Plantibodies and Plant-Derived Edible Vaccines
Throughout history, humans have used plants in the treatment of disease. This includes more traditional methods involving direct consumption with minimal preparation involved and the extraction of compounds for use in modern pharmaceuticals. One of the more recent methods of using plants in medicine involves the synthesis and application of plantibodies and plant produced antigens. These are recombinant antibodies and antigens respectively, which have been produced by a genetically modified plant (1, 2).
Antibodies are a diverse set of proteins which serve the purpose of aiding the body in eliminating foreign pathogens. They are secreted by effector B lymphocytes which are a type of white blood cell that circulate throughout the body. An antigen is a molecule or a component of a molecule, such as a protein or carbohydrate, which can stimulate an immune response. The human body is capable of producing around 1012 different types of antibodies, each of which can bind to a specific antigen or a small group of related motifs (3). When an antibody encounters the antigen of a foreign pathogen to which it has high affinity, it binds to it which can disable it or alert the immune system for its destruction (4).
Figure 1: Each type of antibody has the ability to bind to a specific antigen or group of antigens with high affinity.
Plants do not normally produce antibodies and thus must be genetically modified to produce plantibodies as well as foreign protein antigens. Plantibodies produced in this manner function the same way as the antibodies native to the human body (1). The main ways to do this are to stably integrate foreign DNA into a host cell and place it into a plant embryo resulting in a permanent change of the nuclear genome, or to induce transient gene expression of the specified protein (5). In both cases, the genetic material introduced to the plant codes for the protein of choice. Several of the methods used to induce permanent transgene expression include agrobacterium-mediated transformation, particle bombardment using a gene gun, or the transformation of organelles such as chloroplasts. Transient transgene expression can be done using plant viruses as viral vectors or agroinfiltration (2). Once the genetic material has been inserted, the specified protein is produced via the plant endomembrane and secretory systems, after which it can be recovered through purification of the plant tissue to be used for injection (1). The production of these proteins can also be directed to specific organs of the plant such as the seeds using targeting signals (2). Stable integration techniques are generally used for more large scale production and when the gene in question has a high level of expression, while transient techniques are used to produce a greater yield in the short term (5).
Figure 2: A gene gun being used to introduce genetic material into the leaves of a plant.
Now how can plantibodies and plant produced antigens help us as humans? The primary purpose of producing plantibodies is for the treatment of disease via immunotherapy. Immunotherapy is a method of treatment in which one’s immune response to a particular disease is enhanced. Specific plantibodies can be produced in order to target a particular disease and then be applied to patients via injection as a means of treatment (6). Doing so provides a boost to the number of antibodies against the targeted disease in the patient’s body which helps to enhance their immune system response against it. An example of this is CaroRx, the first clinically tested plantibody which has the ability to bind to Streptococcus mutans. CaroRx has been shown to be effective in the treatment of tooth decay caused by this species of bacteria (1). More recently, a plantibody known as ZMapp has shown potential in the treatment of Ebola. A study by Qiu et al showed that when administered up to 5 days after the onset of the disease, 100% of rhesus macaques that were administered the drug were shown to have recovered from its effects while all of the control group animals perished as a result of the disease (7). In addition, it has been experimentally administered to some humans who later recovered from the disease, although its role in their recovery was not fully ascertained (8).
Plant produced antigens on the other hand can be used to produce oral vaccines (9). Vaccines are typically biological mixtures containing a weakened pathogen and its antigens. Injection of this results in priming of the body’s adaptive immune system against the particular pathogen so that it can more easily recognize and respond to the threat in the future (4). By producing the antigens of targeted pathogens in plants through transgenic expression, edible vaccines can be created if the plant used is safe to eat. Tobacco, potato, and tomato plants have typically been used in past attempts to create them, showing success in both animal studies and a number of human trials. The advantages of using an oral vaccine include ease of administration and lower costs since specialised personel are not required for administration (9). In addition, oral vaccines are more effective in providing immunity against pathogens at mucosal surfaces as they can be directly applied to the gastrointestinal tract (1). The primary issue with the usage of oral vaccines is that protein antigens must avoid degradation in the stomach and intestines before they can reach the targeted sites in the body. Several solutions to this dilemma include using other biological structures such as liposomes and proteasomes as a means of delivery. This helps to prevent the proteins from being degraded by digestive enzymes and the acidic environment of the stomach before they can reach their destination (1, 9).
Figure 3: An overview of one method of producing an edible vaccine using a potato plant. A gene coding for the protein of a human pathogen is used in agrobacterium-mediated transformation to produce a transgenic potato plant. The potatoes from this plant can then serve as an edible vaccine against pathogen from which the protein originated.
There are a number of advantages to using these plant based pharmaceuticals. First of all, they can be produced on a large scale at a relatively low cost through agriculture and are convenient for long-term storage due to the resiliency and size of plant seeds (5). There is also a low risk of contamination by mammalian viruses, blood borne pathogens, and oncogenes which can remove the need for expensive removal steps (1). In addition, purification steps can be skipped if the plants used are edible and ethical problems that come with animal production can be avoided (5). The disadvantages include the potential for allergic reactions to plant antigens and contamination by pesticides and herbicides. There is also the possibility of outcrossing of transgenic pollen to weeds or related crops which would lead to non-target crops also expressing the pharmaceutical.This could lead to public concern along with the potential that other species which ingest these plants may be negatively affected (9). While plantibodies and plant produced antigens have not yet been extensively tested in clinical trials, going forward they represent a new treatment option with great promise.
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7. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, Fausther-Bovendo H, Wei H, Aviles J, Hiatt E, Johnson A. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014 Aug 29.
8. Sneed A. Know the Jargon. Scientific american. 2014 Dec 1;311(6):24-24.
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