How to cure a problem like malaria
Vaccines incorporating novel adjuvants present the best chance in 50 years of eliminating malaria. All that is required is determination and money.
You know what it’s like – you wait fifty years for a game-changing malaria vaccine, then two come along at once.
As delegates gather at the 8th Pan-African Malaria Conference in Kigali on World Malaria Day, expectations are high that this could be the decade that we finally make serious in-roads into malaria – a parasitical disease that kills 625,000 people a year, the majority of them women and children in Africa.
The mood at the conference will be buoyed by the latest phase III trial data of the University of Oxford’s R21/Matrix-M vaccine. In February, the Jenner Institute announced its vaccine had a 78 percent efficacy in children aged five to seventeen months – surpassing the World Health Organization’s licensing threshold of 75 percent efficacy.
The vaccine, which is administered in four consecutive jabs, also provides strong protection in older age groups, and is now in the process of being rolled out in Cameroon and Burkina Faso.
Adrian Hill, the director of the Jenner Institute and the chief investigator of the phase III trial, told me his vaccine could halve mortality from malaria in Africa by the end of the decade.
"The R21/Matrix-M vaccine represents a paradigm shift in malaria prevention. Assuming we combine R21 with blood stage and transmission blocking vaccines, our chances of making a real impact on malaria in the next decade are very high.”
Even before the World Health Organization completed its review of the phase III trial data, Uganda, Ghana and Burkina Faso announced they would approve the vaccine. This follows the WHO’s approval in 2021 of another malaria vaccine, RTS,S.
Manufactured by GSK, RTS,S incorporates similar technology to R21. In Kenya, paediatric admissions for severe malaria have fallen significantly since the vaccine was introduced four years ago under a WHO-coordinated pilot scheme. However, at $9 a dose, it is three times as expensive as R21 and has a lower 36 percent efficacy.
It is also unclear how committed GSK is to manufacturing RTS,S at the scale necessary to make a serious dent in malaria transmission in Africa. So far, GSK has promised to deliver 18 million doses of RTS,S – which goes by the brand name Mosquirix - by 2025, with four million doses available by late 2023, six million doses delivered in 2024, and eight million in 2025. But after 2025, the Indian company Bharat Biotech will become responsible for the vaccine’s manufacture. Although Bharat is aiming to up production to 15 million doses a year, Hill calculates this will fall well short of the amount required.
“Forty-five million children are born each year in malarious parts of Africa,” he told me. “They each need four doses – so, times by four and that’s 180 million doses. But not every dose goes into an arm, so you really need about 200m doses for moderate to high transmission areas.”
Another complication is that both vaccines employ adjuvants incorporating saponins – compounds which, at present, can only be obtained from the bark of the Chilean soapbark tree, Quillaja Saponaria.
Hill has partnered with the Serum Institute of India to produce 200 million doses of R21 a year – more than enough to protect children in areas of seasonal and year-round transmission. But because of the demand for saponins across industry – saponins are also a key ingredient in cosmetics and food and beverage products – there are question marks over Chile’s ability to meet the needs of vaccine manufacturers.
Desert King, a San-Diego based extractor which is the world’s largest supplier of saponins from plantations in Chile, currently harvests around 10,000 tons of trees a year. But only five out of 100 soapbark trees contain enough of the bioactive saponin fractions – known respectively as QS21 and QS7 - to make their extraction commercially viable.
And the extraction process is expensive – for instance, a single gram of QS21 costs between $80,000 to $120,000, making it pricier than cocaine. And although Desert King has begun planting more soapbark trees to meet demand, it takes five to ten years for a tree to reach maturity.
It is difficult to say how important the adjuvants are to the efficacy of the vaccines. RTS,S uses an adjuvant known as ASO1 containing mainly QS21, while the Matrix-M adjuvant contains a mix of QS21 and Q7.
Another difference is that while both incorporate particles that target the sporozoite phase of the parasite’s life cycle - the phase in which it enters the human body from its mosquito host and infects the liver - in the case of R21, the particles are formed from a single circumsporozoite (CSM) protein fused with a hepatitis B surface antigen. This results in a much higher proportion of CSP than RTS,S.
However, because QS7 is more abundant in the bark of the Quillay tree, Matrix-M is cheaper and easier to make, raising hopes that the price of R21 can be kept low enough to make it affordable at scale for donors to malaria immunisation programmes.
“There are people out there saying, Oh, you’re just topping up the supply of RTS,S,” says Hill. “ Well, yes, but what we’re doing is more than topping up. It’s doing the job.”
That job is formidable. The reason it has taken 50 years to reach this point is that malaria is a shapeshifter, taking on different forms at each stage of its lifecycle and changing the proteins on its surface to escape the immune system.
Few experts, least of all Hill, think that vaccines alone will solve the problem. To realise the dream of eliminating malaria, we will also need to employ other tools, such as insecticide-treated bed nets to reduce mosquito transmission of the parasite and treatment drugs, such as artemisinin-combination therapies, to clear the blood reservoirs in humans.
However, following the Covid pandemic, progress against malaria has stalled. In 2022, there were 249 million cases of malaria worldwide, five million more than in 2021, and deaths are rising again 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, it would be a lot cheaper than managing transmission for another fifty years.
“Now we have these vaccines, there is a business case for really having a go at malaria,” says Hill. “It all comes down to funding and what choices we make.”