Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Combination of viral and bacterial antigens
Reexamination Certificate
1997-12-30
2001-12-25
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Combination of viral and bacterial antigens
C424S184100, C424S197110, C424S256100, C424S278100, C424S831000
Reexamination Certificate
active
06333036
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the field of vaccine compositions and more particularly to vaccine compositions comprising at least one antigen formed by the capsular polysaccharide of Haemophilus influenzae type b or high molecular weight polyribosylribitol phosphate coupled to tetanus anatoxin.
2. Description of the Related Art
An antigen which can be used for vaccine purposes in man in order to protect him from infections caused by Haemophilus influenzae type b is known in the prior art, and especially through the article “Quantitative and Qualitative Analyses of Serum Antibodies Elicited in Adults by Haemophilus influenzae Type b and Pneumococcus Type 6A Capsular Polysaccharide Tetanus Toxoid Conjugates” Rachel Schneerson et al, Infect. Immun. May 1986. This antigen is formed by a capsular polysaccharide of the bacteria, polyribosylribitol phosphate (or PRP), which is made T-dependent owing to coupling to a carrier protein, tetanus anatoxin. Trials carried out on rhesus children have shown, as this article reports, that the immune response was at one and the same time greater and earlier if the antigen was associated with aluminium hydroxide. However, as another article entitled “Clinical and Immunologic responses to the capsular polysaccharide of Haemophilus influenzae type b alone or conjugated to tetanus toxoid in 18-23 month-old children”, Bo A. Claesson and al, The Journal of Pediatrics, May 1988, points out, it was noticed that this antigen, adsorbed on aluminium hydroxide, was less immunogenic after storage than the antigen kept in saline solution, which may be due to degradation of the polysaccharide.
In order to resolve this problem of stability of the PRP-T, it was proposed in the prior art to lyophilize it. This solution, even though it allows the antigen to retain its immunogenic character in the course of time, shows some disadvantages, however, especially at the manufacturing level; the lyophilization and the particular operations of conditioning which it requires complicates the production process, which increases the cost. In addition, at the time of administration, it is necessary to take up the lyophilizate again, which means that it is necessary to have in addition to the lyophilizate a liquid for taking up this lyophilizate; this operation represents a supplementary constraint for the practitioner and presents, like any manipulation, the risk of being carried out badly.
In addition, a certain number of liquid vaccine combinations possess antigens adsorbed on an aluminium-based adjuvant and it would be advantageous to be able, without loss of immunogenicity, to add the antigen formed by the PRP-T to them. In fact, the solution proposed in the prior art and consisting in a special syringe with two compartments (a first compartment containing the PRP-T in lyophilized form and a second compartment containing the other antigens in aqueous suspension) whose contents are mixed for use only at the time of administration is not satisfactory either at the level of the costs of production or at the level of the operations to be carried out by the practitioner.
It is thus desirable to be able to have a liquid vaccine composition comprising the antigen formed by the PRP-T having a very good immunogenic character retained in the course of time, and whose conditions of manufacture allow production at the lowest cost.
SUMMARY OF THE INVENTION
This invention relates to vaccine compositions capsular polysaccharide of Haemophilus influenzae type b or high molecular weight polyribosylribitol phosphate (PRP) coupled to tetanus anatoxin, as well as an aluminium-based adjuvant. Such a combination permits a stable, liquid vaccine composition wherein each antigen retains its immunogenicity.
BRIEF DESCRIPTION OF THE INVENTION
The invention relates to a vaccine composition comprising at least one antigen formed by the capsular polysaccharide of Haemophilus influenzae type b or high molecular weight polyribosylribitol phosphate coupled to tetanus anatoxin as well as an aluminium-based adjuvant, characterized in that the aluminium-based adjuvant has a point of zero charge of less than approximately 7.2.
It has thus been noticed that, surprisingly, under these conditions, PRP-T retains in the course of time in liquid medium its very good immunogenic character.
According to a particular characteristic of the invention the aluminium-based adjuvant comprises aluminium hydroxides to which anions have been added.
Thus, it is possible to use an adjuvant perfectly qualified for vaccine use while retaining in the PRP-T in liquid medium a very good immunogenicity.
According to another characteristic of the invention, the anions are chosen from amongst the phosphates or the citrates.
Thus, the composition obtained has all the safety guarantees necessary for a vaccine administration.
According to a particular mode of carrying out the invention, the vaccine composition additionally comprises one or more of the vaccine valencies chosen from amongst: diphtheria, tetanus, whooping cough, hepatitis B and poliomyelitis.
It is thus possible to have liquid, stable vaccine combinations in which each antigen retains its immunogenicity, which allows the practitioner, without supplementary manipulation on his part, to vaccinate simultaneously against several illnesses; this allows the costs to be reduced at one and the same time as far as the products are concerned and as far as the number of visits to be made are concerned.
The invention likewise relates to a method of manufacture of a vaccine composition comprising at least one antigen formed by the capsular polysaccharide of Haemophilus influenzae type b or high molecular weight polyribosylribitol phosphate coupled to tetanus anatoxin, characterized in that it consists in adding an adjuvant to the vaccine composition by means of a suspension of aluminium complexes having a point of zero charge of less than approximately 7.2.
The present invention will be better understood by reading the detailed description which will follow.
The antigen formed by the capsular polysaccharide Haemophilus influenzae type b is a linear polymer consisting of ribose, ribitol and phosphoric acid which has the following monomeric structure:
The number of monomers of this type is high (greater than 100), which leads to a polysaccharide whose molecular weight is of the order of 500,000 to 1,000,000.
In order to induce an immune response of the T cells in young children, this antigen is conjugated to a carrier protein formed by tetanus anatoxin.
Such an antigen can, for example, be obtained according to the method described in “Quantitative and Qualitative analysis of serum antibodies elicited in adults by Haemophilus influenzae type b and Pneumococcus type 6A capsular polysaccharide-tetanus toxoid conjugates” Schneerson et al, Infect. Immun. 52: 519 (1986).
The characteristics appropriate to this antigen: high number of monomers of the polysaccharide, nature of the carrier protein, nature of the link between the polysaccharide and the carrier protein, confers particular qualities on it and especially a very good immunogenicity.
In order to retain these qualities in liquid medium in the course of time, it has now been found that it is possible to use aluminium complexes whose point of zero charge is less than approximately 7.2. In fact, it was found that, surprisingly, when the PRP-T is associated with such aluminium complexes, its very good immunogenicity character is retained in the course of time in liquid medium and this takes place whatever its degree of immobilization on the aluminium complexes.
The point of zero charge of aluminium complexes is the equivalent of the isoelectric point of proteins; it is the pH at which the charge at the surface of the aluminium complexes is zero. In fact, this point of zero charge is approached by measurements of zeta potential which can be carried out according to different techniques, the basic method being electrophoresis. It is possible to carry out the measurements by means of an appara
Arminjon Francois
Cartier Jean-René
Burns Doane Swecker & Mathis L.L.P.
Pasteur Merieux Serums et Vaccins S.A.
Wortman Donna C.
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