The Chilean tree that could help cure malaria (and a host of other diseases)
At first glance, it looks like any other vineyard in Chile’s Casablanca Valley, with rows of terraces strung out across a rocky hillside. But take a closer look and you will see that grapes are not the only crop.
In several places, saplings a foot tall sprout from beneath the vines, their glossy green leaves glistening in the noonday sun. But it is the mature, 40-year-old tree half-way up the hillside that draws the eye.
With its tall, dark-grey trunk and spreading canopy, the Chilean soapbark tree, Quillaja Saponaria, towers above the wine terraces. When it rains, a soapy substance known as a saponin oozes from its bark. In the next few years, molecules derived from these saponins promise to revolutionise vaccinology, enhancing the ability of vaccines to induce immune responses against malaria, Covid-19, influenza and a host of other diseases.
“It is a beautiful tree but it can take up to 25 years before the bark is ready to be harvested,” explains Javier Gonzalez, the forestry manager for Desert King, one of the main suppliers of pharmaceutical-grade saponins from Chile. “Some people don’t want to wait that long and strip the bark after just 20 years.”
In some cases, the bark is peeled from the base of trunk, causing the tree to wither and die. In other cases, loggers fell the tree and strip away all of the bark, leaving the wood to rot in the forest.
By selecting varieties rich in saponins, and cloning them, Desert King hopes to speed up the growing and harvesting process, while preserving the tree for future generations. According to Gonzalez, the vines provide shade and protection for the seedlings when they are young, while watering regularly speeds growth. The aim is to see if, rather than waiting 25 years for the trees to reach maturity before stripping the bark, Desert King can obtain a similar yield from branches and leaves of five to 10-year-old trees.
“Shade and watering makes a big difference,” says Gonzalez. “These trees are only two years old but some are already four metres high.”
Quillaja Saponaria, more familiarly known as Quillay, is indigenous to Chile and thrives in coastal regions and mountainous forested areas from Coquimbo in the north to Araucanía 1,000 miles to the south. Chile’s forests and plantations currently contain around 65,000 tons of Quillay bark, of which 240 tons is harvested annually. In theory, that should be more than enough to meet the global demand for saponins, which are also used in products for the food and beverage and cosmetics industries.
But thanks to climate change, illegal logging in Chile’s national parks, and the overly vigorous stripping of bark, mature Quillay trees – which can live for more than a thousand years – are increasingly rare and concerns are mounting that, as the demand for saponins increases, Chile’s Quillay forests might be denuded to the point where they are unable to meet the needs of vaccine manufacturers.
That is why if Desert King can find a more efficient way of extracting saponins from Quillay no one will be more pleased than the pharmaceutical industry and conservationists. It would also help reassure international health donors, such as the Gates Foundation and the World Bank, as they look to underwrite malaria immunisation programmes in Africa incorporating vaccines with the latest saponin-based adjuvants.
“By finding new ways to extract saponins we are future-proofing the Quillay tree against climate change and illegal logging,” explains Andrés Gonzalez, general manager of Desert King’s Chilean operations. “I feel we are doing important work here.”
Vaccinology’s ‘dirty secret’
Long considered the “dirty secret” of vaccinology, adjuvants are key to how vaccines trigger an immune response. The idea is that by adding an inert substance to a vaccine, you can get the immune system to register the presence of a foreign antigen quicker, prompting antibodies and other immune cells to flood to the injection site.
In the past, scientists incorporated all sorts of substances into adjuvants, including alum, mercury and breadcrumbs. But in some individuals these adjuvants are poorly tolerated and can have unwelcome side-effects. And in the case of parasitical diseases, such as malaria, where the parasite is continually changing its shape, traditional vaccine adjuvants tend to be ineffective.
Not so the new saponin-based adjuvants. These come in different formulations and fractions but are generally much better at kick-starting an immune response. One fraction, known as QS-21, is a key component of the adjuvant employed in GSK’s shingles and malaria vaccines. QS-21 is produced by repeatedly pulverising Quillay bark and soaking it in water to produce a brown, bubbly fluid. The fluid is then pasteurized and dried, reducing it to a chalky powder rich in the fraction.
To render it non-toxic, QS-21 is combined with cholesterol and a lipid and embedded in a microscopic cage-like structure. In phase III trials, GSK’s malaria vaccine, RTS,S, incorporating a QS-21 adjuvant, reduced deaths from malaria by one third. The vaccine is currently being rolled out to children in Benin, Burkina Faso, Cameroon, Ghana, Kenya, Liberia, Malawi and Sierra Leone. And next year, UNESCO and Gavi, the vaccine alliance, plan to distribute further doses in Uganda and the Democratic Republic of Congo. As other countries in Africa add the vaccine to their childhood immunisation programmes, WHO estimates that at least 40–60 million doses will be needed annually by 2026, growing to 80–100 million doses each year by 2030.
Even more promising is another malaria vaccine developed by the University of Oxford’s Jenner Institute and the Serum Institute of India. The vaccine, which was rolled out in the Ivory Coast on Monday (July 15) and will initially be given to infants up to 23 months of age, utilises a saponin-based adjuvant system known as Matrix-M. In phase III trials in Africa involving 4,800 children, R21/Matrix-M had an efficacy of 75 percent – the highest ever recorded for a malaria vaccine. With the World Health Organization’s approval, the Serum Institute has already manufactured 25 million doses for distribution in Africa, with a further 100m doses planned next year. The vaccine has also been authorised by Ghana, Nigeria, Burkina Faso and the Central African Republic.
Matrix-M is the brainchild of a US vaccine company, Novavax, and employs a range of saponin fractions that include both QS-21 and QS-7. Because QS-7 is more abundant in the bark of Quillay, it is hoped that the R21/Matrix-M vaccine will prove more affordable for donor-funded immunisation programmes. In May, UNICEF delivered 43,000 doses of R21/Matrix-M to the Central African Republic, making it the first country to receive the vaccine for use in routine childhood immunisation. A further 120,000 doses are due to be delivered later this year.
“The R21/Matrix-M vaccine represents a paradigm shift in malaria prevention, says Adrian Hill, the director of the Jenner Institute and the chief investigator of the phase III trial. “Assuming we combine R21/Matrix-M with blood stage and transmission-blocking vaccines, we have a real chance of halving the mortality from malaria in Africa by the end of the decade.
Saponins, from the Latin word “sapo” (meaning soap), are plant-derived chemicals with the ability to form foams. Ground up and mixed with water, Quillay bark has long been used by the indigenous peoples of Chile as a shampoo and cleaning agent. Writing in 1782, the Jesuit priest Juan Ignacio Molina observed how “there is never to be seen on their clothes the least spot or dirt”. These same properties recommended saponins to manufacturers of detergents and hair-curling liquids and in the early 1900s the makers of carbonated drinks began adding soapbark to products like root beer to prevent the bubbles escaping.
In the 1950s, a crude saponin extract was added to veterinary vaccines but it proved toxic to humans, causing red blood cells to burst. Then, in 1991, an American research chemist used chromatography to separate some of the 100-plus fractions present in the inner bark of the Quillay tree and test them in mice. She found that QS-21 generated strong antibody and T-cell responses but showed high toxicity in animal models. QS-7 also triggered a strong immune response but with less toxicity. However, there wasn’t nearly as much of it.
By the 1980s the ability of saponins to stimulate adaptive immune responses by recruiting CD4 and dendritic cells was sparking the interest of HIV researchers. However, it wasn’t until 2005 that the first saponin-based adjuvant, known as ASO1, was approved for human use. In 2019, GSK added the adjuvant to it shingles vaccine, Shingrix. The vaccine conferred immunity in 91 percent of people over 70 years old, more than double that of previous shingles vaccines. Two years later, in 2021, GSK added AS01 to its RTS,S vaccine (Mosquirix) and it became the first vaccine endorsed by the World Health Organization for the prevention of malaria.
But while the RTS,S and R21/Matrix-M vaccines have raised hopes for the elimination of malaria, that will only be possible if suppliers can guarantee a continuous pipeline of QS-21 and QS-7. But extracting the QS fractions from Quillay bark is a laborious and expensive process: a single gram of QS-21 can cost as much as $100,000; moreover, only five out of 100 Quillay trees contain sufficient QS-21 to make the process commercially viable.
Under Chilean law, landowners need a special permit to fell Quillaja trees but are permitted to prune up to 35 percent of their biomass every five years. To encourage compliance, CONAF, Chile’s National Forestry Corporation, has set up zones for managed pruning but the zones are difficult to regulate and some people have been abusing the system.
Nevertheless, thanks to CONAF and innovations by producers like Desert King, the outlook today is much better than in 2011 when researchers estimated that the global supply of QS-21 was sufficient for just six million doses of vaccine.
Chile harvests 240 tons of Quillay annually, which is sufficient for around 158,000 grams of QS-21 or 3.2 to 6.4 billion adjuvant doses, depending on the requirements of the vaccine (Shingrix requires 50 micrograms of QS-21 per adjuvant dose, whereas other vaccines require just 25 micrograms per adjuvant dose). However, most of Chile’s bark output is designated for non-pharmaceutical uses – crude saponins that do not require the same level of refining – and, because supply is limited, the price of medical-grade saponins has been rising.
Desert King is one of the few producers specialising in pharmaceutical-grade saponins. To meet the Serum Institute’s requirement for 200m adjuvant doses of R21/Matrix-M annually, Hiley estimates the company will need to harvest up to 15 tons of Quillay bark a year.
“By setting up plantations in Chile with trees that are rich in QS-21 we are confident of being able to supply the needs of the Serum Institute and other vaccine manufacturers going forward,” says Hiley. “Done properly, the tree keeps regenerating, and it keeps offering biomass.”
However, concerns remain. Chile is in the middle of a devastating 15-year drought, straining freshwater resources to the limit and putting intense pressure on farmers and foresters. In the past, Quillay, which is adapted to the heat and thrives in the dry intermontane valleys and sclerophyllous forests lying between the Andes and the Pacific, has coped with these unusual conditions. But now, throughout the Casablanca Valley, it is common to encounter dessicated trees that have shed their leaves.
Adding to pressure on the tree are wildfires, like the one that tore through the Casablanca Valley in February, coating Valparaiso in ash and destroying Vina del Mar’s world-famous botanical garden. The blaze was a particular blow to Desert King as it had just planted 100 hectares of the garden with Quillay.
By leasing land from local farmers, pruning the trees at regular intervals and extracting saponins from the branches, as well as from the bark, Desert King hopes to increase the yield of saponins while staying within official harvesting limits. This requires careful management, however. “Sometimes you can see the trees are struggling from drought and are surviving but not growing,” says Javier Gonzalez.
The central zone of Chile supports extraordinary levels of endemism: more than 691 species of plant are found here, 35 of which are unique to the region. However, conditions are making the cultivation of Quillay increasingly difficult.
To illustrate the challenge, Gonzalez takes me to a Desert King plantation on a farm high above the Casablanca Valley. Here, the summer sun can be fierce and in winter a brisk northerly wind adds to the dryness. It does not take him long to locate the skeleton of a tree that has shed its leaves and another where all that remains is the stump.
Gonzalez breaks off a section of the bark and shows me where the saponins would normally be visible on the inside. Next, he takes me to a lone Quillay tree in a cactus grove and another surrounded by boldo trees. Pneumos boldo is the source of boldine, a natural anti-inflammatory, and is used in traditional Chilean medicine to treat hepatic and gastrointestinal diseases. By planting Quillay alongside Boldo, Desert King hopes to replicate the biodiversity of the sclerophyllous forest, Quillay’s natural habitat.
At present, Desert King has 42 hectares under cultivation in the Casablanca valley and 400 hectares in southern Chile. To meet rising demand for saponins from vaccine manufacturers, it is aiming to double the size of its Casablanca plantations to 90 hectares by 2026.
The Serum Institute is not the only pharmaceutical company counting on a continuous supply of saponins for its vaccines. Last month (May), the French vaccine-maker Sanofi Pasteur signed a $1.3 million licensing deal with Novavax that saw the struggling biotech company’s share price double overnight. Novavax originally developed the Matrix-M system for its Covid vaccine, Nuvaxovid, as part of Operation Warp Speed, the US initiative to fast-track emergency vaccines during the pandemic.
The deal will not only allow Sanofi to market Nuvaxovid as part of a co-exclusive licensing deal with Novavax but enable it to develop vaccines for other diseases in its portfolio, such as influenza, hepatitis and the human papillomavirus and (HPV), using the same Matrix-M system. Because of QS-21 and QS-7’s ability to stimulate innate and adaptive immune responses, it is also hoped that Matrix-M and similar saponin-based adjuvant systems could prove beneficial in the treatment of cancers and degenerative disorders, such as Alzheimer’s disease.
Thanks to an agreement signed with Desert King during the pandemic, Novavax says it is confident of being able to meet the Serum’s Institute’s requirement for 100m doses of R21/Matrix-M next year and in subsequent years.
“During Covid we were prepared to make two billion doses of Nuvaxovid so we don’t have any concerns about being able to produce the volume needed by the Serum Institute,” said Novavax.
The Serum Institute is offering the vaccine at less than $4 a dose. By comparison, RT,S,S costs around $10 a dose.
“The roll-out of the R21/Matrix-M malaria vaccine marks the start of a new era in malaria control interventions with the high efficacy vaccine now accessible at a modest price and very large scale to many countries in greatest need,” says Hill.
But what if there were further wildfires in the Casablanca valley or drought and illegal logging reduced Chile’s stores of Quillay to the point where Desert King and other suppliers were unable to harvest sufficient Quillay to meet the needs of vaccine manufacturers?
In anticipation of that eventuality, biotech companies have begun developing synthetic saponin lines. Last year (2023), SaponiQx , a subsidiary of the Massachusetts-based biotech, Argenix, announced it had succeeded in making QS-21 by extracting saponins from the cells of the Quillay plants that had been cultured in large bioreactors. Its formulation, known as STIMULON QS-21, is already used in vaccines for shingles, malaria and respiratory syncytial virus (RSV), and in a recent press release the company said its platform had the potential to “significantly bolster the global vaccine supply chain for QS-21 without reliance on the traditional tree-bark extract process”.
Meanwhile, plant scientists at the John Innes Centre in Norwich recently elucidated the biosynthetic pathways by which Quillay makes saponins by sequencing the tree’s genome and inserting the genes involved in the production of precursor enzymes into a wild relative of tobacco. According to Anne Osbourn, who lead the team that made the breakthrough, it took twenty steps to produce the precursor molecule for QS-21 in the leaves of the tobacco plants.
So far, Osbourn’s team has only made small quantities of QS-21, but she is already talking to pharmaceutical companies interested in scaling up production. “We’re only at the beginning of being able to assemble these saponin pathways,” she explains. “What’s important is that we can already generate enough material in the lab to test for adjuvant activity.
Malaria researchers are hopeful that such breakthroughs could stimulate further research into QS-21 and other saponin fractions with adjuvant activity. This could avoid potential supply problems as the global demand for vaccines employing saponin adjuvants increases.
The market for QS-21 and other immune-boosting fractions is potentially enormous. In addition to the 100m doses of R21/Matrix-M that the Serum Institute is aiming to deliver next year, GSK has pledged to manufacture 18m doses of RTS,S by 2025. But this pales in comparison with the billions of doses of saponin-based adjuvants that could be needed in the event of another pandemic caused by either influenza or a coronavirus.
However, in the case of malaria, few experts, least of all Hill, think that vaccines alone will solve the problem. To realise the decades-long aspiration of eliminating the disease, we will also need to employ other tools, such as insecticide-treated bed nets to reduce mosquito transmission of the malaria parasite and treatment drugs, such as artemisinin-combination therapies, to clear the blood reservoirs in humans.
The worry is that during Covid progress on malaria stalled. In 2022, there were 249 million cases of malaria worldwide, five million more than in 2021, and today deaths are increasing in the worst-affected parts of Africa.
Now that we have two game-changing vaccines, the question is, are we prepared to grasp the nettle? At present, we spend nearly $5 billion a year on malaria control measures. By contrast, Hill calculates, 200m doses of R21 would cost $600m a year. Even supposing that to achieve elimination that investment would be needed every year for the next ten years, Hill argues it would prove a lot cheaper than continuing to manage transmission for another fifty years.
“Now we have these vaccines, there is a business case for really having a go at malaria,” he says. “It all comes down to funding and what choices we make.”
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