Could COVID-19 Cause 'Biopharming' to Bloom?
Genetically engineered plants offer new platforms for vaccines and therapeutics

Abstract

At an accelerated rate in response to the COVID-19 pandemic, academic and corporate scientists are using genetic engineering techniques to reprogram plants to produce significant concentrations of high-value pharmaceuticals. The concept is not new. Many common medicines, such as certain opiates, the laxative Metamucil, and the anticancer drug Taxol, are all purified from plants, and efficacy has been shown for some herbals in Traditional Chinese Medicine. There is great potential for cost-cutting in the process: The energy for product synthesis comes from the sun, and the primary raw materials are water and carbon dioxide. In addition, biopharming offers tremendous flexibility and economy when adjustments in production are necessary. The need for inexpensive, flexible production techniques for COVID-19 therapeutics and vaccines could be a potent stimulus to biopharming research and development.

The COVID-19 pandemic has spurred profound changes in the scientific research community worldwide. Laboratories have reoriented their research to focus on various aspects of this scourge, and thousands of articles have already appeared on preprint servers and in journals. As scientific researchers race to find solutions, the production of high-value pharmaceuticals in plants, or "biopharming," a technology that has teetered on the brink of recognition for many years, is mushrooming. The pandemic could be an opportunity to prove its worth.

Academics and biotech companies are using genetic engineering techniques to reprogram plants — which have included corn, potatoes, rice, and bananas, among others (discussed below) — to produce significant concentrations of pharmaceuticals, including vaccines. The concept is not new. Many common medicines, such as morphine, codeine, the laxative Metamucil, and the anticancer drug Taxol, are all purified from plants. There are also a few examples of Chinese herbal treatments that have proved effective in randomized controlled clinical trials. One notable product that has emerged from Traditional Chinese Medicine, or TCM, is artemisinin. First isolated by Youyou Tu at the China Academy of Traditional Chinese Medicine in Beijing, the molecule is now a powerful treatment for malaria and led to Tu being awarded the Nobel Prize in Physiology or Medicine in 2015 (Callaway, and Cyranoski, 2015).

But biopharming's great promise lies in using genetic engineering techniques to make old plants do radically new things.

There is also great potential for cost-cutting in the process: The energy for product synthesis comes from the sun, and the primary raw materials are water and carbon dioxide. In addition, biopharming offers tremendous flexibility and economy when adjustments in production are necessary. Doubling the acreage of a crop requires far less capital than doubling the capacity of a bricks-and-mortar factory, making biopharmed drugs potentially much less expensive to produce than those made in conventional ways. As little as 2,000 acres can provide the substrate for a year's supply of some products. Grain from a biopharmed crop can be stored safely for long periods with no loss of activity. The quality of the final drug can meet the same standards as current fermentation technology using microorganisms.

In addition, biopharmed vaccines are inexpensive to produce, easy to upscale, and often do not require refrigeration, needles or trained medical personnel, thus making them attractive for use in developing countries. Many research studies and clinical trials have shown that plant-made vaccines elicit a robust immune response in animals and humans and are safe and efficacious (Paul and Ma, 2011). Examples of plant-made vaccines and therapeutics produced by molecular pharming include vaccines to combat cholera, Dengue fever virus and Hepatitis B virus; and monoclonal antibodies to HIV and Ebola virus.

Although such plant biologics have largely focused on the diseases of the poor in developing countries, they have found other niches as well. For example, several plant-made vaccines to combat pandemic influenza are currently completing clinical trials and will soon be on the market, and plant-based immunotherapies to treat a variety of cancers are in development (Mardanova and Ravin, 2018). A plant-based therapeutic to provide the enzyme glucocerebrosidase in Gaucher Disease patients has also found a reliable market and is currently commercially available (Grabowski et al., 2014).

Several biopharming companies and academic research labs have taken up the challenge to combat COVID-19. Medicago, a Canadian biopharmaceutical company, successfully developed a virus-like particle (VLP) of the coronavirus only 20 days after obtaining the SARS-CoV-2 genetic sequence. Instead of using eggbased methods to produce a vaccine, this technology inserts a genetic sequence that encodes the spike protein of COVID-19 into Agrobacterium, a common soil bacterium that is taken up by plants (Krenek et a., 2015). The resulting plants produce a VLP that is composed of plant lipid membrane and COVID-19 spike protein, and which acts as the vaccine. The VLPs are similar in size and shape to actual coronavirus but lack viral or plant nucleic acid and are thus noninfectious.

Previously, Medicago made VLPs that contain influenza virus hemagglutinin and demonstrated their safety and efficacy in animal models as well as in human clinical trials (Pillet et al., 2019). The cost of producing a plant-made vaccine based on VLPs is a small fraction compared to its conventional counterparts.

Also in Canada, the University of Western Ontario and Suncor are developing serological test kits for COVID-19 using algae as a production factory to make the viral spike proteins (Mackay, 2020). Algae has long been considered a potential platform for generating pharmaceutical proteins as well as industrial proteins such as cellulases (Specht and Mayfield, 2018). Algae is a superior bio-factory alternative because it is easy to grow at scale and can be readily modified to produce the viral proteins.

British American Tobacco, through its biotech subsidiary in the US, Kentucky BioProcessing (KBP), is developing a potential vaccine for COVID-19 that is currently undergoing pre-clinical testing (Gretler, 2020). Experts at KBP cloned a part of the genetic sequence of SARS-CoV-2, which they used to develop a potential antigen that was inserted into Nicotiana benthamiana plants for production. The vaccine elicited a positive immune response in preclinical testing and is expected soon to begin Phase 1-2 clinical trials (Clinicaltrials.gov, 2020). BAT could manufacture as much as 1-3 million doses of COVID-19 vaccine per week. (They were able to make 10 million doses of flu vaccine and of an Ebola vaccine in a month, using the same plant-based approach.)

South African company Cape Bio Pharms (CBP) is also responding to the COVID-19 pandemic with the production of reagents in plants that could be used in diagnostic kits (Nogrady, 2020). CBP is producing SARSCoV-2 Spike S1 reagents consisting of various regions of the glycoprotein attached to various fusion proteins. The company is also collaborating with antibody manufacturers to produce antibodies against these proteins.

Another example of a biopharming solution to COVID-19 is being developed in Professor Nicole Steinmetz's lab at the University of California, San Diego, using Cowpea mosaic virus VLPs with epitopes from COVID-19 displayed on their icosahedral surfaces (Wang et al., 2019). The VLPs harboring these COVID-19 epitopes can be administered in the form of a microneedle technology, which delivers drugs painlessly through the skin, eliciting an immune response to SARS-CoV-2 (Lopez-Ramirez et al., 2020).

A collaboration between research groups in Toronto, Canada, is working on a novel way to both prevent and treat COVID-19 using an antiviral protein that blocks virus replication (Jain, 2020). When loaded onto a plant virus nanoparticle, the protein can enter cells and block virus infection. It is possible that this biopharmed antiviral protein can be loaded into an inhaler and administered to the lungs of infected and uninfected patients. Similarly, a synthetic, plant-made antibody has been designed to prevent virus infection and block person-toperson transmission. It can be produced easily in plants engineered to synthesize antibodies that are as "humanized" as possible, reducing the likelihood that patients' immune system will reject them as "foreign."

In our pandemic world, collaborations and markets have begun to mix and merge in unprecedented ways. While more than a hundred COVID-19 vaccine candidates are moving forward at various stages of development, it is difficult to predict which will ultimately be successful. The rapid and easy scalability of plants, combined with the power and versatility of molecular genetic engineering techniques, could offer the kind of rapid response and flexibility that is needed.

Kathleen Hefferon, Ph.D., teaches microbiology at Cornell University. Henry I. Miller, a physician and molecular biologist, is a Senior Fellow at the Pacific Research Institute; he was the founding director of the FDA's Office of Biotechnology.

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