The role of mutations in PfK13 in malaria pathogenesis and its dependence on the malaria vaccine RTS,S and mosquitoes

Despite such obstacles, there are reasons to be hopeful. The researchers are creating ways to stop and treat the disease. The first vaccine for Malaria has been one of the biggest advances in the past few years. In a handful of countries in Africa, there is a new children’s product calledRTS,S, which has people hoping it will benefit soon. But there is room to improve. Researchers are pursuing several alternative vaccines, including some that target the Plasmodium falciparum parasite at different points in its life cycle. The need for vaccines against other species is also present. There are some people that think that the use of monoclonal antibodies could be used for protection. Others are taking aim at the mosquitoes that transmit the parasites, and also exploring the possibility of using a gene drive to suppress or replace mosquito populations.

The design of the drugs might have an impact on the speed at which this happens. Some mechanisms of action will be easier for parasites to resist than others. Typically, the more important the function is to Plasmodium, the less likely it is that the parasite will develop resistance to the drug that interferes with it. “It is feasible to target essential biological processes within the malaria parasites using multiple drugs so that the development of resistance is either severely delayed or reduced to a very small possibility,” says Sharma.

Researchers have linked artemisinin resistance to mutations in the PfK13 gene. The parasites have an inability to breakdown haemoglobin and reduce iron levels. Because iron seems to be involved in activating artemisinin, the lower levels probably reduce the drug’s effectiveness3. So far, around 20 mutations in PfK13 have been linked to artemisinin resistance, but this might not be the whole story. “It is possible that other mechanisms, which have not yet been identified are playing a role — or will do so in future,” says Philippe Guérin, an epidemiologist at the Infectious Diseases Data Observatory in Oxford, UK.

The deployment of ACTs has made it clear that there is a strong basis for this concern. The first-line drug was a combination of artesunate and partnerdrug sulfadoxine and pyrimethamine. In three years, Sharma says, resistance to that combination had emerged in northeast India, requiring the combination to be changed to artemether and lumefantrine.

In Phase II trials, the combination was given daily for three days to see how well it works against parasites. Guérin says that Efficacy may meet the high bar set by ACTs. The Medicines for Malaria Venture and Swiss pharmaceutical giant Novartis started a phase III trial. Results are expected by 2025.

Some of those being tested by research groups, including Sharma’s, target a key enzyme involved in the parasites’ protein synthesis, called aminoacyl transfer RNA synthetase. He adds that other mechanisms are also involved. It is possible for non-artemisinin-based drugs to target signalling pathways that are crucial to the invasion of the host’s red blood cells by parasites, or the processes involved in making key components of the parasites’ survival.

In Rwanda, parasites with one PfK13 mutation, which is associated with delayed clearance, were found in the blood of one in five people taking part in an antimalarial drug trial in the capital Kigali between 2018 and 20195. Uganda and Eritrea have also reported mutations linked to resistance. The partner drug lumefantrine is still Effective and Failure rates in Uganda have remained below 10%.

The impact on individuals seems small for now, according to Wells. Longer clearance time gives parasites more opportunities to develop resistance, which could cause more dire consequences. The combination doesn’t work if the partner drug fails.

The clinical consequence of artemisinin resistance is that instead of parasite clearance taking three days it can, in some cases, take up to a month, says Tim Wells, chief scientific officer at Medicines for Malaria Venture, a non-profit organization in Geneva, Switzerland.

There are only five species of parasites that cause Malaria in people. Treatments depend on which species a person is carrying, and most cases are caused by either Psythmia or Psythmiavivax.

The first-line treatment is usually chloroquine. This is a synthetic version of quinine, which is derived from the bark of cinchona trees. When it was first introduced, chloroquine was used to kill P. falciparum, the most prevalent Malaria in Africa. But over time, there was resistance. P. falciparum mutated in a way that helped it to clear the drug from its system, reducing its effectiveness and forcing a change of tack. Artemisia annua, isolated from the plant sweet wormwood, is a compound that artemisinin is based on.

We are pleased to acknowledge the financial support of Ehime University (PROS), Medicines for Malaria Venture, Nagasaki University and Malaria No More Japan with funding from the Bill & Melinda Gates Foundation, Sumitomo Chemical, GHIT Fund and Eiken Chemical, in producing this Outlook. As always, Nature retains sole responsibility for all editorial content.