A fight in progress

The world is making progress in its fight against malaria, averting 1.5 billion cases of the disease and preventing 7.6 million deaths since 2000. This is largely thanks to a combination of several vector control tools, including insecticide-impregnated bed nets as well as antimalarial drugs.

While the aim remains to eradicate malaria, fighting the disease is difficult. Progress to meet the target of 90% reduction in cases by 2030 has slowed, particularly in the wake of the COVID-19 pandemic. “The challenge in Africa is how to get from controlling malaria to eliminating it,” says Professor Tiaan de Jager, Director of UP’s Institute for Sustainable Malaria Control. “Malaria parasites are becoming more resistant to antimalarial drugs and insecticide resistance in vectors is increasing, presenting another problem for malaria control.”

A shape-shifting menace

Perhaps the biggest challenge of all is the disease complexity itself. Malaria is caused by a Plasmodium parasite, which is spread by Anopheles mosquitoes. Plasmodium hides in the liver for weeks before infecting the bloodstream, which is when people begin to feel ill. Without antimalarial drugs, victims can experience delirium, high fever and, if left untreated, death. “Antimalarials save lives, but while they target blood-stage infections, they are poor at targeting other forms of the parasite such as transmissible gametocytes,” says Prof Lyn-Marie Birkholtz, Department of Science and Innovation (DSI) and National Research Foundation Research Chair in Sustainable Malaria Control at UP.

Researchers at the Universities of Pretoria and Witwatersrand, the Drug Discovery and Development Centre (H3D) at the University of Cape Town, and the Council for Scientific and Industrial Research have been working together to outwit Plasmodium falciparum, which is not only the most common type of malarial parasite, but the one responsible for the most deaths. 

Plasmodium parasites are “shape shifters” capable of taking on multiple forms, some of which cause the disease; while others allow the parasite to be transmitted back to mosquitoes and continue the life cycle, Prof Birkholtz explains. This makes them tough for our immune system to identify and target. One form, called gametocytes, makes it possible for malaria to be transmitted from humans back to mosquitoes again.

Compound interest

The massive collaborative effort across South Africa enabled scientists to grow gametocytes in the lab. By establishing this technology in the country, the team could expand drug discovery efforts beyond the blood stage, then look for new chemical compounds also capable of killing these gametocytes. 

One recent approach has been to use the Medicines for Malaria Venture and Drugs for Neglected Diseases initiative’s Pandemic Response Box, which contains a collection of 400 diverse drug-like molecules with previously reported activity against bacteria, viruses or fungi. With international partners, this box was screened for efficacy against liver-stage parasites, blood-stage parasites and gametocytes, enabling them to pinpoint compounds with potential for further development towards new drug candidates. 

The team discovered two potent compounds capable of targeting processes that are essential to the parasite’s survival, which they describe in a study published in Nature Communications. Unlike most antimalarials, these chemicals can kill several stages of the parasite and stop them from infecting the mosquitoes. “It’s the first time that we have chemicals that selectively block the transmission between humans and mosquitoes,” Prof Birkholtz says.

A potential game-changer

If this discovery leads to the successful development of new antimalarial drugs, Prof Birkholtz envisages they could be combined with other drugs and used to treat people with the disease while simultaneously preventing the spread of the parasite. 

For example, a patient could be treated for malaria symptoms at a clinic, but if any blood-stage parasites escape the treatment to form gametocytes, the new compounds could be “added on” to kill the gametocytes when they develop. This combination treatment offers hope in the face of drug resistance, because even if parasites evade compounds intended to kill them in the blood stage due to resistance, there is another chance to beat them as gametocytes.  

“We can then cure patients of the disease but, importantly, also block the malaria transmission cycle. This will be a major contribution to achieve malaria elimination.”

The future fight

South Africa aims to eliminate malaria by 2023, while the United Nations hopes that by 2030 the deadly disease will be consigned to history. This will be possible only with a multi-pronged strategy, which will likely include new drugs and a highly effective vaccine. In October 2021, the World Health Organisation approved the first malaria vaccine for widespread use among children in high transmission areas. While this offers some hope to families, the technologies behind the COVID-19 vaccine could also aid in the future fight against malaria. For example, BioNTech, a biotechnology company that worked with Pfizer on a COVID-19 vaccine, aims to develop the first mRNA-based vaccine for malaria prevention.

Prof Birkholtz says the large collaborative team’s breakthrough is the result of five years of technology establishment in Africa and she hopes it will enable more discoveries in the future, with the help of the group’s transdisciplinary approach. At UP alone, all faculties are involved in advancing the fight against the disease. “Everybody has specific experience that they can add and apply to malaria,” Prof De Jager explains. He believes that using innovative tools such as educational children’s books, high-tech fabrics and new drugs, malaria could be beaten within our lifetime. DM