Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-11-12
2001-02-27
Bui, Phuong T. (Department: 1638)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C800S278000, C800S288000, C800S295000, C530S350000, C435S069100, C435S069300, C435S410000, C435S419000, C435S252300, C435S252330, C435S252800, C435S320100, C424S184100, C424S185100, C424S186100, C424S190100, C424S192100, C424S193100, C424S204100, C424S227100, C424S236100, C424S241100, C424S282100, C536S023100
Reexamination Certificate
active
06194560
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the production of oral vaccine adjuvants and oral vaccines in edible transgenic plants and, more particularly, to causing an immune response in animals which eat the transgenic plant material. The present invention relates more specifically to the production of transgenic plants using the genes encoding bacterial toxin subunits LT-A and LT-B or CT-A and CT-B and the use of the expressed protein for inducing immune responses in mammals, alone and with other associated antigenic agents.
Accordingly, this invention relates to the introduction into plants of genes encoding colonization or virulence antigens or antigenic portions thereof of pathogens which colonize on or invade through mucosal surfaces of mammals. More particularly, this invention relates to the introduction of genes encoding LT-B or CT-B containing proteins into plants so that the plants can produce the LT-B or CT-B containing protein.
This invention further represents a significant and unexpected improvement over the prior art in that it enables the actual immunization of animals against bacterial antigens by feeding animals transgenic plants in which sufficient levels of the bacterial antigen has been expressed in order to induce immunity. Further, this invention demonstrates the additional and unexpected improvement of an adjuvant effect caused when immunizing animals with transgenic plants containing bacterial toxin antigens.
BACKGROUND OF THE INVENTION
Infections diseases have plagued life on earth probably from its inception. Such diseases affect not only man but animals. In economically advanced countries of the world, infection diseases are 1) temporarily disabling; 2) permanently disabling or crippling; or 3) fatal. In the lesser developed countries, infections diseases tend to fall into the latter two categories, permanently disabling or crippling and fatal, due to may factors, including a lack of preventive immunization and curative medicine.
It is generally acknowledged that the usefulness of antibiotics to effectively control bacterial pathogens is becoming increasingly difficult, because of the increased occurrence of antibiotic-resistant pathogens. Thus, prevention of infectious diseases is more cost effective than the ultimate treatment of the disease once it has occurred. As a result, increased attention is being focused on the development of vaccines.
Vaccines are administered to humans and animals to induce their immune systems to produce antibodies against viruses, bacteria, and other types of pathogenic organisms. In the economically advanced countries of the world, vaccines have brought many diseases under control. In particular, many viral diseases are now prevented due to the development of immunization programs. The virtual elimination of smallpox is an example of the effectiveness of a vaccine worldwide. But many vaccines for such diseases as poliomyelitis, measles, mumps, rabies, foot and mouth, and hepatitis B are still too expensive for the lesser developed countries to provide to their large human and animal populations. Lack of these preventative measures for animal populations can worsen the human condition by creating food shortages.
Because of simplicity of delivery of vaccines by oral delivery, there is great current interest in discovering new oral vaccine technology. Appropriately delivered oral immunogens can stimulate both humoral and cellular immunity and have the potential to provide cost-effective, safe vaccines for use in developing countries or inner cities where large-scale parenteral immunization is not practical or extremely difficult to implement. Such vaccines may be based upon bacterial or viral vector systems expressing protective epitopes from diverse pathogens (multivalent vaccines) or may be based upon purified antigens delivered singularly or in combination with relevant antigens or other pathogens.
A. Microbial Pathogenesis and Oral Vaccination
Microbial pathogens can infect a host by one of several mechanisms. They may enter through a break in the integument induced by trauma, they may be introduced by vector transmission, or they may interact with a mucosal surface. The majority of human pathogens initiate disease by the last mechanism, i.e., following interaction with mucosal surfaces. Bacterial and viral pathogens that act through this mechanism first make contact with the mucosal surface where they may attache and then colonize, or be taken up by specialized absorptive cells (M cells) in the epithelium that overly Peyer's patches and other lymphoid follicles. Organisms that enter the lymphoid tissues may be readily killed within the lymphoid follicles, thereby provoking a potentially protective immunological response as antigens are delivered to immune cells within the follicles (e.g.,
Vibrio cholerae
). Alternatively, pathogenic organisms capable of surviving local defense mechanisms may spread from the follicles and subsequently cause local or systemic disease (e.g., Salmonella spp., poliovirus in immunocompromised hosts).
Secretory IgA (sIgA) antibodies directed against specific virulence determinants of infecting organism play an important role in overall mucosal immunity. In many cases, it is possible to prevent the initial infection of mucosal surfaces by stimulating production of mucosal sIgA levels directed against relevant virulence determinants of an infecting organism. Secretory IgA may prevent the initial interaction of the pathogen with the mucosal surface by blocking attachment and/or colonization, neutralizing surface acting toxins, or preventing invasion of the host cells.
Parenterally administered inactivated whole-cell and whole-virus preparations are effective at eliciting protective serum IgG and delayed type hypersensitivity reactions against organisms that have a significant serum phase in their pathogenesis (e.g.,
Salmonella typhi,
Hepatitis B). However, parenteral vaccines are not effective at eliciting mucosal sIgA responses and are ineffective against bacteria that interact with mucosal surfaces and do not invade (e.g.,
Vibrio cholerae
).
Oral immunization can be effective for induction of specific sIgA responses if the antigens are presented to the T and B lymphocytes and accessory cells contained within the Peyer's patches where preferential IgA B-cell development is inititated. The Peyer's patches contain helper T cells (TH) that mediate B-cell isotype switching directly from IgM cells to IgA B cells then migrate to the mesentric lymph nodes and undergo differentiation, enter the thoracic duct, then the general circulation, and subsequently seed all of the secretory tissues of the body, including the lamina propria of the gut and respiratory tract. IgA is then produced by the mature plasma cells, complexed with membrane-bound Secretory Component, and transported onto the mucosal surface where it is available to interact with invading pathogens. The existence of this common mucosal immune system explains in part the potential of live oral vaccines and oral immunization for protection against pathogenic organisms that initiate infection by first interacting with mucosal surfaces.
A number of strategies have been developed for oral immunization, including the use of attenuated mutants of bacteria (e.g., Salmonella spp.) as carriers of heterologous antigens, encapsulation of antigens into microspheres composed of poly-DL-lactide-glycolide (PGL), protein-like polymers-proteinoids, gelatin capsules, different formulations of liposomes, adsorption onto nanoparticles, use of lipophilic immune stimulating complexes, and addition of bacterial products with known adjuvant properties.
Underlying the development of most current vaccines is the ability to grow the disease causing agent in large quantities. At present, vaccines are usually produced from killed or live attenuated pathogens. If the pathogen is a virus, large amounts of the virus must be grown in an animal host or cultured animal cells. If a live attenuated virus is utilized, it must be clearly prov
Arntzen Charles J.
Haq Tariq A.
Mason Hugh S.
Bui Phuong T.
Fulbright & Jaworski L.L.P.
Texas A & M University System
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