Conference Agenda
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Daily Overview |
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CP14: Top Rated Contributed Abstracts 15 min talks Location: Plenary Lecture Theatre Session Chair: Danielle Stanisic, Institute for Biomedicine and Glycomics, Griffith University | |
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A late liver-stage chemical vaccine for malaria 1: Walter and Eliza Hall Institute, Australia; 2: Department of Medical Biology, University of Melbourne; 3: The Peter Doherty Institute, University of Melbourne; 4: University of New South Wales; 5: Merck & Co., Inc., USA Late-arresting sporozoite vaccines against Plasmodium falciparum achieve high efficacy but pose manufacturing and intravenous delivery challenges. We describe an alternative chemo-attenuation strategy that exploits first-in-class antimalarials targeting parasite aspartyl proteases plasmepsin IX and X. A single low-dose infection with virulent Plasmodium berghei sporozoites, delivered intravenously or by mosquito bite, followed by cure with a dual plasmepsin IX/X inhibitor prevented blood-stage infection by generating chemo-attenuated liver merozoites (CALM) that are incapable of erythrocyte invasion. CALM vaccination conferred sterile protection in mice for up to 2 years. Protective immunity involved both antibodies and CD8+ T cells recognising a spectrum of Plasmodium antigens including CSP, SERA1, RPL6, GAP50, RNT, PHIST, S20 and RBP. Studies in humanised mice confirmed plasmepsin IX/X inhibition similarly prevents Plasmodium falciparum liver-to-blood transition, demonstrating conservation of the drug’s late liver-stage mechanism across species. By enabling controlled liver-stage arrest without complex genetic attenuation or irradiation, plasmepsin IX/X-targeting drugs provide a practical, broadly applicable pathway to whole-parasite chemovaccination. This approach may convert seasonal mosquito exposure into progressive immune education if long-acting injectable (LAI) formulations prove feasible. These findings lay the foundation for clinical evaluation of CALM vaccination including via mosquito-bite immunisation. Aspirationally, LAI CALM could transform malaria prevention programs at scale. | |