Can tiny lab-grown plants solve a big vaccine problem?

Chile is home to the rare soapbark tree, known in the scientific community as Quillaja saponaria. These evergreens, which can stand 15 to 20 m tall and take a quarter of a century to mature, are by no means ordinary. All their organs—but especially the bark—contain soapy compounds called saponins that have been used in skin-care creams, beverages, detergents, and cough and cold remedies for over a century.

In the last 5 years, soapbark tree saponins have made headway as adjuvants—molecules added to vaccines to boost the immune response. The adjuvant made from the soapbark tree is known in the industry as QS-21, and it is used in several vaccines approved by the US Food and Drug Administration, including Novavax’s COVID-19 shot and GSK’s malaria and shingles vaccines. The molecule is also being tested in over 100 vaccine clinical trials.

Rising QS-21 demand from the pharmaceutical industry inevitably led to unsustainable harvesting—to the point that the Chilean government enforced strict regulations on soapbark lumbering. A California-based company, Botanical Solution Inc. (BSI), is one of several firms betting on lab-grown soapbark plants to ensure sustainable production and a robust supply of the adjuvant.

“In the pharma industry, the whole value chain associated with the supply of QS-21 relies on native Chilean forests, which is kind of worrying from a sustainability, geopolitical, and supply chain point of view,” says BSI cofounder Gastón Salinas, an industrial engineer by training and a native of Chile. The company’s other cofounder, Gustavo Zúñiga, is a plant biotechnologist who stepped down from his role but continues to advise the firm.

The two founded BSI in 2013 to grow seedlings in the laboratory without having to chop down wild trees. They rear tiny saplings in shoe-box-sized vessels. They start out looking like microgreens but can grow to the size of a cauliflower.

For the two founders, entering the pharmaceutical business wasn’t the initial plan. Their first product using the lab plant extracts was a fungicide, which they commercialized in Chile in 2016 and began selling globally in 2019.

Around that time, they started noticing interest in the soapbark compounds from the vaccine industry as studies had begun to highlight QS-21’s ability to elicit immune responses. Then, when the COVID-19 pandemic arrived, and companies were racing to develop new vaccines, QS-21 demand increased exponentially. “It soon became apparent that the pharma industry was relying on the wild Quillaja saponaria,” Salinas says.

The coveted molecules have been sourced mainly from the tree’s bark for years. Pieces of the bark are pestled and subject to multiple rounds of purification, often using solid-phase extraction and reversed-phase HPLC. “Even the purification steps require extensive usage of organic solvents, which isn’t environmentally friendly,” Salinas says.

Only a handful of companies, including industry leader Desert King, make QS-21 on a commercial scale. Desert King is the main QS-21 supplier to GSK, and the two recently announced a partnership to produce over 8 billion vaccine doses annually for diseases like malaria, respiratory syncytial virus, and shingles.

BSI’s method requires just a tiny part of the wild tree as starting material. The tissues are grown into saplings in a unique nutrient medium. But the process isn’t straightforward, Salinas says. “To get the right quality, one has to ensure the right amount of oxygen and other atmospheric factors associated with the plants, temperature, and conditions,” he says. Producing saplings from wild plant tissue can take about a month. “But once you get the system up and running, you can harvest fresh material weekly.”

BSI extracts QS-21 from the plants’ leaves using a series of cost-effective purification methods that don’t require harmful solvents, Salinas says.

The company isn’t the only one trying to develop QS-21 in the lab—a few academic groups are exploring ways of expressing it in engineered yeast. Other firms are growing cells that express QS-21.

SaponiQx is one of the companies that uses this cell culture approach. The firm supplies QS-21 to over a dozen drug companies worldwide and has partnered with Gingko Bioworks to deploy artificial intelligence to screen for new adjuvants.

“QS-21 is a very hot commodity right now. Everyone is trying to get their hands on it,” says Rebecca Kurnat, head of operations at SaponiQx. The company’s technique of making the adjuvant has several advantages, she says. Pharmaceutical companies and contract manufacturing organizations can license SaponiQx’s technology and make the adjuvant on their premises.

“Our process utilizes commonly available infrastructure which most companies already have access to. They don’t have to go and set up a million fish bowls with saplings growing out of them,” Kurnat says.

Salinas contends that BSI’s approach has more potential to meet the industry’s needs. “In addition to QS-21, our approach produces a few other saponins that can be converted to QS-21, increasing the overall yield,” he says. But, Kurnat says comparing yields is difficult because each company tends to hold that information close to its chest.

But Kurnat and Salinas agree on one thing: lab-based methods hold the promise of bringing down the cost of QS-21. According to BSI’s website, the adjuvant can sell for as much as $400,000 per gram.

Salinas says the next challenge for BSI will be to produce quantities that match the industry’s increasing requirements. While the company currently can make a few kilograms of QS-21 a year, it is ramping up its production abilities to match the industry’s annual demand of over 100 kg, he says.

BSI has secured $23 million in series A funding. In addition to increasing production, the company is investing in genetically modifying its lab plants to increase the yield of QS-21.

In 2023, BSI partnered with Croda International, a British specialty chemical maker, to advance QS-21. As per the contract, the companies will codevelop and test the compound to ensure that its quality is on par with adjuvant obtained from the Chilean trees. For now, BSI supplies its QS-21 exclusively to Croda, which in turn plans to supply it to pharmaceutical companies.

Croda executives say BSI’s adjuvant fits perfectly with other products it makes by sustainable processes.

Angela Kleiner, Croda Pharma’s global head of insights and innovation, says her company plans to supply BSI’s QS-21 to pharmaceutical companies that are developing new vaccines and are interested in sustainable sources of the adjuvant. “It had become quite obvious that the current way of obtaining QS-21 from the trees is not the solution for the future,” she says.