Edible Plant Vaccines: What are they?

Tse, Clarice

As the COVID-19 pandemic plagued our world, we are no strangers to the latest research and development of vaccines and medications. With our enhanced awareness towards vaccination, the recent innovation of edible vaccines has gained wide attention. “Edible vaccines” is a self-explanatory name; vaccines that are edible, usually in the form of plants such as banana, potatoes and tomatoes.  This type of vaccine is still under development. While it has a wide range of advantages such as its cost-effectiveness, it also faces several limitations. 

Edible vaccines are edible food such as fruits/ plants that contain the viral antigen of the pathogen and are devoid of pathogenic genes. It works by inducing the systemic and mucosal immune response system (MIS). As pathogens initiate their infection at the mucosal surfaces of the digestive tract, respiratory tract and urino-reproductive tract, MIS is the first line of defense (Criscuolo et al., 2019). When edible vaccines are eaten, the plant cells are degraded by digestive enzymes, releasing the antigens into the intestines. Induction of a mucosal immune response begins with the specialised cells called M cells recognizing the antigen. The M-cells are located in the mucosal membranes of lymphoid tissues like Peyer’s Patch in the small intestine. The antigen is channelled to the underlying tissues, internalised and processed by antigen-presenting cells (APCs). APCs present the antigenic epitopes, and with the assistance of helper T cells, activates B cells.  Activated B cells migrate to the mesenteric lymph nodes where they mature into plasma cells and travel to mucosal membranes to secrete immunoglobulin (Ig) A. The Ig A secreted into the lumen is called secretary IgA (sIgA); it neutralizes the invading pathogen through interactions with specific epitopes (Sahai, Shahzad & Shahid ). 

There are several approaches to producing edible vaccines. The first one would be transformation, in which the transgene is incorporated into the selected plant cell through direct and indirect gene delivery methods (Sahai, Shahzad & Shahid). 

Direct gene delivery uses a biolistic gun (a.k.a gene gun) to directly incorporate tungsten/ gold coated DNA/RNA into the target site of a plant cell and therefore can be called the “biolistic method” (Kurup & Thomas, 2019). Coated DNA/ RNA bombardment against the plant cells causes the DNA to penetrate walls and into the cell, where it would be integrated in the nuclear genome or the chloroplast (Chan & Daniell, 2015). 

Indirect gene delivery method is a vector-mediated gene delivery in which plants are infected with suitable plant bacteria that are genetically engineered to contain the antigen producing gene. Agrobacterium mediated transformation uses Agrobacterium tumefaciens or agrobacterium rhizogenes as vector for the incorporation of the target gene. This is due to their ability to integrate their plasmid DNA with the nuclear genome of plants. During transformation, not only the target gene, but also antibiotic resistance genes were added into the plasmid as markers. The successfully transformed plant tissues are then identified by their antibiotic resistance and further regenerated into whole plants. However, the production yield is low for this method, which is a limitation (Sahai, Shahzad & Shahid). 

Another approach utilizes plant viral expression systems to produce transient gene expression in plant cells. The rationale behind this is based on the notion that target gene is amplified during viral replication, resulting in enhanced expression of the recombinant protein in a short amount of time. Therefore, this method tackles the low yield issue of the transformation approach. Other benefits include the wide host range of plant viruses which allows the production of the desired antigen in different plant species, and a large scale up of antigen production. However, this method poses some limitations as subsequent plant generations will not inherit the gene of interest as it is not incorporated into the genome parent plant. Also, it is difficult to initiate transient expression in plants (Sahai, Shahzad & Shahid). 

There are many benefits of edible vaccines. One apparent advantage is the lower production cost and the large production scale by breeding. Another benefit is that unlike production of biomolecules, edible vaccines requires no pre-administration treatment and purification (Gunasekaran & Gothandam, 2020). This makes plant vaccines efficacious and affordable.  Moreover, they can be stored and transported without refrigeration. Its inexpensiveness and convenience in storage makes it easier for developing countries to prevent devastating diseases (Mishra et al., 2008).

Currently, there are many potential candidates of fruits and vegetables for the production of edible vaccines. Experiments were conducted on vegetables and fruits such as tomatoes, potatoes and bananas. Clinical trials have shown that transgenic potatoes were able to induce immune response to Norwalk virus which leads to diarrhea and vomiting. Other trials have shown the induction of immune response with antigen expressing transgenic lettuce (Mishra et al., 2008). However, transgenic potatoes have a major downside that it needs to be eaten raw or else the antigens may be denatured during cooking. 

An alternative is the transgenic banana, which has  recently been tested as bananas are inexpensiveto produce, can be eaten raw, and easy to grow in many countries(Mishra et al., 2008). Even so, only a few trials have advanced beyond phase I clinical trial due to the many technical adversities encountered. The inadequate expression levels in edible plants, the low success rate of induction of sufficient immunity to the pathogens are major impediments in the application of edible vaccines in real life. In the experiments mentioned above, the antigen level expressed in plant tissues were not sufficient for practical use, in order to produce sufficient immunity, a huge quantity of plants has to be consumed in order to achieve the required immunity (Chan & Daniell, 2015). 

Currently, there are a few options being explored to overcome the hurdles that were mentioned above. For example, engineering plant promoters to increase transcription levels. There are many factors that affect antigen expression, including the presence of intra and extracellular targeting and compartmentalization sequences and the site of gene integration in the genome, so determining the best site and what sequences to include can greatly affect the quality and quantity (Kurup & Thomas, 2019). Optimization of coding sequences of bacterial and viral genes for transient expression are also being researched (Kurup & Thomas, 2019). Albeit the promising prospects of plant vaccines, the acceptance and awareness of the public has to be gained in order for it to successfully launch its application worldwide. If in the near future, these challenges can be overcome, many diseases of our concern may be eradicated.

References:

Chan, H. & Daniell, H. (2015) Plant-made oral vaccines against human infectious diseases-Are we there yet? Plant Biotechnology Journal. 13 (8), 1056-1070. Available from: https://search.datacite.org/works/10.1111/pbi.12471. Available from: doi: 10.1111/pbi.12471.

Criscuolo, E., Caputo, V., Diotti, R. A., Sautto, G. A., Kirchenbaum, G. A. & Clementi, N. (2019) Alternative Methods of Vaccine Delivery: An Overview of Edible and Intradermal Vaccines. Journal of Immunology Research. 2019 1-13. Available from: https://search.datacite.org/works/10.1155/2019/8303648. Available from: doi: 10.1155/2019/8303648.

Gunasekaran, B. & Gothandam, K. M. (2020) A review on edible vaccines and their prospects. Brazilian Journal of Medical and Biological Research. 53 (2), e8749. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31994600. Available from: doi: 10.1590/1414-431X20198749.

Kurup, V. M. & Thomas, J. (2019) Edible Vaccines: Promises and Challenges. Molecular Biotechnology. 62 (2), 79-90. Available from: https://search.datacite.org/works/10.1007/s12033-019-00222-1. Available from: doi: 10.1007/s12033-019-00222-1.

Mishra, N., Gupta, P. N., Khatri, K., Goyal, A. K. & Vyas, S. P. (2008) Edible vaccines: A new approach to oral immunization. Indian Journal of Biotechnology. 7 (3), 283-294. Available from: https://search.proquest.com/docview/19546442.

Sahai, A., Shahzad, A. & Shahid, M. Plant Edible Vaccines: A Revolution in Vaccination. Recent Trends in Biotechnology and Therapeutic Applications of Medicinal Plants. 225-252. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=7120501&tool=pmcentrez&rendertype=abstract. Available from: doi: 10.1007/978-94-007-6603-7_10.

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