Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
2001-06-21
2002-10-01
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S816000, C435S235100, C435S236000, C435S810000
Reexamination Certificate
active
06458363
ABSTRACT:
The present invention is related to inactivated vaccines and a method to produce said vaccines.
Vaccines have been widely used for the prophylaxis and treatment of infectious diseases in both animals and man. The vaccines used can be divided in two main categories: live vaccines and inactivated vaccines. Live vaccines make use of naturally occurring mild strains or attenuated strains of live pathogens. Inactivated vaccines comprise antigens constituting whole inactivated micro-organisms or specific components (subunits) of said micro-organisms. In case of the latter, two types of inactivated vaccine are distinguished: subunit vaccines in case of components that have been obtained via biochemical purification, or recombinant vaccines in case the isolated components of the microorganism have been prepared via recombinant technology.
Inactivated vaccines have the advantage over live vaccines in that this way of immunisation against pathogens has no risk of infection. The general problem perceived with the use of inactivated vaccines is their inability to raise an immune response that is sufficient for protection. As a consequence, inactivated vaccines are often combined with an adjuvant, i.e. a compound or composition that is capable to increase the general or specific immune response in the vaccinated subject. The administration of inactivated micro-organisms or components thereof and the adjuvant leads to a strong, effective and generally protective immune response. One of the most commonly used adjuvants is a water-in-oil (w/o) emulsion. W/o emulsions provide a two phase system for the vaccine: an aqueous phase in which the antigen can be dissolved or suspended and an oil phase in which the aqueous phase is dispersed as small droplets.
Inactivated vaccines that make use of a w/o emulsion as adjuvant are usually prepared by emulsifying an aqueous solution comprising the inactivated antigen, a suitable oil and emulsifying agents until a w/o emulsion is obtained in which the antigens are homogeneously distributed over the aqueous phase. The production of these inactivated w/o emulsion adjuvated vaccines takes considerable time and costs, but is generally regarded as necessary: only thorough emulsification of the antigen would lead to a homogeneous distribution of said antigen in the w/o emulsion. This is generally considered to be necessary for effectively stimulating the immune response. The emulsification process however is a highly energetic process carried out under vigorous process conditions including high temperatures and/or strong shear forces. For some antigens, these vigorous emulsification conditions can alter the structure or conformation of the antigen and as such reduce the efficacy of the resulting vaccine. Storage in emulsified form can decrease the stability of the antigen because the antigen is present in a dissolved or suspended state. Furthermore, during storage the chemical components that are. present in the emulsion can reduce the stability of the antigen, as is the case for example with enveloped viruses: prolonged contact with the emulsifying agent destroys the viral envelope resulting in a decreased efficacy of the vaccine.
Surprisingly it was now found that inactivated, w/o emulsion adjuvated vaccines can be prepared by simply mixing of an aqueous solution comprising the inactivate,d antigen and a ready-made w/o emulsion, said mixing carried out under mild conditions. The vaccines thus obtained were found to be homogeneous compositions, which remained homogeneous for extended periods of time, despite the fact that the aqueous solution comprising the inactivated antigen had not been subjected as a whole to an emulsification process.
As already indicated emulsification is a highly energetic process in which an aqueous phase, an, emulsifying (surfactant) agent and a non-aqueous phase, preferably an oil phase, are mixed under vigorous process conditions. The mixing process according to the present invention however is carried out under extremely mild process conditions compared to the process conditions of the emulsification process, said mild conditions including low or no shear forces and ambient temperatures. Preferably the mixing process according to the present invention, is carried out by hand at ambient temperature.
Mixing of said aqueous antigen solution and said ready-made w/o emulsion according to the invention can be carried out by mere shaking, stirring or any other way of combining the two constituents without the excessive process parameters that are necessary for emulsification. Compared with the time needed for emulsification, mixing according to the invention can be carried out in a short time period. Preferably the mixing is achieved in a few seconds or minutes. More surprisingly, it was found that the mere shaking by hand of said aqueous solution and the already prepared w/o emulsion was sufficient to obtain a stable and homogeneous inactivated vaccine composition with an efficacy similar to an inactivated vaccine prepared according to a standard emulsification process.
The aqueous solution according to the invention comprises one or more inactivated antigens. An aqueous solution comprising two or more different inactivated antigens can be used in the method according to the invention to obtain multivalent inactivated vaccine emulsions.
The method of preparation according to the invention has several advantages over standard methods of preparation: it is easy to carry out, less time consuming and a more economical process. An important advantage of the method according to the present invention is the fact that the inactivated antigen is not exposed to the damaging shear forces and/or high temperatures that occur during the emulsification process: the chemical structure of the antigen is better preserved.
In a specific embodiment of method according to the invention the w/o emulsion adjuvated vaccine is prepared in the field prior to vaccination. The method provides a veterinarian a more flexible and adequate reaction upon field circumstances: in case of an outbreak the necessary inactivated antigens can be dissolved in an aqueous solution, mixed by hand with a suitable amount of a stable, ready-made w/o emulsion, and subsequently administered to the subject animals. Thus the method according to the invention provides for a quick and effective preparation of inactivated vaccine emulsions in the field just prior to use.
A further advantage of the method according to the invention is that in this way inactivated antigens which are normally not compatible, can be mixed together prior to vaccination to obtain a multivalent inactivated vaccine emulsion. Since the incompatible inactivated antigens are combined just prior to vaccination, they are only present in the emulsion for a short-lived period during which they cannot exert their adverse effect on each other.
Another advantage of the method according to the invention is that the inactivated antigens can be stored separately in dried form, preferably in lyophilised form, to prevent deterioration of the components during storage. The stability of the inactivated antigens declines much faster during storage in solution or suspension than in dried form. Just prior to vaccination the dried components are re-constituted with water into an aqueous solution. The dried vaccine components furthermore need less storage capacity than their corresponding solutions or suspensions.
Thus, the present invention provides for a method to prepare an inactivated, w/o emulsion adjuvated vaccine, wherein an aqueous solution comprising one or more inactivated antigens is mixed under mild conditions with a ready-made w/o emulsion. Preferably the aqueous solution and the w/o emulsion are stirred or shaken. The aqueous solution and the w/o emulsion can be mixed, preferably stirred or shaken, by mechanical means or by hand, more preferably by hand. The ready-made w/o emulsion may additionally comprise one or more antigens.
In a further embodiment the invention provides for a method to prepare an inactivated, w/o emul
Rijke Eric Onno
Schrier Carla Christina
Akzo Nobel N.V.
Blackstone William M.
Ramey III William P.
Scheiner Laurie
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