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The emergence of human infections of Plasmodium knowlesi, a zoonotic malaria parasite, poses a growing threat to malaria elimination efforts across the Asia Pacific region. While surveillance for P. knowlesi is improving, the emergence of other simian Plasmodium species presents additional challenges that could further undermine progress towards elimination beyond P. knowlesi.
A Hidden Threat
Since 2011, several simian Plasmodium infection in humans beyond P. knowlesi, including P. cynomolgi, P. inui, and P. coatneyi, have been identified in Malaysia, particularly among communities living in forest fringe areas. These parasites commonly circulate among long-tailed (Macaca fascicularis) and pig-tailed (Macaca nemestrina) macaque reservoirs in Southeast Asia, particularly Malaysia and Thailand. A study in 2016 found that P. cynomolgi was found in 53.3% of samples from seven macaque populations in Southeast Asian countries, compared with 20.4% for P. coatneyi, 12.3%for P. inui, 3.4% for P. fieldi, and 0.4% for P. knowlesi. Evidence of human P. cynomolgi infection has also emerged in Thailand, where a case identified in 2018 in a tourist who had travelled to Southeast Asia was considered to have been infected in Thailand.
Evidence suggests that land use and land cover changes (LULCC) are important drivers of zoonotic malaria emergence. LULCC, including agricultural expansion, expansion of human settlements, forest fragmentation, and deforestation, have brought humans, macaques, and mosquitos in increasingly closer proximity to each other while creating favourable conditions for mosquito proliferation. This relationship is reflected in the epidemiology of emerging simian malaria. Reported cases of P. cynomolgi in Thailand and cases of P. inui in Pahang, Malaysia have largely occurred in areas where humans live in close proximity to primate reservoirs.
Public Health Implications and Challenges
However, there remains limited understanding of the implications of human P. cynomolgi and P. inui infections in the real-world. Human cases are relatively rare and evidence of symptoms of P. cynomolgi and P. inui infections under experimental conditions exhibit varying levels of severity. The presence of dormant liver-stage parasites (hypnozoites) that can cause malaria relapse – as observed with P. vivax – have been described in P. cynomolgi and P. fieldi, suggesting that P. cynomolgi and P. fieldi may carry a similar risk of relapse as with P. vivax. However, current evidence indicates that existing antimalarial drugs remain effective. P. cynomolgi can be treated with chloroquine and primaquine, while both P. inui and P. fieldi respond well to treatment with chloroquine or artemisinin-mefloquine.
Nevertheless, accurate diagnosis remains a major challenge due to the morphological similarities between these species with other known human malaria species. Although Polymerase Chain Reaction (PCR) testing remains the gold standard in detection, standard assays may not reliably differentiate between these species, necessitating the use of species-specific PCR tests which further complicates rapid and effective diagnosis efforts. As a result, the true burden of simian malaria in humans is likely to be underestimated. For instance, during the 2015-16 outbreak in southeastern Brazil, several cases initially diagnosed as P. vivax were later confirmed to be P. simium using species-specific diagnostic test. Such misdiagnosis demonstrates how diagnostic limitations can obscure the true burden of zoonotic malaria transmission and hinder the rapid identification of emerging simian malaria threats in the community.
The Way Forward
While infections of other simian malaria remain relatively rare, their emergence underscores the need for sustained surveillance and diagnostic improvements. At the same time, greater efforts are needed to better characterize the distribution of simian malaria among groups most at-risk, such as communities living at the forest fringe. In addition, LULCC data could offer valuable opportunities to strengthen surveillance and control measures, yet existing tools remain under-utilised and under-developed within health programmes amid broader resource challenges and competing priorities. Continued vigilance and targeted investment in surveillance and diagnostic will be critical to ensuring that emerging simian malaria threats are detected early and addressed promptly, safeguarding the region's progress towards a malaria-free future.
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