Chemistry: molecular biology and microbiology – Virus or bacteriophage – except for viral vector or...
Reexamination Certificate
1993-11-22
2001-07-03
Minnifield, Nita (Department: 1645)
Chemistry: molecular biology and microbiology
Virus or bacteriophage, except for viral vector or...
C435S258100, C424S278100, C424S184100, C424S234100, C424S200100, C424S203100, C424S261100, C424S093100
Reexamination Certificate
active
06255097
ABSTRACT:
BACKGROUND OF THE INVENTION
The method common in medicine of producing effective protection against infectious diseases in human beings and animals is based on the principle of active immunisation by using pathogen-specific antigens. There are, for example, prophylactic vaccinations against a number of diseases in human beings which are caused by bacteria or viruses. However, vaccinations against fungi and parasites are possible in principle too.
The basis for the protective effect of such vaccines is that important antigens, which in general originate or are derived from the pathogen, are brought into contact with the immune system of human beings or animals by infection or another suitable administration so that a specific immune response directed to the administered antigens is induced. The aim and object of this is to select the administered antigens in such a way and to present them to the immune system such that the induced immune response is directed against the pathogen and a subsequent infection is thus prevented. The induced immune response can be of either humoral (based on antibodies) or cellular nature or both.
The vaccine containing or forming antigens can be constructed or composed in a different way (see Bloom, Nature, 342:115-120, 1989). A simple method consists in using killed pathogens as the vaccine. Improvements are often achieved by only employing a few isolated components of the pathogen in the vaccine which represent important antigens. Moreover, new vaccines often only contain a few well-defined (e.g. purified from the pathogen, or prepared by genetic engineering or otherwise) components which act as an antigen by suitable presentation. Furthermore, every combination of the cited possibilities is conceivable. The common factor of the vaccines is that they consist of inactivated antigen material.
In contrast to these inactivated vaccines, the further possibility of immunising with biologically intact pathogens (so-called live vaccines) and conveying effective protection has long been known. Vaccination with living viruses (Zanetti, Immunology Today, 8:18-25, 1987) and BCG bacteria (Lotte, Adv. Tuberc. Res. 32:107-193, 1984) fall under this category, for example, as well as oral immunisation with living Ty21a Salmonella (Germanier, J. Infect. Dis. 131:553-558, 1975). The principle of such live vaccines is based on the use of an attenuated (or immunologically related non-virulent for a certain species) pathogen strain which is able to cause infection and effective immunological protection against the actual pathogen but is no longer pathogenic per se. Experience in the application of live vaccines lies above all with viruses and bacteria; in principle, however, similar vaccines can also be developed on the basis of fungi and parasites. Live vaccines often have advantages over comparable inactivated vaccines because they e.g. convey better immunological protection and are safer and less expensive.
New developments have furthermore shown that it is possible to change live vaccines by genetic engineering so that they not only present their own antigens to the immune system but also additional antigens which are derived from a different pathogen species. With such hybrid live vaccines it is possible to achieve immunological protection not only against the pathogen from which the live vaccine is derived or with which it is related but also against pathogens against which the immune response to the additional antigen is directed. Depending on the species on which the live vaccine is based, one or more additional antigens can be presented to the immune system and immunological protection can thus be conveyed. This is already realizable in practice with viral and bacterial live vaccines (see Dougan, J. Gen. Microbiol. 135:1397-1406, 1989). In contrast to bacterial or other cellular live vaccines, it is however natural for viral live vaccines (as well as for viruses in general) to be able to express their genetic information only after infection of a cell. In this case the formation of additional antigen by a viral live vaccine consequently requires the infection of cells of the individual to be protected. The presentation of additional antigens to the immune system can on the one hand take place via the infected cell per se or on the other hand via the viral live vaccine which carries additional antigen in its packaging.
A considerable problem with the construction and use of such hybrid live vaccines is however the circumstance that the production of additional antigens often changes the biological properties of the live vaccine and destabilizes the immunological effect so that the desired immunological protection is not achieved or only to a reduced extent. This can be the case in particular if the additional antigen is produced in large quantities as would often be required for the induction of a good immune response, and/or if the additional antigen is otherwise toxic for the live vaccine itself. In other words: The hybrid live vaccine behaves differently to the original live vaccine with respect to the course of an infection and thus with respect to its immunisation potential because it produces one or more additional antigens. This also means that, depending on the kind of additional antigens produced by the live vaccine, the infectious properties and the effectiveness of the immunisation of the live vaccine cannot be inferred in so far as it is at all possible to achieve an effective immune response.
Current experiments to solve this problem in bacterial systems pursue the goal of controlling the formation of additional antigens in a live vaccine by external influences, i.e. to bring the genes which code for the formation of additional antigens under the control of an inducible promoter. The additional antigens of the live vaccine would consequently only be formed in dependence on their external influences or the environment. Such external influences can be e.g. a certain substance or a certain temperature (e.g. lac system: De Boer, Proc. Natl. Acad. Sci. USA, 80:21-25, 1983; P
1
-system: Remaut, Gene, 15:81-93, 1981). It would be ideal if the external influences required for the formation of the antigens were only to be present where the live vaccine came into contact with the immune system but not in the course of the infection process so that the infection process necessary for the immune response is not disturbed. However, this is hardly realizable in practice not only because the infection process and the initiation of contact with the immune system are biologically linked but also because the conditions at the site of action of the live vaccine, i.e. in certain areas of the body of the person to be vaccinated, can be purposefully controlled with the available means neither with respect to location nor with respect to time.
SUMMARY OF THE INVENTION
It is therefore the object of the present invention to introduce a genetic element into the construction of hybrid live vaccines which, on the one hand, allows the production of sufficiently large quantities of additional antigen at the immunological site of action and, on the other hand, does not interfere with the course of infection by the hybrid live vaccine and thus the expected immunological protection. This object was achieved by making the formation of the additional antigens of the hybrid live vaccine dependent on random genetic events which occur relatively frequently. This principle implies the existence of two subpopulations/phases which originate from the live vaccine, namely of the hybrid live vaccine itself (subpopulation/phase A) which does not produce any additional antigen and therefore reproduces without its properties changing in relation to the original strain and is capable of a normal course of infection and a normal immune response, and a subpopulation/phase B which may have lost these properties but is constantly newly regenerated from subpopulation A and releases large quantities of additional antigen at the site of action (see FIG.
1
). Subpopulation A therefore has the task of
Meyer Thomas
Pohlner Johannes
Reuss Frank U.
Yan Zhengxin
Birch & Stewart Kolasch & Birch, LLP
Max-Planck-Gesellschaft Zu Forderung der Wessenchaften
Minnifield Nita
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