The extraordinary biological complexity of malaria, which features a parasite with an elaborate life cycle involving two hosts — mosquitoes and humans — may be a scientific challenge but it presents medical researchers with many potential opportunities to stop the disease in its tracks.
Scientists are targeting the Plasmodium parasites at various stages of development inside insects and humans with genetic and chemical weapons, as well as finding new ways to attack the Anopheles mosquitoes that carry them between people.
The need for new treatments is becoming urgent as the parasite evolves resistance to the most effective drugs available: compounds based on artemisinin, a herbal derivative originally developed as an antimalarial in 1970s China. These have largely replaced the traditional remedy of quinine as first-line treatment for severe malaria.
A large-scale clinical study of four artemisinin combination therapies (ACTs) in west Africa, published in medical journal The Lancet last month, confirmed that all work well and safely in children and adults. That finding “underscores the importance of protecting these highly effective drugs from resistance”, says David Reddy, chief executive of Medicines for Malaria Venture. MMV, a public-private partnership, has a portfolio of eight new drugs in clinical development. One of the most promising is KAF156, which Novartis, the Swiss company, is developing with MMV and charities including the Gates Foundation and Wellcome Trust. Five hundred adults and children with malaria are taking part in a two-year trial across Africa and Asia. They will take KAF156 in combination with an old antimalarial called lumefantrine.
Resistance to ACTs is spreading rapidly in south-east Asia. A study led by the Wellcome Sanger Institute, a non-profit British research body, and published in February in The Lancet Infectious Diseases, traces this to two genetic mutations in Plasmodium that combined in western Cambodia during 2008. The drug-resistant parasite then spread through the region for five years, unnoticed by health workers, until the outbreak became apparent in 2013.
“Malaria policymakers now face a dilemma,” says Roberto Amato, first author of the paper. “On one hand, malaria remains treatable and its prevalence has been reduced to low enough levels to aim to eliminate the disease in Cambodia and neighbouring countries. However, the situation is fragile, and it is unclear how the parasite population will evolve in response to new interventions.”
Dr Amato adds: “While it would be catastrophic if resistance developed in the same way for the last remaining anti-malarial drugs, it is now possible to conduct genetic surveillance of malaria cases, allowing researchers to respond as soon as possible to changes in the parasite population.”
An intriguing prospect is to produce a treatment that can kill both parasites and mosquitoes at the same time. A clinical trial in Kenya suggests that this could be achieved by supplementing ACTs with ivermectin, an old drug discovered in the 1980s that is used extensively to kill parasitic worms in tropical diseases such as river blindness.
The study, published last month in The Lancet Infectious Diseases, shows that multiple high doses of ivermectin, paired with a standard ACT, can kill mosquitoes feeding on humans for at least a month after treatment. Modelling suggests that the addition of ivermectin to antimalarials could cut malaria prevalence by half, and help to eliminate the disease in some regions.
“This is the first study to show the safety and efficacy of multiple high doses of ivermectin on mosquito mortality,” says Menno Smit of the Liverpool School of Tropical Medicine, who led the research. “Despite these encouraging findings, further rigorous safety and efficacy trials in younger age groups are needed before high-dose ivermectin can be administered at scale.”
Scientists are using new research tools to find other antimalarial compounds. A recent example is the discovery — made by a “robot scientist” called Eve at Cambridge university — that triclosan, an anti-bacterial chemical often incorporated in toothpaste, could be effective against drug-resistant malaria.
Using artificial intelligence and automation for rapid testing, Eve found that triclosan attacks Plasmodium by inhibiting two of its vital enzymes, DHFR and ENR. Results were published in the journal Scientific Reports.
“The discovery by our robot colleague Eve that triclosan is effective against malaria targets offers hope that we may be able to use it to develop a new drug,” says lead author Elizabeth Bilsland. “We know it is a safe compound, and its ability to target two points in the malaria parasite’s lifecycle means the parasite will find it difficult to evolve resistance.”