Malaria, man and mozzie: scientists fight deadly parasite on two innovative fronts

Hundreds of thousands of people die from malaria infection every year, but recent advances in labs around the world show promise for cutting mortality.

Malaria is a disease caused by five species of Plasmodium – single-celled, parasitic protozoans – which make their way into their human hosts via an animal vector, usually a mosquito. The disease is life-threatening, with symptoms including fever and headache. In severe cases, symptoms can escalate to cognitive impairments, loss of consciousness and breathing difficulties.

Treatments are available, selected by clinicians based on the type of parasite, but antimalarial resistance has recently emerged as a challenge to medical care.

Preventative measures include the use of insecticide-treated netting and indoor spraying, chemoprophylaxis drugs (antimalarial medications) and preventative chemotherapies and, since 2021, vaccines.

What differing approaches to malaria tell us

Until recently, the only approved vaccine was RTS,S/AS01 – trade name Mosquirix – which is recommended for use by the World Health Organization in regions with moderate to high Plasmodium falciparum infection rates. It’s delivered intravenously to children aged four months to three years of age in four doses.

While it targets the most prevalent (and deadly) of the five malaria-causing Plasmodium species, P. falciparum, it’s only effective about 30% of the time.

Another Oxford-developed, protein-based vaccine recently received approval for use in children in Ghana. In Phase 2 clinical trials, the R21/Matrix-M vaccine was effective 77% of the time.

Vaccines against the parasite are the final tool in the fight against malaria for nations looking to slash the health and economic burden caused by the disease, and save lives.

“We basically know, for any infectious pathogen that’s not under control, it’s always going to disproportionately adversely impact lower socioeconomic populations,” says Professor Gavin Painter from Te Herenga Waka-Victoria University of Wellington’s Ferrier Research Institute.

Along with colleagues at the NZ-based Malaghan Institute and Doherty Institute in Melbourne, Painter is developing a prospective mRNA vaccine to combat Plasmodium sporozoites that progress to the liver.

While existing vaccines try to catch sporozoites when they’re released into the bloodstream via the needle-prick of a mosquito’s proboscis, this Trans-Tasman candidate – the subject of research published today in Nature Immunology – instead aims to generate an immune response from T cells that reside within the liver. These killer T cells find and eliminate infected liver cells called hepatocytes.

While it’s only been tested against Plasmodium species that infect mice, the target gene coded by the vaccine is near-identical to those of their human-infecting cousins. The aim will be to create mRNA vaccines that can be stored and used in similar ways to those developed in response to the COVID-19 pandemic.

“We’re looking to design our vaccine so it’s very similar to all of the COVID-type vaccines that we got during the pandemic, and that’s because we want to be able to leverage all of that manufacturing infrastructure and ‘know how’,” Painter says.

“mRNA vaccines are, generally, really, really good at making T cell responses. For COVID-19, the predominant protective mechanism was the neutralising antibodies, and what people probably didn’t understand or really know was that there was an underlying T cell response there: in the end, when the strains weren’t matched [to the vaccine], the T cells were still having a positive effect, they were stopping people getting really, really sick.”

“I think that’s a key point. We’re using the T cell component that mRNA vaccines are really well suited to generating.”

The next step for the Ferrier-Malaghan-Doherty candidate is to progress testing over the coming years in, potentially, primate models, and eventually human clinical trials.

Suppress the malaria vector

While vaccinologists develop new ways to attack the parasite in the human body, others are looking at ways to try to attack Plasmodium within the mosquito itself.

Gene drives have long been investigated as ways of modifying animal or plant populations to confer advantageous genetic characteristics. In places like Australia, they’ve been considered as means to control mouse plagues and feral animals.

Recently, researchers have developed a system that suppresses females being born within African mosquito species. Such a process, if implemented in real-world populations, would effectively guide these parasite-vector species towards a reproductive dead-end.

But mosquitoes, at best an annoyance and at worst a transmitter of deadly disease to humans, also provide important, hidden ecological services. They’re pollinators, as well as a food source for many other animal species. So knocking deadly mozzies out of ecological systems could lead to equally deadly knock-on effects in malaria-plagued nations.

Other scientists around the world have focused on developing similar gene systems that are passed by mosquitoes to their offspring.

One group in California is trying to get genes to produce antibodies that attack Plasmodium within the mosquito itself. Epidemiological modelling performed by the researchers suggests the introduction of modified species could reduce the incidence of malaria by more than 90% within three months.

Such technology, the authors from the University of California suggest in their research, would complement emerging vaccines to combat malaria’s persistence in tropical parts of the world.

Researchers like Painter see new vaccines being used in combination, and alongside other preventative measures, to target malaria parasites throughout their lifecycle once they enter the body.

Together with advances in gene editing technology, societies around the world may soon find the most advanced tools yet available to prevent the spread of the deadly disease, and without relying on treatments liable to wane in their effectiveness, and the environmental dangers posed by insecticides.