Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Virus or bacteriophage
Reexamination Certificate
2001-12-05
2003-10-21
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Virus or bacteriophage
C424S206100, C424S278100, C435S235100, C435S236000, C435S238000, C435S239000, C530S826000
Reexamination Certificate
active
06635246
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a vaccine composition containing at least one inactivated influenza virus antigen and aluminum as an adjuvant for nasal or oral application for the prophylaxis of influenza virus infections.
BACKGROUND OF THE INVENTION
Influenza virus infections represent an ever greater health risk, especially in the elderly and in persons with chronic diseases, because the infection in these groups often leads to higher mortality rates. Since the introduction in the 1940s of an inactivated influenza vaccine containing inactivated virus material from infected incubated eggs, the risk and course of the infection as well as the mortality rates in elderly persons have dropped.
To date, inactivated influenza virus vaccines from eggs are licensed for parenteral administration to people, and induce anti-HA-IgG antibodies in the serum. The cross-protection against heterologous influenza viruses, however, can be traced primarily to the cross-reactivity of IgA antibodies in a natural infection. (Liew et al., 1984, Eur. J. Immunol. 14:350-356). Therefore, with the development of new immunization methods against influenza virus infections, an attempt is being made to stimulate the production of the mucosal IgA immune response.
To this end, a series of developments for intranasal or oral administration of influenza virus vaccines has been developed. Thus, for example, the administration of an inactivated virus vaccine (Waldman et al., 1968, Nature 218:594-595), an inactivated vaccine combined with carboxyvinyl polymer (Oka et al., 1990, Vaccine 8:573-576), or with pertussis toxin B oligomer (Oka et al., 1994, Vaccine 12:1255-1258), a split virus vaccine with cholera toxin, E. coli heat-labile enterotoxin or liposomes (Tamura et al., 1992, J. Immunol. 149:981-988, Komasse et al., 1998, Vaccine 16:248-254, de Haan, 1995, Vaccine 13:155-162), an emulsion inactivated vaccine (Avtushenko et al., 1996, J. Biotechnol. 44:21-28), or a cold adapted live attenuated influenza virus vaccine (Belshe et al., 1998, N. Engl. J. Med. 338:1405-1412) produces not only the induction of HAI-IgG antibodies in the serum, but also the secretion of IgA antibodies of the mucosal membrane as well.
Inactivated viruses as orally or nasally applied vaccines must, however, be given in high concentrations in order to bring about a significant increase of antibodies. The administration of inactivated influenza virus or antigen in convenient commercial doses, free of side effects, with nasal or oral administration, does not produce a satisfactory immune response without the use of an adjuvant.(Chen et al., 1989, Current Topics in Microbiology and Immunology 146:101-106, Couch et al., 1997, J. Infect. Dis. 176:38-44). Thus, for example, for the optimum induction of the immune response with oral administration of an emulsion-inactivated vaccine, an antigen content between 66 &mgr;g antigen/dose and 384 &mgr;g antigen/dose is required (Avtushenko et al., 1996, J. Biotechnol. 44:21-28). Thus, this dose lies far above that of an inactivated vaccine for parenteral administration, which is at approximately 15 &mgr;g antigen/dose.
Although cholera toxin, E. coli heat-labile toxin and pertussis toxin have an effective adjuvant effect in oral or nasal administration of influenza antigen, they are not used for human application because of the toxic side effects. The only adjuvant approved to date for application to humans is aluminum.
A cold-adapted, live attenuated influenza virus vaccine to be found in clinical studies for nasal administration is based on virus antigens from which reassortants must be produced annually by means of genetic methods, in which the genes for the hemagglutinin and neuramidase antigens of the corresponding influenza A or B strain are transferred to an attenuated, cold-adapted master virus strain. This method is very time consuming and labor intensive. In addition, there is the danger that through reversion the attenuated virus back mutates into a virulent virus and thus can trigger viremia. When immunization is carried out with living viruses there is also a further spread in the body of the immunized individual. When cold-adapted viruses are used, there is also the constant necessity of storing the virus vaccine below the freezing point, as close to −20° C. as possible, which then requires the absolute maintenance of a chain of refrigeration to ensure sufficient storage life of the vaccine.
Eggs are used for the production of the virus reassortants and the propagation of the vaccine viruses, which entails the risk that any contaminating infectious agents that may be present may be transferred into the eggs. The purification of live viruses is also not without problems because they represent infectious material and thus a higher standard of security must be maintained.
The problem of the present invention is, therefore, to make available an influenza virus vaccine composition that does not have the disadvantages described above, and that effectively induces the IgA and IgG immune response in mammals.
BRIEF SUMMARY OF THE INVENTION
The problem is solved according to the invention by the use of a vaccine composition containing at least one inactivated influenza virus or influenza virus antigen and aluminum as an adjuvant for nasal or oral administration. The composition described is suitable in particular as a vaccine for the prophylaxis of influenza virus infections.
In the context of the present invention, it was shown that an inactivated influenza virus vaccine containing aluminum as adjuvant for nasal or oral administration triggers an effective IgG as well as IgA immune response in mammals. This was especially surprising because with the approaches to date towards the development of effective influenza virus vaccines it was found that the adjuvant effect of aluminum in elevating the immunogenicity of the antigen is very slight, even in a vaccine for parenteral administration (Davenport et al., 1968, J. Immunol. 100:1 139-1140).
Furthermore, it was found that with the nasal or oral application of the vaccine composition according to the invention a considerably higher IgG and IgA titer as well as a higher HAI titer is achieved in mammals than with the vaccine formulations known to date that contain either only inactivated influenza viruses, inactivated viruses with cholera toxin, or live viruses (Table 1).
Therefore, the application according to the invention is suitable in particular for the induction of a protective mucosal IgA and a systemic IgG immune response.
Since aluminum is the only adjuvant approved for application in humans, the application, according to the invention, of the vaccine combination of inactivated influenza virus and aluminum has the great advantage that it can be administered directly to humans without any problem. The special advantage of the use according to the invention, therefore, aside from the elevated immunoreactivity of the vaccine composition for nasal or oral administration is that through use of an adjuvant that has been tested over a number of years and whose application to humans is approved, the vaccine is completely free of side effects.
DETAILED DESCRIPTION
For use according to the invention, the composition can contain aluminum preferably in the form of aluminum hydroxide (Al(OH)
3
) or aluminum phosphate (AlPO
4
). In this case, the concentration of the aluminum is preferably in a final concentration of 0.05% to 0.5%.
The influenza virus antigen quantity in the vaccine in this case is the customary antigen quantity for a vaccine dose. Preferably, the antigen quantity that is contained in a vaccine dose is between 1.5 &mgr;g antigen/dose to 50 &mgr;g antigen/dose in humans.
The influenza virus antigen can be produced from infected eggs via conventional methods, and purified.
Preferably, however, the virus antigen is obtained from an infected cell culture, such as described, for example, in WO 96/15231. Particularly preferred for the use according to the invention to produce an influenza virus vaccine is an influenza virus
Barrett Noel
Dorner Friedrich
Gerencer Marijan
Kistner Otfried
Baxter Healthcare S.A.
Heller Ehrman White & McAuliffe LLP
Stucker Jeffrey
LandOfFree
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