Malaria is caused by five species of Plasmodium parasites. The most deadly, Plasmodium falciparum, jumped from apes to humans around 40,000 to 60,000 years ago¹.

The periodic fevers that characterise malaria have been recorded throughout history – from 2700 BC China, to texts from physicians around the world up to the 19th century. The earliest detailed Western accounts of the disease are from Hippocrates in the 5th century BC².

The first commercial treatment for malaria available in Europe, quinine, was extracted from the bark of the cinchona tree (called ‘quin’ by the Incas). Indigenous peoples of Peru used a tincture of cinchona tree bark to control fever, which was brought to Europe by returning Jesuit missionaries in around 1640. The active ingredient, quinine, was isolated in 1820, and became the predominant malaria medication at the time.

Pharmacological studies on quinine led to the development of more effective, synthetic compounds. One of these, chloroquine, was used extensively from the 1920’s. But by the 1950s, P. falciparum in parts of Southeast Asia and South America had developed resistance.

During the Vietnam War, both sides set to developing new drugs to protect soldiers who were succumbing to chloroquine-resistant malaria. ‘Project 532’ was initiated in China, unknown outside of the country at the time, to try and find new treatments to help the North Vietnamese³. Tu Youyou, working at the China Academy of Traditional Chinese Medical Sciences, Beijing, led work to screen Chinese herbs and traditional remedies. By 1971, her team had assessed over 2,000 traditional Chinese recipes and made 380 herbal extracts for testing.

They found one which was effective, from the sweet wormwood plant Artemisia annua. It had been used for ‘intermittent fevers’, a hallmark of malaria. Its preparation was described in a 1,600-year-old text, in a recipe titled “Emergency Prescriptions Kept Up One’s Sleeve”. In 1972, Tu and her colleagues extracted the active ingredient, and named it qinghaosu, or artemisinin. In 1981, she presented the findings at a meeting with the World Health Organization (WHO).

By this time, resistance to chloroquine was spreading. In South East Asia, there was a possibility that malaria would become untreatable, having evolved resistance to all available drugs⁴.  Artemisinin and artemisinin combination therapies (ACTs) were introduced in the 1990s. And in 2005, the WHO recommended artemisinin as the treatment of choice for falciparum malaria in endemic countries. Illness and deaths from the disease plummeted.

Professor Tu Youyou was awarded the Nobel Prize in Medicine in 2015 in recognition of her work and the millions of lives saved by her discovery.

It was first reported that artemisinin was becoming less effective in Cambodia in 2008⁵. Soon, artemisinin was seen to lose potency in other countries in the region too. The situation had worsened by 2013, as resistance to combination therapies was also reported.

In 2016, researchers based at the Sanger Institute who were also part of the MalariaGEN network, published research into piperaquine resistance in South East Asia. Piperaquine (related to chloroquine) was used in combination with artemisinin as a first-line treatment in several southeast Asian countries at the time. The combination of the two drugs was initially successful, but in 2013, research showed that malaria parasites in Cambodia had become resistant to both. A rise in the number of treatment failures in the country was recorded in 2016.

The researchers wanted to uncover the molecular markers of resistance in the parasites’ DNA. These could then be used to identify and track resistance across the region. The markers could also be used to understand the mechanisms of resistance – how was the parasite evading the drug. Underlying both those aims was a desire to support national malaria control programmes and provide information that could help public health officials decide if and when to switch treatments.

They carried out a genome-wide association study, looking at thousands of variations in the DNA of the parasites from Cambodia, comparing these across samples with different levels of resistance to piperaquine. This was followed up with laboratory studies. The team found two genetic markers linked with piperaquine resistance.

Now that specific markers in the genome had been identified, which could be looked for across the region, it would be possible to map how far the resistance had spread.

The MalariaGEN network, including organisations in malaria endemic countries and scientists across Africa and South East Asia, aimed to make the data available and useful for national malaria control programmes. This data sharing was vital so that they could rapidly deploy alternative therapies where possible and where needed, enhancing treatment for patients

Speaking at the time, Professor Dominic Kwiatkowski, who led the research, said:

“Our study shows that modern genomic surveillance can detect patterns of resistance much sooner than was possible in the past, providing vital information and allowing public health officials to respond as soon as possible. There is now an urgent need to provide national malaria control programmes with the tools for active genomic surveillance that will help to detect new emergences of resistance as soon as they arise and thereby reduce the risk of a major global outbreak.”

In South East Asia, different combinations of drugs, both with and without artseminin, are used in different countries – and are usually still effective⁸.

But multi-drug resistant parasites do exist, and their spread is worrying. Researchers are particularly concerned about the appearance of multidrug resistance in Africa, which has the highest malaria burden in the world⁹.

The MalariaGEN team at the Sanger Institute are working closely with colleagues in endemic countries around the world, to set up genomic sequencing and surveillance. This includes building and integrating laboratory and bioinformatics capacity to analyse the data. They have developed methods to quickly and easily analyse a parasite’s genome from a pinprick finger test of an infected person – with a system called SpotMalaria. A tiny blood spot is collected on filter paper, which can easily be stored and transported, even in remote areas.

Parasite DNA can be extracted and sequenced from the dried blood spot sample. Usually this happens at the Sanger Institute, but increasingly this is done locally too. Researchers across the MalariaGEN network have rapid access to the raw DNA data, as well as standard analysis in the form of a ‘genetic report card’. The report cards are periodically refined based on feedback from partners that use them in endemic countries. They show the parasite species present, as well as which drug or drugs it is likely to be resistant to.

Olivo Miotto is a professor at the MORU Mahidol Oxford Tropical Medicine Research Unit, Thailand, and has been working to implement genomic surveillance of malaria across South East Asia.

“When we were setting this up, we didn’t call it surveillance, we actually called it reconnaissance. The idea was that we were stepping into enemy territory by looking at the parasites rather than their effect on people. We wanted an early warning of what’s coming in terms of drug resistance, so we can stay ahead.”

In 2020 researchers in Vietnam reported on how genetic information, leveraging the SpotMalaria technology, has contributed to anti-malarial drug policy changes in several provinces¹⁰. There are challenges for integrating genomic information into policy and practice – there isn’t a one-size-fits-all approach – but it’s clear that it can make an impact¹¹.

However, MalariaGEN researchers are also acutely aware that while genomic surveillance is important, and will continue to be as malaria vaccines are introduced, it is only one weapon. Controlling malaria is about more than just treatments and resistance. Studies have shown that artemisinin combination therapies, which have a cure rate of over 95 per cent, may have as low as 20 to 40 per cent effectiveness in some areas, due to health system weaknesses. Underlying factors may include poor accessibility, poor compliance with clinical protocols, suboptimal patient adherence due to socioeconomic or cultural factors, or supply chain constraints, among others¹¹.

There are other interventions too, focused on the mosquitoes that carry the parasites from one person to the next. Bed nets, insecticides and environmental changes are all part of the picture.

National Malaria Control Programmes have a multifaceted challenge. Malaria-endemic countries need combinations of interventions that are integrated and tailored. MalariaGEN researchers aim to make genomic surveillance an easily accessible tool for those who need it.

“What we are working towards is elimination. And we don’t mean just the reduction of malaria – we really want those parasites to go away. We need to provide ever more targeted information that makes it possible for the control programs to more effectively intervene to eliminate them. For example, we have made great progress in the study of local outbreaks. As the systems become more informative for national control programs, we’re going to enable regional strategies of elimination.  If I’m out of a job in five years’ time, I’ll be very happy.” – Olivo Miotto.