parenteral administration to an animal, a saponin and a polycationic adjuvant. The essence of the invention is that the vaccine is formulated as solid to be implanted in the animal to thereby induce a long-lasting immune response. There is no suggestion of the presence of an immunoadjuvants oil in the composition and, indeed, the specification teaches away from the use of an oil as it is critical to the invention that this formulation be solid.
In the present invention it has been found, surprisingly, that combinations of certain adjuvants enhance the effectiveness of an antigenic substance in stimulating an immune response to a much greater extent than the sum of the profiles that would be obtained by the use of the components separately or through the use of a two-component immunoadjuvant.
DISCLOSURE OF THE INVENTION
According to a first aspect of the present invention there is provided an adjuvant composition for stimulating an effective immune response in an animal to an antigenic substance when co-administered to said animal with said antigenic substance, comprising:
(a) a saponin with immune stimulating activity;
(b) a polycationic polyelectrolyte with immune stimulating activity; and
(c) an immunoadjuvant oil.
According to a second aspect of the present invention there is provided a vaccine for administration to an animal, comprising:
(1) an antigenic substance; and
(2) an adjuvant composition comprising:
(a) a saponin with immune stimulating activity;
(b) a polycationic polyelectrolyte with immune stimulating activity;
(c) an immunoadjuvant oil.
According to a third aspect of the present invention there is provided a method of stimulating an effective immune response in an animal to an antigenic substance, comprising the steps of:
(1) providing said antigenic substance;
(2) providing an adjuvant composition for stimulating an effective immune response to said antigenic substance, comprising:
(a) a saponin with immune stimulating activity;
(b) a polycationic polyelectrolyte with immune stimulating activity; and
(c) an immunoadjuvant oil; and
(3) challenging said animal with said antigenic substance and said adjuvant composition.
According to a fourth aspect of the present invention there is provided the use of an adjuvant composition comprising:
(a) a saponin with immune stimulating activity;
(b) a polycationic polyelectrolyte with immune stimulating activity; and
(c) an immunoadjuvant oil to stimulate an effective immune response in an animal challenged with an antigenic substance.
According to a fifth aspect of the present invention there is provided the use of an adjuvant composition comprising:
(a) a saponin with immune stimulating activity;
(b) a polycationic polyelectrolyte with immune stimulating activity; and
(c) an immunoadjuvant oil in the preparation of a medicament for administration to an animal, wherein said medicament further comprises an antigenic substance.
The saponins are common secondary constituents of plants and typically are glycosides composed of several (hydrophilic) sugars in association with a (hydrophobic) molecule, which can be either a steroid or triterpenoid structure. In particular, an extract from the South American tree
Quillaja saponarioa
shows good adjuvant activity and is now denoted “Quil A”. While the precise chemical composition of Quil A is not known, the sugar moieties detected in the mixture include rhamnose, fucose, arabinose, xylose, galactose, glucose, apiose and glucuronic acid and the hydrophobic moiety has a triterpenoid structure. The nature of Quil A is discussed as length in Australian patent application no. 10777/95, the disclosure of which is inc
Edgar John Alexander
Tahan Khin Aye
Commonwealth Scientific and Industrial Research Organisation
Pillsbury & Winthrop LLP
Saunders David
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