CASABLANCA, Chile – On a dusty farm track in Chile’s wine region, behind a wooden door surrounded by chains, forestry experts tend to a plantation of saplings whose bark holds the promise of potent vaccines.

Quillay trees, technically known as Quillaja saponaria, are rare evergreen trees native to Chile that have long been used by the indigenous Mapuche people to make soap and medicine. In recent years, they have also been used to make a highly effective shingles vaccine and the world’s first malaria vaccine, as well as foaming agents for products in the food, beverage and mining industries.

Now, two molecules of saponin, made from the bark of pruned branches of older trees in the forests of Chile, are being used for a COVID-19 vaccine developed by drug maker Novavax Inc. (NVAX.O). The chemicals are used to make an adjuvant, a substance that strengthens the immune system.

Over the next two years, Maryland-based Novavax (NVAX.O) plans to produce billions of doses of vaccine, mainly for low- and middle-income countries, which would make it one of the largest suppliers of COVID-19 vaccines in the world.

With no reliable data on the number of healthy quillay trees remaining in Chile, experts and industry officials are divided over how quickly the supply of older trees will be depleted by growing demand. But almost everyone agrees that industries that rely on quillay extracts will at some point have to switch to plantation-grown trees or a lab-grown alternative.

A Reuters analysis of export data from trade data provider ImportGenius shows that the supply of older trees is under increasing pressure. Exports of quillay products more than tripled to over 3,600 tonnes per year in the decade leading up to the pandemic.

Ricardo San Martin, who developed the pruning and extraction process that created the modern quillay industry, said growers should immediately work on making quillay products from younger trees grown in plantation. .

“My estimate four years ago was that we were heading towards the limit of durability,” he said.

San Martin said he worked hard during the COVID-19 pandemic in the basement of his oceanfront cabin in Sea Ranch, Calif., To refine a process that could help produce saponins from leaves and twigs to maximize yield.

“I work as if this should be done yesterday,” said San Martin, who also sponsors a project in which drones count quillay trees in remote and hard-to-reach forests, to determine how many are left.

Quillay growers and their customers say the harvest can continue for now without decimating the supply of older trees.

“We continue to monitor the situation in Chile, working closely with our supplier, but for the moment we are confident in our supply,” Novavax said in a statement to Reuters. The company also said it was confident that uses such as “life-saving vaccines will be prioritized.”

The desert plant extract company Desert King International Ltd, which manages the Casablanca plantation, is the sole supplier of quillay extracts to Novavax and by far the largest quillay exporter from Chile.

A bottle with wood from quillay trees is shown in a nursery lab in Casablanca, Chile on April 20, 2021.Tamara Merino / Reuters

Company director in Chile Andres Gonzalez told Reuters it is planned to produce enough quillay extract from older trees to produce up to 4.4 billion doses of the vaccine by 2022 With new supplies from private native forests, they have enough raw materials to meet demand. for the rest of this year and part of next, he said.

Gonzalez said the company, where San Martin is a consultant, has built a new production facility and has the ability to supply other interested pharmaceutical companies, all without harming the forests.

He acknowledged, however, that “at some point these native forests will come to an end.”

“We want to start having very productive plantations, and we are working on it,” he said.

A relatively small volume of quillay extract is needed to make vaccines – just under a milligram per dose – but supply is stretched by demand from other industries. Quillay products are used, for example, as a natural additive in animal feed, as a biopesticide and as a pollution reduction agent in mining.

Individual quillay trees grow outside of Chile, but Chile is the only country where mature quillay is harvested from forests in large quantities.

An elusive ingredient

Novavax adjuvant, known as Matrix-M, contains two key saponin molecules. One of them, called QS-21, is more difficult to access because it is mostly found in trees that are at least 10 years old.

Among the large pharmaceutical companies, only GlaxoSmithKline PLC (GSK.L) and Novavax have put a lot of emphasis on QS-21, a relatively new pharmaceutical ingredient.

GSK’s highly effective shingles vaccine, Shingrix, and several other promising experimental vaccines contain QS-21 supplied by Desert King. In a statement, GSK said it had “no specific challenges related to the sustainable sourcing” of QS-21.

The quillay adjuvant used in Shingrix is ​​also part of the world’s first malaria vaccine, Mosquirix. Despite its low efficacy, it was approved by European regulators in 2015 and recommended for pilot introduction by WHO in 2016 due to urgent need.

No other COVID-19 vaccine manufacturer relies on quillay bark extracts. Some drug makers are developing synthetic alternatives, but it could take years for regulatory approval. Replacing the ingredients of any existing vaccine would require further clinical studies to prove that the product is safe and effective.

Massachusetts-based pharmaceutical company Agenus stopped selling the bark-derived QS-21 several years ago to focus full-time on growing from quillay plant cells in a lab.

“The shortage of QS-21 has been a problem for some time,” said Jason Paragas, vice president of strategic initiatives and growth exploration at Agenus. “We saw it before COVID, and we made the difficult decision that we had to change. “

Paragas said it was too early to say when an alternative might be ready.

Entrepreneur Gaston Salinas said his Davis, Calif., Based startup Botanical Solution Inc can already produce QS-21 from quillay tissue starting with seeds in the lab, and eventually aims to produce the large-scale chemical to supply pharmaceutical companies.

“You cannot afford to over-harvest the Chilean native forest because of a desire to develop modern vaccines. You have to find other ways to develop your products, even if it’s something so important, ”he said.

A look to the future

Inside the carefully guarded Desert King plantation gate, gardeners carefully tend the saplings with fertilizer and abundant water supplies. They were cloned from adult cousins ​​whose dusty gray bark was particularly rich in saponins.

If all goes well, the plantation could produce for a client within two to three years, according to Damian Hiley, director of business development for Desert King. He declined to name the company.

Desert King has his eye on future vaccines, some already in the works.

In early 2020, for example, GSK licensed an investigational tuberculosis vaccine containing GSK’s QS-21 adjuvant to the Bill and Melinda Gates Institute for Medical Research. It showed promising results in a mid-term trial.

And in April, researchers at the University of Oxford announced that a new malaria vaccine containing Novavax’s adjuvant Matrix-M appeared to be very effective in a trial involving 450 children in Burkina Faso.

Gustavo Cruz, a researcher at the University of Chile who worked with San Martin to industrialize quillay production, said he generally trusted quillay producers to manage supply and demand. He is more concerned about other threats, in particular drought and fires.

“Trees do grow back,” he said, “but there comes a time when they don’t grow again. “

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