The Use of Plants to make Vaccines (Part-1) is the first of a 3-set series of articles that will discuss the entire gamut of issues involved in making vaccines in plants. In this Part-1 article we will focus on why plants are suitable for making vaccines; and then compare and contrast conventional vaccines with plant-based vaccines. Subsequent articles will discuss other aspects of making vaccines in plants.

Vaccines prime the immune system in our body to make more of antibodies. This quest for making vaccines started in the 18th century with Edward Jenner. Since then, it has evolved from the use of weakened or inactivated whole organisms (to achieve immunization) to the present day biotech trends including the use of plants to make vaccines. Vaccines are generally administered through injection or sometimes orally and intra-nasally (which is the mucosal route). But now there exists the possibility of expressing vaccines in plants (as plants can be transformed easily) and by eating the vegetables and fruits of such plants, immunization can be achieved. Moreover, such edible vaccines (vegetables or fruits) can be easily stored and distributed. This reduces the cost of future immunization programs. Another possibility is to extract and purify the vaccines expressed in plants and make them available in the usual injectable dosage form.

Human serum albumin was the first ever plant derived protein. This was in the year 1990 when human serum albumin was successfully expressed in transgenic tobacco and potato plants. Since then several proteins and vaccine antigens have been successfully expressed in plants.

Vaccines made in plants are the result of genes encoding bacterial and viral antigens that are expressed, and assembled in plant cells to give immunogenic proteins. These vaccines can be eaten------and the technology that has made this possible is called Transient Gene Expression. In other words, as plant viruses have the capacity to reprogram plants to make more viruses---- these viruses can be used as transient gene vehicles to make specific proteins and vaccines. Thereafter there are two ways to administer the vaccines-----either the plants can be eaten to acquire immunity------or else the expressed vaccines in the plants can be extracted, purified and administered as an injection. Using Transient Gene Expression technology epitope or subunit vaccines can be made in plants. Transgenic plants can also be used to make vaccines.

Why plants are used to make vaccines and other proteins?

Some proteins cannot be chemically synthesized. In fact most of them are produced using mammalian and microbial cell cultures. But significantly plants are higher eukaryotes and by using them as bioreactors complex molecular forms of therapeutic multimeric proteins, peptides and polypeptides can be made which is otherwise not possible using mammalian systems. In other words, plants can effectively make a diverse range of recombinant molecules abundantly including vaccines.

Although both transgenic plants and the Transient Gene Expression technology can be used to make vaccines, the transgenic plant has advantages over the transient system because the proteins get encoded in the genetically heritable transgene and this permits stable and regular (continuous) protein expression. Besides the transgenic plant could be planted in a green-house or in the field and it will continue to produce the proteins. Moreover it is economically advantageous too. For example, a transgenic tobacco plant could be grown in a small dish and yet continue to make sufficient proteins.

Several factors have contributed to the emerging trend of engineering vaccines in plants. They are:

1) We now have a greater understanding of the molecular basis of pathogenecity.
2) We also have a better understanding of cellular immunity as relating to immune response.
3) We have better technology to sequence and express vaccine antigens in plants, especially in edible fruits and vegetables.


According to a pan-European group of scientists funded by the EU, plants (maize, tomato and potato plants) are possibly the only way to make huge quantities of vaccines for HIV, diabetes and rabies and other diseases in the developing world without compromising on safety aspects.


Conventional vaccines versus Vaccines made in plants

The functioning of vaccines made in plants is no different from that of conventional vaccines. Both produce antibodies to fight pathogens. So whatever be the vaccine that is injected in the body, this event is recorded by the immune system, so that at a later date if a specific pathogen invades the body the immune system produces a stronger response to counter that pathogen.

Conventional vaccines (that are usually injected) are made from attenuated pathogens and involve the synthesis of antigenic proteins using mammalian cell culture which is easily prone to contamination with harmful pathogens. If microbial systems are used to make vaccines there is the possibility of endotoxin contamination. When cell culture and transgenic animals are used to make vaccines the contamination possibility arises with viruses, prions and oncogenic DNA. These processes involve the use of sophisticated and expensive sterile fermentation technology followed by purification processes. On the contrary, plant based systems only need greenhouses and not SS tanks for cell cultures----besides purification from plant extracts are simpler because plants are not carriers of viruses that could possibly be detrimental to humans. As an example, a fermenter produced anthrax vaccine could get contaminated with Bacillus anthracis toxin. But if the same vaccine were to be produced in plants it would be completely toxin free. In other words, a recipient of a plant sourced vaccine is only exposed to a non-infectious and non-toxic bit of protein.

That apart, if plants are used to produce these vaccines, then problems of logistics, costs, transportation, refrigeration, delivery mechanisms like syringes and needles can be avoided. In short, vaccines expressed in plants are functional, cheap, safe, easy to store, deliver and administer. A vaccine that is expressed in bananas would cost just a few cents as compared to the injectable version that may cost over one hundred dollars. Similarly a plant based vaccine in tobacco costs just one third of egg based vaccines and the time required to make the vaccine is less as well. So, cost and time constraints are not an issue in making vaccines in plants. Besides, administration of plant vaccines can be easy as eating a cup full of vegetables or fruits.


Although almost invariably it is the antigen that is recognized by the immune system, antigen alone cannot stimulate the immune system to elicit a sufficiently strong counter response----but researchers have concluded that vaccines made in plants have an element of plant sugars that gives a markedly stronger immune response. In that case the vaccine can get into the cells and stimulate the immune system to make more of WBC's. So vaccines sourced from plants give greater immune response because of the attachment of plant sugars to antibodies-----although sugars also get attached to antibodies when vaccines are made from animal cells---but that is not reckoned to be beneficial.


Noroviruses (that causes diarrhea and nausea) and the flu virus are for ever mutating and evolving new strains -----and to make a vaccine to combat these viruses is a challenge----the best bet seems to be the use of plants and plant biotechnology. For example, it takes several months to make influenza vaccines(example H1N1 flu vaccine) using hundreds of thousands of fertilized chicken eggs and this is a limiting factor in making sufficient quantity of vaccines and to address issues of mutating virus strains. But now these vaccines can be grown within plants, especially tobacco plants. An example of this is the Project GreenVax facilitated by the Texas Plant-Expressed Vaccine Consortium for producing vaccines in tobacco plants that are grown hydroponically in a closed system.

Because of the uniqueness of each person's cancer antibody the ideal situation is to have personalized vaccines for combating cancer. However, making personalized vaccines for cancer entails heavy costs and time requirements. Plants are the answer to this. In future plants could become factories for growing antibodies to treat cancer on an individualized basis. For example giving chemotherapy to patients suffering from deadly and rare cancers such as non-Hodgkin's lymphoma elicits very severe side effects. But growing cancer vaccines in plants could help develop individualized treatments to vaccinate a lymphoma patient with several copies of their cancer specific antibody in order to prime the patient's immune system and destroy the malignancy. Although this is just a concept, in future it could very well become a mode of treatment.

When cell culture and transgenic animals are used to make vaccines the scale-up capability is restricted or rather the possibility of scale-up is on the lower side. On the contrary, the entire demand of Hepatitis B virus vaccine in SE Asia could be met by producing the vaccine in transgenic potato plants grown in about a two-hundred and fifty acre greenhouse. Another example of the scale-up capability of making vaccines in plants is the fact that one acre of transgenic plants could produce more than three-hundred and fifty million doses of anthrax vaccine.


Conclusion

Hippocrates is reported to have said, "Let thy food be thy medicine"----this is probably coming true now. One day, plant derived vaccines and other proteins would even help treat cancer without any side effects which is the bane of current day therapy

More than 3 million child deaths occur in Mexico from Hepatitis B as mass vaccination projects are hampered by problems of cost, storage, logistic, and the requirement of trained personnel(to administer vaccines). So importantly, plant derived vaccines is possibly the answer to this problem, to remove the scourge of diseases that occur due to failure of vaccination efforts.

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PART 2: https://www.biotecharticles.com/Agriculture-Article/The-Use-of-Plants-to-Make-Vaccines-Part-2-432.html

PART 3: https://www.biotecharticles.com/Agriculture-Article/The-Use-of-Plants-to-Make-Vaccines-Part-3-435.html