Researchers have discovered a new way to help prevent malaria that could one day transform mosquito bites from a source of deadly infection into immunity boosters against the disease.<\/p>\n
The WEHI-led team demonstrated a new vaccination approach that can prime the immune system to fight malaria parasites before they cause disease, with\u00a0subsequent mosquito bites acting as boosters to strengthen immunity over time.<\/p>\n
This approach protected mice against malaria for the study period \u2013 a rare outcome that could inform the development of next-generation prevention strategies for one of the world\u2019s deadliest infectious diseases.<\/p>\n
WEHI researchers develop a new vaccination approach that turned mosquito bites into ongoing immune boosters, in landmark research published inScience.The preclinical study is the first to target malaria parasites at the late liver stageusing an\u00a0antimalarial drug candidate discovered by WEHI and global biopharmaceutical company MSD, (tradename of Merck & Co., Inc., Rahway, N.J., USA), triggering an unusually strong and multi-layered immune response.This approach protected mice from developing disease for up to two years -a timeline that covers two malaria seasons in real-world settings.\u00a0<\/p>\n
The \u2018sweet spot\u2019 for malaria intervention<\/p>\n
More than 600,000 people \u2013 predominantly pregnant women and children under the age of five \u2013 die from malaria every year.\u00a0\u00a0According to the\u00a0World Health Organization,\u00a0one child in Africa dies from malaria every two minutes.\u00a0<\/p>\n
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.<\/p>\n
In the preclinical study published in\u00a0Science, 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.<\/p>\n
The compounds blocked the parasite\u2019s development at a critical stage of the malaria lifecycle, preventing disease and triggering a robust immune response that provided durable protection against malaria.<\/p>\n
Subsequent mosquito bites then reinforced this immunity and protection.<\/p>\n
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.<\/p>\n
\u201cUsing this new drug compound, we\u2019ve found a way to turn mosquito bites\u00a0\u2013the very thing that spreads malaria\u00a0\u2013into vaccination events in mice,\u201d Assoc Prof Boddey said.<\/p>\n
\u201cThis represents a shift in the way drugs could be employed to prevent malaria.\u201d<\/p>\n
The compounds were able to trap malaria parasites at the very end of liver-stage development\u00a0\u2013\u00a0just before they enter the bloodstream and cause disease. \u00a0<\/p>\n
To date, there had been no drug treatment available that could arrest the parasite at this immunological sweet spot.<\/p>\n
\u201cThis means the parasite was stopped just before it could cause illness, while giving the immune system a fuller preview of the potential threats,\u201d Prof Boddey said.<\/p>\n
\u201cThe immune response generated required only a very small dose of parasites but was broader and longer lasting than most current vaccine approaches.<\/p>\n
\u201cThis is because our approach allowed parasites to amplify and then triggered both antibodies and CD8+ T cells to protect against reinfection.<\/p>\n
\u201cImportantly, this included liver\u2011resident memory T cells, which have the potential to respond rapidly to future infections and eliminate them before disease develops.\u201d<\/p>\n
Researchers hope the drug compounds may enable a \u2018vaccinate and boost naturally\u2019 approach, where progressive long-term immunity is learned and sustained through repeated natural mosquito bites in endemic areas.<\/p>\n
Critical industry collaboration<\/p>\n
The antimalarial drug candidates used in the study, WM382 and MK-7602, are both dual inhibitors of plasmepsin IX and X \u2013 two \u2018master regulators\u2019 that are crucial for parasite survival.<\/p>\n
The drug candidates are the result of a decade-long research collaboration between WEHI and MSD.<\/p>\n
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.<\/p>\n
John A. McCauley, Senior Director, Discovery Chemistry at MSD, said: \u201cCurrent approaches often rely on\u00a0genetically attenuated parasites, which can provide strong protection but require high doses and are difficult to produce, scale and administer in real\u2011world settings.<\/p>\n
\u201cBy using a drug to arrest parasites at the late liver stage, we\u2019ve enabled the immune system to recognise a broader range of malaria antigens using a smaller parasite dose.<\/p>\n
\u201cThis 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.\u201d<\/p>\n
\u201cDespite using smaller parasite doses, we were able to generate strong and durable protective response in this study.\u201d<\/p>\n
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 \u2018variants\u2019 in the future \u2013 potentially allowing people in endemic areas to build immunity from natural mosquito bites over time.A\u00a0Long-Acting Injectable<\/a>\u00a0based on the compounds is in preclinical development.<\/p>\n 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.<\/p>\n This work is supported by MSD, The Wellcome Trust, National Health and Medical Research Council of Australia (NHMRC) and Victorian State Government.<\/p>\n