Emerging zoonotic malaria in Malaysia: strengthening surveillance and evaluating population genetic structure to improve regional risk prediction tools

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Project Summary/Abstract Southeast Asia remains a global hotspot for emerging zoonotic infectious diseases. The recent increase in transmission of the monkey malaria parasite Plasmodium knowlesi, endemic to Southeast Asia, exemplifies how land-use change can drive disease spill-over to humans. In Malaysia, P. knowlesi now accounts for the vast majority of malaria cases and is the predominant cause of malaria-related deaths. Recent reports suggest that P. knowlesi is also the predominant species in parts of western Indonesia, and that due to misidentification by microscopy, under-diagnosis is likely widespread across the region. Molecular surveillance is essential for monitoring the emergence of zoonotic P. knowlesi, informing malaria control strategies, and assessing progress towards elimination of the human-only malaria species. In this study in Sabah, Malaysia, we firstly plan to further improve molecular state-wide malaria surveillance detection systems to monitor for changing epidemiological and clinical features of disease, including in pregnancy, which potentially could occur with adaption of P. knowlesi to human-human transmission. We will supplement these data with targeted longitudinal health facility surveys of healthy and febrile attendees to understand the true burden of asymptomatic or submicroscopic P. knowlesi infections, in addition to screening for other simian malaria species such as P. cynomolgi. A high-throughput multiplex serological malaria surveillance platform will also be used to integrate recently developed novel antigens targeting P. knowlesi. This platform will enable evaluation of population-level markers of P. knowlesi exposure and transmission intensity in the context of potential waning cross-species immunity from other human malaria species, and allow concurrent assessment of other public health priorities including SARS-CoV-2. Secondly, recent advances in multiplexed deep targeted sequencing of microhaplotypes offer potential advantages if these tools are adapted for P. knowlesi. Our previous surveillance study collected >5500 P. knowlesi isolates, and we plan to develop novel genome-based tools to evaluate P. knowlesi population structure at sufficient resolution to understand increasing transmission and disease severity in Sabah, and relate these findings to elsewhere in Southeast Asia. Finally, we will also use an updated georeferenced database of state-wide P. knowlesi cases over time to characterise changing fine spatial scale incidence patterns, and to generate regional predictive P. knowlesi risk mapping incorporating environmental remote-sensing satellite data and predicted human, monkey and mosquito population distributions to inform and guide planning, surveillance and prevention activities in other countries in the region at risk of P. knowlesi transmission.