WHY THE FIGHT AGAINST MALARIA IS HAVING A ‘RED QUEEN’ MOMENT
As Alice and the Red Queen run towards a chessboard in Lewis Carroll’s childhood classic, the wind whistling in their ears, the little girl makes a curious discovery: despite running very fast for a very long time, she hasn’t actually moved.
The Red Queen appears unfazed. “Here, you see, it takes all the running you can do, to keep in the same place,” she explains. “If you want to get somewhere else, you must run twice as fast as that.”
For malaria researchers and practitioners, this sensation feels all too familiar. Despite several exciting advances, efforts to tackle the parasitic pathogen have stalled since 2015: then, according to the World Health Organization (WHO), 586,000 people died from the disease; in 2022, it killed 608,000.
“It really does seem like a Red Queen scenario, we do an awful lot of running [to] make small steps forward,” says Prof Chris Drakeley, a professor of infection and immunity at the London School of Hygiene and Tropical Medicine.
That’s because both the malaria parasite and the mosquitoes which spread it are wily opponents, constantly evolving to evade efforts to wipe out the disease. “Any organism, when you put pressure on it, will change,” Prof Drakeley says. “I think the challenge at the moment is really: how do we deal with these changes?”
Three biological threats are of particular concern to experts grappling to eradicate malaria: stealth parasites, super mosquitoes, and mounting resistance.
“Right now we are in this sort of turning point moment, where it could go either way,” says Prof Olivo Miotto, a malaria genomics expert at the Mahidol-Oxford Tropical Medicine Research Unit in Bangkok.
Stealth parasites
The first issue affects diagnostics. In 2010, researchers in the Peruvian Amazon detected an unusual mutation: some parasites no longer had HRP2 proteins, which many lateral flow tests use to detect malaria. This meant cases could be missed, giving the disease – and the genetic quirk – space to circulate.
Since then, the deletion has spread across continents. While prevalence estimates vary, a concerning hotspot has emerged in the Horn of Africa – some studies have suggested as many as 80 per cent of asymptomatic cases in Djibouti and Eritrea have could not be picked up by rapid diagnostics reliant on the HRP2 and HRP2 protein. In 2022, according to the WHO, 415.5 million such tests were sold worldwide.
“There’s a different antigen [test] to pick this up, but it’s not as well researched and developed,” says Dr Stephen Woolley, an honorary clinical researcher and malaria specialist at the Liverpool School of Tropical Medicine. “WHO is trying to validate these newer tests… but I think this could be a really big challenge to global health and malaria control.
“We’re seeing that in the Horn of Africa, and it’s now spreading to Kenya and Uganda,” he says, adding that doctors have also identified the issue in clinics in Britain. Earlier this week, the UK Health Security Agency said the number of malaria cases diagnosed here among travellers exceeded 2,000 for the first time since 2001.
But the deletion does not mean the malaria parasite is “under an invisibility cloak”, says Prof Drakeley, as cases can still be diagnosed in the laboratory. He is optimistic that the issue – which affects only a tiny proportion of global malaria infections – can be contained, and that newer rapid diagnostics to solve it are on the horizon.
Super mosquitoes
Super mosquitoes have also emerged and appear to be driving an unexpected surge in malaria across the Horn of Africa. Combined with the changing parasite, the impact could be terrible.
“The genotype of the parasite, mixed with Anopheles stephensi [mosquito]… is a recipe for disaster potentially in Africa, and could make elimination extremely difficult,” says Dr Woolley.
Unlike the Anopheles gambiae mosquito, the most widespread carrier of malaria, the highly adaptable Anopheles stephensi thrives in urban areas and breeds almost anywhere – in a dirty puddle between slum shacks, a rubbish dump, or even water in an abandoned car tyre.
It also survives in high temperatures in dry seasons, when malaria transmission usually lulls.
Native to parts of Asia and the Arabian peninsula, its arrival in Africa has triggered concerns that the burden of disease could shift from rural to urban areas. It was first spotted in Djibouti in 2012, and was a key driver of a 2,800 per cent surge over the next eight years.
It has since spread to countries including Ethiopia, Somalia and Nigeria, while the WHO has described it as a “threat to malaria control and elimination”, especially in African megacities.
“There’s clearly a concern around the arrival of the anopheles stephensi in Africa and the impact of that is still, in my view, extremely uncertain,” says Prof Nick White, a professor at the Mahidol-Oxford Tropical Medicine Research Unit, who specialises in malaria.
“It’s a worry because we have an increasing change in the demography in Africa, with a move from rural areas to cities. It follows that a city-dwelling mosquito would do quite well – but it’s not a fantastic vector.”
But with the stephensi, “it feels like for once we are above the curve”, says Dr Jackie Cook, co-director of the Malaria Centre at the LSHTM. The vector was detected early, surveillance networks have been established, and vector control efforts are ramping up.
Resistance
The same cannot be said for drug and insecticide resistance, which have repeatedly emerged.
“We’re a little bit slow at having new things coming through the pipeline, we never seem to be ahead of the curve,” she warns. “We’re always waiting for something bad to happen, and then we react to it.”
There are two forms of resistance: resistance among mosquitoes to insecticides, and resistance among parasites to antimalarial drugs.
In the WHO’s latest malaria report, published in November, the agency warned that 87 per cent of countries have reported some resistance to pyrethroid-based insecticides, 82 per cent to organochlorines, 69 per cent of carbamates, and 60 per cent to organophosphates.
This problem has not emerged overnight – reduced efficacy of pyrethroid, which is used on bednets, was first noticed more than a decade ago. While there have been efforts to rotate or mix insecticides, it was not until last year that the WHO updated its recommendations to also use chlorfenapyr – the first insecticide in some 40 years, which grounds mosquitoes by causing their wings to spasm.
This has proven to be incredibly effective: a study earlier this month found that the rollout of the potent insecticide has prevented at least 13 million cases in Africa.
Dr Cook says the new insecticide coated bednets are “fantastic”, but is concerned they will lull us into a false sense of security.
“It feels like we’re all piling on chlorfenapyr – lots of companies are pivoting because it’s been shown to be more effective, which creates more competition and brings prices down. But what’s next? Will we find ourselves in the same situation 10 years down the line? There doesn’t seem to be much else coming through the pipeline.
“We’re spending all this money monitoring the situation, but we should have put a lot of that money into developing the new tools,” Dr Cook adds. “I think we’ve done things badly in terms of insecticide resistance. The concern is we do the same with drug resistance as well.”
This would be a major blow. At the moment, doctors are predominantly reliant on artemisinin-based treatments to tackle malaria – between 2010 and 2022, more than four billion courses were delivered to clinics by manufacturers.
Currently, the WHO describes the status as “partial resistance” – drugs still work, just more slowly. But the issue is spreading, having jumped from the Greater Mekong Region where it was first noted, to Africa.
“We rely entirely on artemisinin combination treatments, of which there are over half a billion treatments given each year,” says Prof White. “If we lose these, we’re in serious trouble – because despite all the large investments in antimalarial drug discovery in the past 20 years, we’ve been rather unsuccessful.
“There are new drugs that could save us – candidates from Novartis look most promising – but they are still three to five years away,” he says.
He adds that efforts are underway to reduce the rise of resistance – such as using two other drugs alongside artemisinin, not just one, and encouraging people to finish their course. But this is likely only “sticking a plaster” on the issue – at some point, full resistance will spread.
Slither of light – and age-old issues
Of course, it’s not all doom and gloom, and there have been huge steps forward in efforts to eradicate malaria.
Most significant is the rollout of two new malaria vaccines: in July 2022 GSK’s RTS,S shot, also known as Mosquirix, was approved, followed by Oxford University’s R21 immunisation in December. Experts say these shots, which are around 75 per cent effective at preventing the disease in areas where transmission is seasonal, could save tens of thousands of children’s lives every year.
“The vaccine is the latest ‘shiny thing’ for humans, but alone it’s not going to end malaria transmission,” says Prof Drakeley. “But it will save lives… it’s a nine per cent reduction in all cause mortality in children, that’s massively impressive.”
Other exciting tools – from gene drive mosquitoes to spatial repellents for homes and buildings – are also emerging, with researchers describing it as an “exciting time” to be in the malaria field.
Countries are also containing the disease: in 2023, Azerbaijan, Belize and Tajikistan all eliminated the parasitic pathogen, joining 40 other countries certified as malaria-free, while regions like southeast Asia – where the disease once thrived – now have minimal infections.
Yet there are concerns that the funding needed to replicate these successes is dwindling – according to analysis from Malaria No More and the Oxford Economics Group, the proportion of global research and development funding dedicated to malaria has fallen from $707m in 2019 to $604m in 2022.
“Governments, research institutions and funding organisations must keep their foot on the accelerator to continue fostering novel interventions and treatments to maintain a robust malaria pipeline for the future,” says Gareth Jenkins, an executive director at Malaria No More UK. “If we don’t, this disease can thrive again.”
There are other “not very politically digestible” issues too, says Prof White, “such as incompetence, corruption, fabrication of data, wrong results – all those sorts of things that no one ever talks about, but are actually quite important”.
And then there are the broader societal issues – including climate change, extreme weather events, conflict and mass migration – that could derail eradication efforts, providing opportunities for malaria to thrive and new obstacles to deliver services.
“The playground for this disease is basically social circumstances – it’s poverty, lack of resources, lack of accessibility to the really basic health services,” says Prof Miotto. “And in that sense, the failure of rapid tests or partial artemisinin resistance makes little difference if you don’t have any rapid tests, and you don’t have any drugs. We can’t lose sight of the basics.”
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2024-04-25T11:43:44Z dg43tfdfdgfd