Background The zoonotic malaria parasite Plasmodium knowlesi has emerged across Southeast Asia and is now the main cause of malaria in humans in Malaysia. A critical priority for P. knowlesi surveillance and control is understanding whether transmission is entirely zoonotic or is also occurring through human-mosquito-human transmission. Methods A systematic literature review was performed to evaluate existing evidence which refutes or supports the occurrence of sustained human-mosquito-human transmission of P. knowlesi. Possible evidence categories and study types which would support or refute non-zoonotic transmission were identified and ranked. A literature search was conducted on Medline, EMBASE and Web of Science using a broad search strategy to identify any possible published literature. Results were synthesized using the Synthesis Without Meta-analysis (SWiM) framework, using vote counting to combine the evidence within specific categories. Results Of an initial 7,299 studies screened, 131 studies were included within this review: 87 studies of P. knowlesi prevalence in humans, 14 studies in non-human primates, 13 studies in mosquitoes, and 29 studies with direct evidence refuting or supporting non-zoonotic transmission. Overall, the evidence showed that human-mosquito-human transmission is biologically possible, but there is limited evidence of widespread occurrence in endemic areas. Specific areas of research were identified that require further attention, notably quantitative analyses of potential transmission dynamics, epidemiological and entomological surveys, and ecological studies into the sylvatic cycle of the disease. Conclusion There are key questions about P. knowlesi that remain within the areas of research that require more attention. These questions have significant implications for malaria elimination and eradication programs. This paper considers limited but varied research and provides a methodological framework for assessing the likelihood of different transmission patterns for emerging zoonotic diseases.
Reported incidence of the zoonotic malaria Plasmodium knowlesi has markedly increased across Southeast Asia and threatens malaria elimination. Nonzoonotic transmission of P. knowlesi has been experimentally demonstrated, but it remains unknown whether nonzoonotic transmission is contributing to increases in P. knowlesi cases. Here, we adapt model-based inference methods to estimate RC, individual case reproductive numbers, for P. knowlesi, P. falciparum and P. vivax human cases in Malaysia from 2012–2020 (n = 32,635). Best fitting models for P. knowlesi showed subcritical transmission (RC < 1) consistent with a large reservoir of unobserved infection sources, indicating P. knowlesi remains a primarily zoonotic infection. In contrast, sustained transmission (RC > 1) was estimated historically for P. falciparum and P. vivax, with declines in RC estimates observed over time consistent with local elimination. Together, this suggests sustained nonzoonotic P. knowlesi transmission is highly unlikely and that new approaches are urgently needed to control spillover risks.
Land conversion is understood to increase the risk of emergent zoonotic diseases. In simians and humans, infection risk has been linked to fragmented habitats. However, the role of fragmentation on disease dynamics in wildlife hosts is rarely quantified at macroecological scales due to the lack of systematic surveys. In Southeast Asia, non-human primates (NHPs) host Plasmodium knowlesi, a prominent zoonotic malaria. We examine reported primate P. knowlesi to investigate how landscape impacts parasite prevalence. Firstly, we conducted a meta-analysis of NHP P. knowlesi prevalence. Overall prevalence was 9.6% (CI95% 6.3-13.4), with considerable regional heterogeneity (I2=96.6%; CI95% 95.7-97.3) and high estimates in Borneo (52.4%, CI95% 22.8-81.3). Higher prevalence in NHPs shows clear spatial overlap with human infection foci. Secondly, environmental covariates were assembled from remote sensing data and statistical models were fitted to prevalence at multiple spatial scales. We demonstrate a strong relationship between forest fragmentation (20km, p<0.0001) and P. knowlesi in NHPs, suggesting that zoonotic malaria prevalence is maximised at intermediate levels of habitat complexity. Findings indicate a previously hypothesised trade-off between epidemiological and ecological mechanisms determining P. knowlesi infection in wildlife reservoirs, and that parasite prevalence in NHPs may be a key driver of human spillover risk.
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