Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-10-20
2004-11-02
Graser, Jennifer E. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S184100, C424S234100, C424S248100, C424S261100, C424S200100, C435S069100, C435S069300, C435S173300, C435S320100, C435S243000, C435S252300
Reexamination Certificate
active
06811787
ABSTRACT:
The invention described herein was made under a grant from the United States Department of Agriculture. Therefore, the U.S. government may have certain rights in this invention.
The invention pertains to an over-expressing homologous antigen vaccine, a method of producing the same, and a method of using the vaccine for prophylaxis or treatment of a vertebrate suffering from or at risk from a pathogen. The vaccine is derived from an attenuated or avirulent version of the pathogen, and over-expresses one or more genes from the pathogen, thereby providing immunity greater than that induced by a vaccine of the same pathogen without over-expression of a gene.
BACKGROUND OF THE INVENTION
Vaccines are used to protect against diseases, which are caused by pathogens. These pathogens are microbial organisms, such as bacteria and viruses, which affect animals, including humans. Vaccines are primarily derived from a pathogen by producing and administering either: a) an attenuated or avirulent version of the pathogen; b) the killed pathogen; c) extracted protective antigens or antigen mixes of the pathogen (homologous antigens); or d) a micro-organist expressing one or more protective antigens encoded by cloned genes originating in a microbial pathogen different from the vaccine strain (heterologous antigens).
Vaccines for both bacteria and viruses are engineered from microorganisms expressing one or more protective antigens, as described by K. Jones and M. Sheppard in Designer Vaccines, CRC Press (1997). Vaccines are intended to produce an immune response in the recipient consisting of at least one of an antibody mediated or T cell mediated immune response, thereby preventing future infection by a pathogen, or fighting a current pathogenic infection. In particular, vaccines against facultative intracellular pathogens, those growing inside the cells of the infected host, need to induce a strong and appropriate cell mediated immune response. In contrast, vaccines against obligate extracellular pathogens need to induce an appropriate antibody mediated immune response. Often, regardless of the pathogen, an appropriate combined antibody and cellular mediated immune response leads to sufficient protection or relief from infection. In order to achieve this protection or relief from infection, vaccines may express one or more homologous antigens, heterologous antigens, or a combination of both.
Vaccines may be administered to vertebrates both to prevent and treat infection by pathogens. Thus, vaccines are frequently administered to prevent the spread of a disease caused by a pathogen. In particular, herd animals, such as cows, goats, sheep and swine, are often vaccinated to prevent the spread of a disease among members of the herd. Further, because certain diseases may travel between vertebrates, including travel between various animals and between animals and humans, vaccines are used to prevent the spread of disease between various species, usually by administration to the infected animal and other uninfected animals in the immediate vicinity. However, other animals in the area which are less likely to contract the disease may also be vaccinated as a prophylactic measure. For example, an infected cow and its as yet uninfected herd may be vaccinated to treat a disease and prevent its further spread. As a prophylactic measure, other animals which are likely to contract the disease from the infected cow, such as neighboring cows, sheep or humans, may be vaccinated as well.
It has been found that vaccines derived from an attenuated or avirulent version of a pathogen are highly effective in preventing or fighting disease caused by that pathogen. In particular, it is known that such attenuated or avirulent pathogens can be modified to express heterologous antigens (antigens which are derived from a pathogen of a different species). In order to express heterologous antigens in a desired attenuated or avirulent pathogen, a gene encoding an antigen capable of providing protection against the pathogen is identified from the deoxyribonucleic acid of a heterologous species. The desired gene is isolated and then inserted into a plasmid capable of replication and expression in the attenuated or avirulent pathogen. The plasmid is then introduced into the attenuated or avirulent pathogen, and causes expression of the heterologous antigen upon administration to a subject vertebrate.
An example of such expression of an heterologous antigen is the bacterial vaccine Salmonella, which expresses a Streptococcus spaA protein. See U.S. Pat. No. 4,888,170. This vaccine comprises an avirulent derivative of a pathogenic microbe of the genus Salmonella, which in turn expresses a recombinant gene derived from a pathogen of the species Streptococcus mutans, thereby producing an antigen capable of inducing an immune response in a vertebrate against the pathogen.
A further example of heterologous expression is
Vibrio cholera
vaccines. A number of live attenuated strains of
Vibrio cholera
have been developed to vaccinate humans against cholera. See Kaper, J. B., et al.,
New and improved vaccines against cholera in New Generation Vaccines
(eds. MM Levin et al.) Marcel Deker, Inc., NY, 1997. Some of these strains over-express heterologous antigens. See Butterton, J. R. and S. B. Calderwood, Attenuated
Vibrio cholera
as a live vector for expression of foreign antigens in New Generation Vaccines (eds. MM Levin et al.) Marcel Deker, Inc., NY, 1997. The immunity induced by the attenuated vaccine strains is the result of inducing antibodies which have either antibacterial and/or antitoxic activities. Some strains have been attenuated by the deletion of a number of genes encoding toxigenic components, including the A subunit of the cholera toxin encoded by the ctxA gene. However, in order for a cholera vaccine strain to be fully protective, it is necessary that the ctxb gene encoding the B subunit (to which the A subunit binds) be expressed to allow for the production of antibodies that neutralize the cholera toxin. The ctxB gene has been over-expressed in Vibrio cholera for the purpose of producing large amounts of the antigen cholera toxin 2 (CTB). The over-expressed antigen CTB is collected, purified and used as a subunit vaccine which is the extracted CTB antigen. See Lebens M., et al., 1993, Biotechnology (NY) Dec; 11:1574-1578. However, although an over-expressed antigen has itself been used as a vaccine, an attenuated or avirulent pathogen of
Vibrio cholera
which over-expresses the ctxB gene, or any other homologous gene, has not been used as a live vaccine.
Another example of heterologous expression is in Mycobacterium spp. vaccines, used to prevent tuberculosis in humans. The
Mycobacterium tuberculosis
GroEL protein induces protective immunity when expressed by the groEL gene transfected into macrophages (Silva, C. L. and Lowrie, D. B., 1994, Immunology 84:244-248), indicating that GroEL protein is a protective antigen if presented to T cells by this type of antigen presenting cell (APC). Naked DNA vaccines using Mycobacterium genes coding for a variety of antigens (hsp70, 85 kDa, 65 kDa, 36 kDa, 6 kDa) are also able to induce protective immunity. See Lowrie, D. B. et al., 1997, Vaccine 15:834-838; Tascon, E. et al., 1996, Nat. Med. 2:888-892; and Lozes, E. et al., 1997, Vaccine 15:880-833. It is believed that the naked DNA vaccines work because they transfect APCs (Chattergon, M. et al., 1997, FASEB J. 11:753-763.) which in turn present the antigen appropriately to T cells, thereby inducing a protective cell mediated immunity.
M. bovis
BCG, a live, attenuated strain of Mycobacterium, is used to induce protective immunity against
M. tuberculosis
infection in humans. Fine, PM. 1988, Br. Med. Bull. 44:91.
Antigen vaccines developed against Brucellosis provide examples of homologous-antigen expression, wherein the antigen is derived from the same species as the attenuated pathogen. Brucellosis is an infectious bacterial disease which can be transmitted to human beings by animals. It is caused by any of a variety
Boyle Stephen M.
Corbeil Lynette
Cravero Silvio
Schurig Gerhardt
Srirnaganathan Nammalwar
Graser Jennifer E.
The Regents of the University of California
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