Newly emerging virus strains are a constant threat to global health, and the SARS-CoV-2 (the virus behind COVID-19) global pandemic is just the latest example.
Plant-based edible vaccine technology is emerging as an affordable and efficient alternative for vaccination against common diseases. As a vaccine production strategy, plant cell culture systems yield the highest protein levels, and they may be incredibly important tools for mass immunization strategies due to existing infrastructure for growth and supply chains.
Plant biotechnology, i.e. genetically engineering plant cells with animal proteins, has already played an important role in the production of pharmaceutical compounds: antibodies, antigens, sub-units, growth hormones, and enzymes in the past quarter century. As bioreactors, plants yield high amounts of recombinant proteins; these proteins are not contaminated with human or animal pathogens and can be stored without refrigeration at low cost. Occasionally, individuals have allergies to animal based proteins, for example to egg yolk produced vaccines or in the case of “Lone Star Tick Bite” allergies (colloquially referred to as “alpha gal”).
A number of recombinant therapeutic proteins (insulin for example) have been produced in plants, and the production of protein-based pharmaceuticals has partially shifted from bacterial, fungal, and mammalian cell cultures to plants and plant cell cultures.
In the United States, the Food and Drug Administration ensures the safety for both manufacturing and clinical use of plant-based biopharmaceuticals and vaccines; it also approves and licenses them. Similar to other biopharmaceuticals, plant-based vaccines should be free of impurities, including other transgenes and resistance marker products, which must all be evaluated under the same criteria.
Most vaccines that are available today rely on either inactivated (killed) or live attenuated (weakened) technologies. There are numerous problems with traditional vaccine manufacturing. Among them are:
- Vaccines grown in eggs, tissue culture, or simply culture medium may contain unwanted “foreign” proteins, which make them potential allergens.
- Inactivated vaccines must be totally innocuous and noninfective. Problems with field outbreaks in the past have occasionally been attributed to incomplete inactivation.
- Manufacture involves the culture of large amounts of the infectious agent, there is a potential hazard to the personnel involved and the environment.
- Inactivated vaccines have certain limitations on their mode of presentation and the immune response they can elicit. The response to vaccination may be limited and of short duration with adjuvants or immunostimulants required.
- Attenuated vaccines must be precisely controlled to provide the required level of protective immunity without causing significant disease symptoms.
- Attenuated antigen may revert to full virulence.
How can plant cells make vaccines? Genetic engineering!
Plant cells provide a useful expression system for mammalian proteins. To express foreign genes in plants, it is necessary to splice a plant promoter, terminator, and, generally, a regulatory sequence onto cloned complementary DNA.
The first licensed vaccine to use a plant cell expression system was against Newcastle disease virus (NDV) infection for poultry, which is produced in suspension-cultured tobacco cells. That system is now being investigated for many other vaccine applications, including infectious bronchitis virus, infectious bursal disease virus, ETEC, BVD, and bovine herpes virus. Only a few plant-based human vaccines have reached clinical trials, including for E. coli, Hepatitis B, Influenza and Cholera.
Questions still remain about how to produce plant-based vaccines. For example, how best to cultivate them? Open-field cultivation is less expensive than greenhouse or in-house cultivation, but plant factories offer controllable, reproducible cultivation conditions suitable for GMP manufacturing. Finally, we need to define the procedures for manufacturing and processing of plant-based pharmaceuticals. The challenge for the industry is to facilitate the procedures without compromising quality, which is a prerequisite for manufacturing plant-based human and animal vaccines.
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