More than 600,000 people – predominantly pregnant women and children under the age of five – die from malaria every year. According to the World Health Organization, one child in Africa dies from malaria every two minutes.

With drug resistance continuing to undermine malaria control, there is an urgent need for new drugs and strategies that can stop infections before they have a chance to take hold.

In the preclinical study published in Science, researchers developed a novel immunisation strategy that paired mosquito-delivered malaria parasites with an investigational class of antimalarial drug compounds, developed by WEHI and MSD.

The compounds blocked the parasite’s development at a critical stage of the malaria lifecycle, preventing disease and triggering a robust immune response that provided durable protection against malaria.

Subsequent mosquito bites then reinforced this immunity and protection.

Corresponding author and WEHI laboratory head Associate Professor Justin Boddey said the findings are an example of a drug candidate potently priming the immune system before disease could begin.

“Using this new drug compound, we’ve found a way to turn mosquito bites – the very thing that spreads malaria – into vaccination events in mice,” Assoc Prof Boddey said.

“This represents a shift in the way drugs could be employed to prevent malaria.”

The compounds were able to trap malaria parasites at the very end of liver-stage development – just before they enter the bloodstream and cause disease.

To date, there had been no drug treatment available that could arrest the parasite at this immunological sweet spot.

“This means the parasite was stopped just before it could cause illness, while giving the immune system a fuller preview of the potential threats,” Prof Boddey said.

“The immune response generated required only a very small dose of parasites but was broader and longer lasting than most current vaccine approaches.

“This is because our approach allowed parasites to amplify and then triggered both antibodies and CD8+ T cells to protect against reinfection.

“Importantly, this included liver‑resident memory T cells, which have the potential to respond rapidly to future infections and eliminate them before disease develops.”

Researchers hope the drug compounds may enable a ‘vaccinate and boost naturally’ approach, where progressive long-term immunity is learned and sustained through repeated natural mosquito bites in endemic areas.

The antimalarial drug candidates used in the study, WM382 and MK-7602, are both dual inhibitors of plasmepsin IX and X – two ‘master regulators’ that are crucial for parasite survival.

The drug candidates are the result of a decade-long research collaboration between WEHI and MSD.

WEHI researchers were able to achieve the strong immunity seen in the preclinical study by combining the drug compounds with small doses of malaria parasites transmitted by mosquito bites.

John A. McCauley, Senior Director, Discovery Chemistry at MSD, said: “Current approaches often rely on genetically attenuated parasites, which can provide strong protection but require high doses and are difficult to produce, scale and administer in real‑world settings.

“By using a drug to arrest parasites at the late liver stage, we’ve enabled the immune system to recognise a broader range of malaria antigens using a smaller parasite dose.

“This approach may provide a broader response against the diversity of malaria parasites seen in the real-world and go beyond what genetically attenuated laboratory strains can achieve.”

“Despite using smaller parasite doses, we were able to generate strong and durable protective response in this study.”

As WM382 and MK-7602 target enzymes that are highly conserved across malaria species, researchers hope this will enable their approach to provide protection against a wide range of malaria ‘variants’ in the future – potentially allowing people in endemic areas to build immunity from natural mosquito bites over time.

A Long-Acting Injectable based on the compounds is in preclinical development.

If developed, this could prevent malaria by targeting the late liver stage, with the potential upside of vaccinating and boosting people with each mosquito bite.

This work is supported by MSD, The Wellcome Trust, National Health and Medical Research Council of Australia (NHMRC) and Victorian State Government.

The study, “Chemovaccination with a late liver-stage antimalarial induces durable immunity against malaria”, with first author Dr Ryan Steel, is published in Science.

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Header image: A late liver-stage malaria parasite growing inside an infected liver cell (hepatocyte), expressing different antigens for immune education (red and green). DNA from the parasite (center) and neighboring uninfected liver cells (smaller circles) are shown in blue.  Credit: Boddey Lab, WEHI