Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1997-09-15
2001-12-11
Mosher, Mary E. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S278100, C424S283100
Reexamination Certificate
active
06328965
ABSTRACT:
The present invention relates to novel vaccine adjuvants.
An antigen is defined as a foreign substance for a given organism, which when administered, for example, parenterally, induces an immune response, for example, the formation of antibodies.
Antibodies are substances contained in the blood and other fluids of the body, as well as in the tissues, and which bind to the antigen to make it innocuous. Antibodies constitute one of the natural defense mechanisms of the body. They are highly specific and they can kill, bind or make innocuous the antigen which has induced their formation.
The antigen, in contact with the immune system, thus activates a complex series of cellular interactions to eliminate the antigen and/or to reestablish the preceding equilibrium.
Two of the characteristic features of antigens are their immunogenicity, that is their capacity to induce an immune response in vivo (including the formation of specific antibodies), and their antigenicity, that is their capacity to be selectively recognized by the antibodies whose origins are the antigens.
It is known how to stimulate the immune response deliberately by administrating a specific antigen by means of a vaccine. The procedure allows the obtention of a state of immune response in the organism which allows a more rapid and more effective response of the organism during subsequent contact with the antigen.
However, some antigens have only a weak immunogenicity and they induce an insufficient immune response to procure an effective protection for the organism.
The immunogenicity of an antigen can be increased by administering it in a mixture with substances, called adjuvants, which increase the response against the antigen either by directly acting on the immunological system or by modifying the pharmacokinetic characteristics of the antigen and by thus increasing the interaction time between the latter with the immune system.
At this time, a great number of veterinary vaccines use adjuvants still comprising the standard emulsions of mineral oil, such as the adjuvant of the water in mineral oil type (W/O) or of the mineral oil in water type (O/W). For several years, research studies have been carried out to find alternatives having a similar efficacy at a reduced toxicity. The injections of these standard adjuvants based on mineral oil are often accompanied by local reactions whose severity depends to a large extent on the type of the emulsion and the nature of oil used. The use of adjuvants based on mineral oil is consequently limited to domestic animals (pigs, hens, ruminants, etc.) and laboratory animals.
Earlier, it has been shown that a synthetic copolymer of polysucrose and epichloridrin [sic; epichlorohydrin]—Ficoll—bearing sulfate and lipid groups (SL-Ficoll), incorporated in an emulsion of squalane (S) in water (S/W), had high adjuvant effect on different animal species—including pigs—against different types of antigen, including a few important viral antigens (Vaccine, Vol. 12, pp. 653-660 (1994) and Vaccine, Vol. 12, pp. 661-665 (1994), EPO 0,549,074). These formulations of Ficoll-based adjuvants are sufficiently effective to replace the standard formulations of mineral oil in water used in different porcine vaccines.
However, the local toxicity, that is the reactogenicity of these Ficoll-based formulations in pigs and mice did not turn out to be weaker than that of the standard formulations of mineral oil of the O/W type.
In addition, for the Ficoll-based formulations, the temperature has a pronounced effect on the stability of the emulsions. Some of these emulsions were stable for years at 4° C., but the aqueous phase and the oil phase separate within a few days at 37° C., and within approximately 10 min at 60° C.
The purpose of the present invention is to propose an effective adjuvant for vaccines having an increased stability at high temperature and presenting a lower local toxicity.
This purpose is achieved by an adjuvant for vaccines comprising a sulfolipid polysaccharide combined with an interface-forming constituent (for example, an emulsion of the oil/water type (O/W)).
One of the advantages of the adjuvant according to the present invention is that it is more stable at high temperature than the Ficoll-based adjuvants.
This purpose is achieved by an adjuvant for vaccines comprising a sulfolipid polysaccharide combined with an interface-forming constituent.
The expression “polysaccharide” denotes a compound having at least three repeating sugar units connected covalently to each other.
The expression “sulfolipid polysaccharide” denotes a compound having at least three repeating sugar units connected covalently to each other, at least one sulfate group and at least one lipid group.
Preferably, the sulfolipid polysaccharide is a hydrophobic polysaccharide.
The expression “hydrophobic polysaccharide” denotes a polysaccharide which is less soluble in an aqueous phase than an a polar organic phase.
According to a first advantageous embodiment, the sulfolipid polysaccharide is selected from the group consisting of cyclodextrin, maltodextrin, insulin, Ficoll and Pullulan.
Preferably, the sulfolipid polysaccharide is selected from the group consisting of cyclodextrin, maltodextrin and insulin.
The preferred sulfolipid polysaccharide is cyclodextrin.
The sulfolipid polysaccharide contains, on average, at least 0.01 sulfate group per monosaccharide, while maintaining its hydrophobic character. Preferably, the sulfolipid polysaccharide contains, on average, at least 0.12 sulfate group per monosaccharide, while maintaining its hydrophobic character.
The sulfolipid polysaccharide on average contains not more than 1.0 sulfate group per monosaccharide, while maintaining its hydrophobic character. Preferably, the sulfolipid polysaccharide contains, on average, not more than 0.23 sulfate group per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is maltodextrin, it contains, on average, approximately 0.23 sulfate group per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is cyclodextrin, it contains, on average, approximately 0.20 sulfate group per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is insulin, it contains, on average, approximately 0.19 sulfate group per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is pullulan, it contains, on average, approximately 0.16 sulfate group per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is Ficoll, it contains, on average, approximately 0.12 sulfate group per monosaccharide, while maintaining its hydrophobic character.
On average, the sulfolipid polysaccharide contains at least 0.01 lipid group per monosaccharide, while maintaining its hydrophobic character. Preferably, the sulfolipid polysaccharide contains, on average, at least 1.05 lipid group per monosaccharide, while maintaining its hydrophobic character.
On average, the sulfolipid polysaccharide contains not more than 2.0 lipid groups per monosaccharide, while maintaining its hydrophobic character. Preferably, the sulfolipid polysaccharide contains, on average, not more than 1.29 lipid groups per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is maltodextrin, it contains, on average, approximately 1.29 lipid groups per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is cyclodextrin, it contains, on average, approximately 1.05 lipid groups per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is insulin, it contains, on average, approximately 1.24 lipid groups per monosaccharide, while maintaining its hydrophobic character.
Preferably, when the sulfolipid polysaccharide is pullulan, it contains, on average, approximately 1.24
American Cyanamid Company
Levis John F.
Mandel Adley
Mosher Mary E.
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