Scientists are finding that fields of crops might be easier to manage than vats of cells
Most pharmaceutical companies currently pursuing a coronavirus vaccine are doing so with bioreactors — large, metal, temperature-controlled tanks holding millions of cells that are engineered to pump out viral bits that can protect people from Covid-19. But a few companies designing these vaccines are approaching their production differently. When they generate vaccine candidates, their scientists will tend to a bed of plants.
If all goes to plan, each rounded leaf sprouting from the bright green crops will fill up with proteins that elicit Covid-19 immunity, once extracted and packaged into a shot. These so-called plant-based vaccines are the product of 30 years of work from a handful of scientists determined to turn crops into tiny pharmaceutical factories. People outside this small circle of expertise used to wonder whether the protein-building equipment in plants could also assemble human virus particles.
“People had questions around, well, can the plant machinery really make the virus? Because the virus doesn’t normally replicate there, is the machinery adapted to do that?” Matthew Miller, PhD, an infectious disease researcher at McMaster University in Canada, asked Future Human. “Now we’re understanding that, by and large, it is.”
Canada-based Medicago and the U.S. company Kentucky BioProcessing each hope to develop a vaccine against SARS-CoV-2, the virus that causes Covid-19, using this technique. If either vaccine is proven safe and effective, it could become the first plant-based variety ever approved by the U.S. Food and Drug Administration. Medicago is already moving through phase 1 trials. Compared to traditional manufacturing methods, plant-powered vaccine production promises to be efficient and relatively worry-free. And, as concerns mount about the ability of manufacturers to meet international vaccine demands during a pandemic, its allure skyrockets. Those pursuing the greenhouse-based vaccine technique are now working quickly to overcome the final barriers to their success.
“I’m afraid it’s still viewed as a niche technology,” Kenneth Palmer, PhD, a microbiologist studying plant-based vaccines at the University of Louisville School of Medicine, told Future Human. “And in some ways, maybe it is a niche technology that’s just waiting for products that are specifically well-suited to that manufacturing system.”
When producing a vaccine, manufacturers need viruses — dead, alive, or just their bits and pieces. Once extracted and injected, viral fragments force a sort of immune system dry run and prepare the body’s infection defense mechanisms in case the real-deal pathogen shows up. In the mid-1900s, companies began obtaining viral matter by infecting vats of cells with viruses to grow and harvest their parts. The tank system, which is still widely used, carries single-celled organisms, like yeast, or cells propagated from organs, like worm ovaries or dog kidneys, which feed off nutritious fluids to assemble the goods. Another popular method that’s been used since the 1940s involves injecting chicken eggs with a virus so that they churn out those necessary vaccine ingredients for a range of illnesses.
Both chicken and cell production options come with complications. Because viruses tend to mutate inside eggs, the extracted pathogens may stray too far from the version originally injected, making the vaccine less effective. And to use bioreactors to grow cells, companies must shell out for expensive fluids that keep the cells alive.
Most often, the tanks carry mammalian cells, like those from dog kidneys or hamster ovaries. “There’s always the possibility that those cells could be contaminated with some sort of pathogen that could affect humans,” Miller said. That’s because viruses that infect one mammal may hop to another, as the coronavirus has demonstrated. That nightmare came true in the 1950s when some polio vaccines grown in monkey kidney cells wound up carrying a potentially carcinogenic virus. Though the cancers never materialized in people who got the vaccine, the contamination sparked the development of federal guidelines to avoid the scenario ever happening again. Following the stringent but necessary regulations drags out the vaccine manufacturing timeline, Miller said.
Plant-based production relieves these concerns: Instead of a temperature-controlled factory and expensive liquids, crops need only sun, soil, fertilizer, and water. Though of course, the setup can get fancier — Medicago, for example, operates greenhouses with robotic arms that lift plants around. Additionally, no known viruses hop from plant to human, so that worry — and the precautionary measures they necessitate — disappear. Increasing production with bioreactors means repeatedly achieving a delicate balance between nutrients and cells or installing new and expensive equipment. But when crops are your factory, scaling up is more straightforward: Plant more rows.
Palmer and many other plant-based vaccine researchers want to turn this concept into reality with Nicotiana benthamiana, a close relative of the tobacco plant. It’s also the species of choice for Medicago’s and Kentucky BioProcessing’s SARS-CoV-2 vaccines. “I like to refer to it as the lab rat of tobacco research,” Palmer said. The species grows fast, handles lab conditions well, and most importantly, is susceptible to infection — a weakness researchers take advantage of.
To make plant-based vaccines, researchers like Palmer take what he calls the “old-fashioned” route and insert a modified human virus directly into plants. But most labs co-opt a natural disease process to sneak virus genes into crops. In the wild, pathogens like the bacteria Agrobacterium tumefaciens infect plants by slipping their DNA into its cells, coercing the plant’s protein production tools to manufacture more of the pathogen. To make vaccine elements in plants, many developers essentially swap the bacterial DNA that makes the crop sick with genes that code for human virus proteins. The plant can’t tell the difference between human and bacterial DNA, so leaf cells follow orders to assemble the new proteins.
It only takes a few days for the foliage to push out enough of the virus structures and reach harvest time, which is much faster than cell or egg-based production.
“I think that there are significant advantages in terms of the speed with which you can go from identifying an urgent need to have products available to test,” Palmer said. “If there are products that plants inherently naturally produce better than other systems, why not use the system that’s most efficient?”
That’s a question many people in Palmer’s line of work would like to answer. Despite their promise, plant-based therapeutics have had limited success. For example, in 2006, Dow AgroSciences got closer to a plant-based vaccine reality with livestock: The company earned U.S. Department of Agriculture approval for technology that protected chickens against the Newcastle disease virus. Ultimately, however, the company never brought the vaccine to market, and no human vaccine available today relies on greenhouse technology. An experimental therapeutic drug given to Ebola patients in 2014 was produced in the same tobacco relative in use for SARS-CoV-2 and some of the recipients recovered, but other, more effective options ultimately replaced the experimental drug.
One reason the technology has been slow to develop may be because the necessary expertise is hard to find, Miller said. Scientists who specialize in both human pathogens and plant metabolisms are relatively rare. Some vaccine developers might be intimidated by the approval process, Kathleen Hefferon, PhD, a microbiologist at Cornell University, tells Future Human. While the FDA has clear protocols for cell-based production, it has limited experience regulating living plants, and companies could hesitate to engage — or invest — if they don’t know how the federal agency would oversee a pharma farm. That might explain why there is only one plant-based pharmaceutical product approved by the agency, which comes from bioreactors full of N. benthamiana cells.
The lone FDA-approved vaccine is called Elelyso, a drug that treats Gaucher disease, a condition affecting multiple organs and tissues, by providing patients with proteins that their bodies struggle to supply. The drug inventor and manufacturer, Israel-based Protalix Biotherapeutics, knows that its plant cell technique is unusual for the FDA to handle, company CEO Dror Bashan told Future Human, even though the product earned approval in 2012. Yet the relationship seems to have gone smoothly, as Protalix has a second medication under review.
Another roadblock to plant-based vaccines is that older pharmaceutical developers are entrenched in traditional manufacturing — habits that might stand as the largest barrier to any of these companies planting seeds. Large companies have sunk decades of research and millions of dollars into the infrastructure for eggs and bioreactors, and the motivation to change isn’t there. “If the system isn’t broke,” Palmer said, “why fix it?” Protalix, for its part, has focused on plant cell-based therapeutics since its inception.
For a pharmaceutical giant to trade bioreactors for farmland, vaccines might have to deliver a larger financial incentive than they currently do. Even if key vaccine ingredients are more cheaply produced in crops than bioreactors, the second half of manufacturing — distilling and packaging injections — is expensive. A production method that eliminated assembly steps might reach the rock-bottom prices and could turn industry executive heads. Henry Daniell, PhD, a biochemist at the University of Pennsylvania, thinks plant-based vaccines could reach bargain prices if they are edible. Many of his colleagues have dreamed for decades of either ready-to-eat vaccines, like engineered bananas that go straight from the farm to patients’ mouths, or something akin to what Daniell is pursuing — foods that can be dehydrated down before consumption. To Daniell, “that’s the real goal.”
Daniell is getting closer to that aspiration with a heart medication grown in lettuce that would allow people to swallow pills full of the dehydrated leaf particles or mix the powder into a drink. Daniell and his colleague Kenneth Margulies, PhD, recently received funding to investigate whether the drug could assist Covid-19 patients with cardiac complications.
The medication isn’t yet approved by the FDA, and there’s still no vaccine administered via a snack, let alone extracted from tobacco-like leaves. However, the pandemic — and desperation for tools to stop its progression — has opened the door for several tantalizing technological innovations to finally become part of human medical care.
Plant-based vaccines could still cross through to the other side. “I’m concerned that this appeared to be a good opportunity and that [plant-based vaccines] may just be beaten to the market,” Palmer said. Several other, more traditional SARS-CoV-2 vaccine candidates are further along in development, and all of them had big pharma financial backing.
But being a leading contender doesn’t guarantee success for plant-based vaccines. “In the next six months, their true capacity is going to be tested,” Daniell said. If the most promising bioreactor-grown vaccines don’t work out, who knows — there might be room for a lean, green Covid-19 vaccine machine to flourish after all.