EDIBLE VACCINES

 

About Author:
K.Kranthi Kumar
SKU College of Pharmaceutical Sciences,
S.k.univrsity, Anantapur
kranthikumarkotta@gmail.com

Abstract
Molecular farming officially known as transgenic non-food GM plant pharming and biopharming, is a type of genetic modification used in farming involving the use of plants, and potentially also animals, as the means to produce compounds of therapeutic value. The idea is to use such crops as biological factories to generate drugs difficult or expensive to produce in any other way. The issue of genetically modified crops has been around for a number of years and continues to be a controversial subject.

REFERENCE ID: PHARMATUTOR-ART-1928

History
Edible vaccines were first tested on humans in 1997, when scientists asked volunteers to eat anti-diarrhoea potatoes produced by the Boyce Thompson Institute at Cornell University, Ithaca, NY, USA. Roswell Park Cancer Institute in Buffalo, New York also developed edible vaccines in raw potatoes and foreign proteins (HBs IgA) can help to cure human being from Hepatitis B virus Molecular biologist of the London Health Sciences Centre developed edible vaccines to combat autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, lupus and even rejection  The first recombinant plant-derived pharmaceutical protein (PDP) was human serum albumin, initially produced in 1990 in transgenic tobacco and potato plants. Fifteen years on, the first technical proteins produced in transgenic plants are on the market, and proof of concept has been established for the production of many therapeutic proteins, including antibodies, blood products, cytokines, growth factors, hormones, recombinant enzymes and human and veterinary vaccines. Furthermore, several PDP products for the treatment of human diseases are approaching commercialization, including recombinant gastric lipase for the treatment of cystic fibrosis, and antibodies for the prevention of dental caries and the treatment of non-Hodgkin's lymphoma. There are also several veterinary vaccines in the pipeline; Dow Agro Sciences announced recently their intention to produce plant-based vaccines for the animal health industry.

Introduction
Vaccines are primary tools in programmes for health intervention for both humans and animals. They would be more widely used especially in developing countries. It would be helpful for human society if cost of production could be reduced and they could be distributed without refrigeration. Vaccines couldn’t be very popular because of unavailability of electricity for its storage in remotest area in developing countries.

Vaccines and antibodies play a key role in healthcare. However, the cost of production and maintaining a chain for vaccine distribution has so far hampered realizing their full potential. Expression of antigens as vaccines and of antibodies against antigens of pathogens in transgenic plants is a convenient and inexpensive source for these immunotherapeutic molecules.

Research underway is dedicated to solving these limitations by finding way to produce oral (edible) vaccines in transgenic plants. Edible vaccines can be produced by transgenic plants in large amount and cost will be also cheap and no problem of refrigeration and all section of people can afford to buy it for remedy of a large number of diseases Hepatitis B virus (HBV) infection is probably the single most important cause of persistent viremia in humans.

The disease is characterized by acute and chronic hepatitis, which can also initiate hepatocellular carcinoma. The prevalence of the disease in developing countries justified initial efforts to express HBV candidate vaccines in plants. Currently two forms of HBV vaccines are available, both of which are injectable and expensive- one purified from the serum of infected individuals and the other a recombinant antigen expressed and purified from yeast.

This antigen has already been entered in transgenic plant either through Agrobacterium mediated transformation or Particle gun bombardment (Biolistics)   and encoding the hepatitis B surface antigen (HBsAg); this is the same antigen used in the commercial yeast-derived vaccine. An antigenic spherical particle was recovered from these plants which is analogous to the recombinant hepatitis surface antigen (HBsAg) derived from yeast. Parenteral immunization of mice with the plant–derived material has demonstrated that it retains both B and T-cell epitopes, as compared to the commercial vaccine.

Diarrhoeal disease causes up to 10 million deaths per year in the developing world, primarily among children. Relatively little research to prevent these diseases is underway, as they represent more of a nuisance than a severe problem in developed countries. Studies supported by the World Health Organization have demonstrated an effective vaccine for cholera, which provides cross protection against enterotoxic Escherichia coli. This vaccine is not available, however, in large part due to cost of production of the bacterial toxin protein which is a component of its formulation.

To address this limitation, plants were transformed with the gene encoding the B subunit of the E.coli heat labile enterotoxin (LT-B). Transgenic potatoes expressing LT-B were found to induce both serum and secretory antibodies when fed to mice; these protective in bacterial toxin assays in vitro. This is the first “proof of concept” for the edible vaccine.

The selection of a plant system for delivery of edible vaccines for humans has been addressed. Recognizing that it is necessary to express the desired protein in a food that is consumed raw (to avoid denaturation of the candidate vaccine protein), a system to transform banana plants has been developed. The expression of candidate vaccines in banana fruit will be dependent upon identification of suitable specific promoter to drive the desired gene expression. Research to find these genetic regulatory elements are now underway.

Edible vaccine research is currently directed at human diseases, with a special emphasis on the developing world. The technology will also have immediate value for the production of inexpensive vaccines as food additives for agricultural animals. Since various plant tissues are fed to animals, other plants such as alfalfa, maize and wheat could be valuable vehicles to deliver vaccines (and perhaps pharmaceuticals) for the betterment of animal health.

Recent progress in the area of transgenic plants has however, once again attracted attention of the scientists, and plants are being looked upon as potential bio-reactors or bio-factories for the production of immunotherapeutic molecules.

In 1989 firstly Hiatt and co-workers attempted to produce antibodies in plants which could serve the purpose of passive immunisation but it was appeared in 1990 in the form of patent application, the concept of edible vaccine got impetus after Arntzen and co-workers expressed hepatitis B surface antigen in tobacco in 1992 to produce immunologically active ingredient via genetic engineering of plants. This generated a good deal of excitement among biotechnologists, particularly in light of the potential of edible vaccines and antibodies for immunotherapy for countries like India.

Various strategies for expression of foreign genes in high amounts in plants include use of strong and organ specific plant promoters, targeting of the protein into endoplasmic reticulum (ER) by incorporating ER-targeting and ER-retention signals, creation of optimized translation start site context as well as alteration of codons to suit the expression of prokaryotic genes in a plant. Though promoters of genes, like maize ubiquitin and rice actin, have been reported to direct high level of expression in monocots, the 35S promoter of cauliflower mosaic virus remains the promoter of choice for dicots . Targeting of the protein to appropriate cellular compartment may be helpful in stabilizing the protein. Retention of heat labile E.coli enterotoxin in ER of potato by using ER-retention signal has been reported to elevate the expression levels of the recombinant protein.

Though signals for membrane targeting, protein folding, oligomerization and N-glycosylation are highly conserved in animals and plants, while expressing bacterial proteins targeted to ER, it is important to consider the sequence of a signal peptide for targeting to periplasmic space in bacterium may not be equally efficient in plants. Substitution of signal peptide of bacterial origin with a plant specific ER-targeting sequence was observed to dramatically increase the glycosylation and secretion efficiency of chitinase.

For production of edible vaccines or antibodies, it is desirable to select a plant whose products are consumed raw to avoid degradation during cooking. Thus, plants like tomato, banana and cucumbers are generally the plants of choice. While expression of a gene that is stably integrated into the genome allows maintenance of the material in the form of seeds, some virus based vectors can also be used to express the gene transiently to develop the products in a short period. This may have the additional advantage of allowing expression of the product at very high level; not always attainable in transgenic systems.

While plant system may have the capability of producing any vaccine in large amounts and in a less expensive manner, purification of the product may require the use of existing or even more cumbersome procedures. Attention therefore has been paid to mainly those antigens that stimulate mucosal immune system to produce secretory IgA (S-IgA) at mucosal surfaces, such as gut and respiratory epithelia.

In general, a mucosal response is achieved more effectively by oral instead of parenteral delivery of the antigen. Thus, an antigen produced in the edible part of a plant can serve as a vaccine against several infectious agents which invade epithelial membranes. These include bacteria and viruses transmitted via contaminated food or water, and resulting in diseases like diarrhoea and whooping cough.

The first report of the production of edible vaccine (a surface protein Streptococcus) in tobacco, at 0.02% of total leaf protein level appeared in 1990 in the form of a patent application published under the International Patent Cooperation Treaty. Subsequently, a number of attempts were made to express various antigens in plants. Hein is one of handful researchers using the tools of bioengineering to transform ordinary fruits and vegetables into botanical cargo vessels that carry life saving vaccines. Edible vaccines promise to be an affordable and safe way for people in even the most poverty stricken parts of the world to protect themselves against disease. Normal vaccines need for refrigeration and purified serum, hypodermic needles, or even trained medical professional to distribute and oversee vaccinations but these conditions are not required for edible vaccines.

The goal is to give people in developing countries the genetically engineered seeds that will sprout edible vaccines. “Every culture on this planet raises food” explains Hein. “This can provide developing countries with a stable vaccine source because it will be genetically coded into the food”. Using recombinant DNA technology, researchers can now isolate the genes—called antigens—that mobilize our natural defences.

But impregnating plants with these antigens requires an impressive bit of molecular legerdemain. At Scrips Research Institute, for instance, the antigen is snipped off the deadly cholera pathogen. Then it is inserted into the cells of a bacterium that causes a plant disease called crown gall. The alfalfa plants are infected with these transgenic crown gall organisms, which can penetrate the plant’s cell walls. The plant cells containing the foreign genes are then cultured in a Petri dish until they are mature enough to be transplanted.

The next step is to test the potency of the antigens in plants raised in the field, outside of the cloistered laboratory. “We’ve just harvested this crop of alfalfa” says Hein, who’s in the midst of measuring its antigen level and feed this transgenic grain to mice.

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