Lead Institution: Mahidol University
Research Areas
The epidemiology of malaria in Southeast Asia (SEA) is dynamic and rapidly changing as a result of modifications to the environment and human factors. As SEA countries strive to eliminate malaria, they encounter unique challenges, including the transition from predominantly Plasmodium falciparum to increasing P. vivax infections and spatial heterogeneity of disease distribution. The emergence and rapid spread of human P. knowlesi infections in Malaysia and Thailand pose serious concerns that necessitate research to inform mitigation and elimination efforts. This new iteration of the International Centers of Excellence for Malaria Research (ICEMR) program builds on the impactful scientific findings of prior funding periods, which have fostered international collaborations among researchers from academic institutions in Thailand, Malaysia, Japan, and the United States. The program's primary goal is to comprehend the intricate interplay between malaria epidemiology and vector biology in SEA, with a particular emphasis on the dynamics of human and zoonotic malaria transmission, to inform strategies for malaria elimination. To achieve this, research sites across Thailand and Malaysia have been selected to encompass diverse landscapes and malaria transmission patterns. The research program consists of two interdependent projects:
Project 1 studies the epidemiology of malaria in Thailand and Malaysia. This project seeks to obtain insights into disease heterogeneity and clinical outcomes, and to identify new biomarkers to inform development of new and improved rapid diagnostic tests.
Project 2 scrutinizes the impact of vector biology on the transmission dynamics of both human and zoonotic malaria. By examining vector community structure, population genetics, vector-parasite interactions, and vector control tools related to human and zoonotic malaria, this project aims to improve the understanding of the vectorial system and its role in malaria transmission in SEA.
Both projects will be conducted concurrently at selected study sites across Thailand and Malaysia, emphasizing border regions, where malaria transmission is ongoing. The program's multidisciplinary approach, which blends epidemiology, vector biology, and translational science, aims to inform integrated control strategies tailored to SEA's distinct challenges. The outcomes of this program will inform policy decisions related to malaria control and elimination, ultimately contributing to efforts to reduce the burden of this disease in the region.
Key Achievements
This project will continue from the previously funded “Southeast Asia Malaria Research Center” (July 2010 - March 2024). The previous study sites included China-Myanmar and Thailand-Myanmar borders in the Greater Mekong sub-region (GMS).The third iteration of this ICEMR will investigate the landscape changes in human and zoonotic malaria transmission. The study sites will include malaria-endemic areas along the Thai-Myanmar and Thai-Malaysian borders as well as Malaysia’s Sabah and Sarawak regions.
Past Achievements
Using Surveillance to Understand Transmission Patterns in the Greater Mekong Sub-Region
The transmission patterns of malaria in the GMS are complex and rapidly evolving. The distribution of malaria in this area is very heterogenous, with higher prevalence along international borders and little to no locally acquired infections in the central plains. This not only poses great difficulties for accurate surveillance and delivery of control measures but also creates a danger of parasite reintroduction from cross-border migrant populations. By initiating disease surveillance through passive case surveillance, active case detection, and conducting cross-sectional surveys at sentinel sites along international borders (Thailand-Myanmar, and Myanmar-China), researchers are studying both long-term and short-term trends of malaria burden, parasite species composition, and seasonality. Despite overall reduction of malaria in this region, some border areas, especially areas with military conflicts, have experienced malaria outbreaks. P. vivax is resilient to existing control measures and has emerged as the predominant parasite species in most parts of the GMS and is responsible for many of these outbreaks.
Spatial epidemiology has identified townships near the border areas as high-risk for malaria. Since risk is dynamic and changes spatially and temporally, multi-criteria decision analysis is used to create spatial models of risk maps, providing the foundation for action plans during the pre-elimination period. On the micro-geographical scale, malaria cases are clustered in villages at the China-Myanmar and Thailand-Myanmar borders. Together with mosquito surveillance, these observations inform targeted malaria control. Studies in multiple sentinel sites along the international borders of Myanmar and Thailand identified high risk groups such as school-age children, soldiers, and forest-related occupation as being associated with malaria infection and repeated episodes of malaria. In areas where malaria was near elimination in southwest China and western Thailand, cross-border travel was associated with malaria introduction. These findings identified at risk human populations in the border areas for targeted and enhanced control activities. Detailed epidemiological and entomological surveys conducted along the Thai-Myanmar border further identified outdoor transmission foci (subsistence farm huts and forest), highlighting gaps in the current control measures.
Identification of the reservoirs for malaria transmission is critical for achieving malaria elimination. In multiple sentinel sites with different levels of malaria transmission, molecular epidemiology studies through cross-sectional surveillance at sentinel sites of Myanmar and western Thailand identified high prevalence of asymptomatic and submicroscopic infections, even in areas where clinical cases are rarely detected. Using mosquito-feeding assays, researchers showed that the submicroscopic vivax infections (positive by PCR only, with no clinical symptoms) occurring near the Thailand-Myanmar border were infective to mosquitoes, further corroborating asymptomatic infections as reservoirs sustaining continued malaria transmission. These studies laid the foundation for testing new control strategies such as mass primaquine treatment, whose evaluation was recently completed in northern Myanmar and southern Thailand regions, where P. vivax transmission was persistent or increased in the preceding years. Researchers also evaluated the effectiveness, feasibility, sustainability, acceptability, and community engagement of mass primaquine treatment as a strategy for malaria elimination in areas where glucose-6-phosphate dehydrogenase deficiency is prevalent in human populations.
In the GMS, where malaria epidemiology is spatially and temporally heterogeneous, it is important to understand the role of human migration in malaria introduction. Having the ability to differentiate parasite populations is essential to tracing parasite migration and identifying the sources and sinks of parasites. Using a variety of genetic markers, researchers demonstrated both temporal and spatial divergence of parasite populations and unidirectional cross-border migration of the parasites, providing direct evidence for supporting strengthened control efforts at the sources of the parasites. The identification of a small set of single nucleotide polymorphism (SNP) markers suitable for fine-scale mapping of P. vivax populations within the GMS now enables a more powerful study of parasite migration.
Identifying and Studying the Diverse Population of Mosquito Vectors
The GMS has a complex malarial vectorial system with species richness and high genetic diversity. Significant environmental changes such as deforestation and extensive use of insecticides in both public health and agricultural sectors have led to changes in vector species composition and development and spread of insecticide resistance. This has led to renewed interests in determining the Anopheles composition, seasonal dynamics, and their significance in malaria transmission in different areas of Thailand, Myanmar, and China. These new vector surveillance studies provided further evidence of the species richness of the Anopheles mosquitoes, reaffirmed the vectorial status of An. minimus and An. maculatus, and identified An. annularis and An. barbirostris groups as new vectors. The latter species were abundant in outdoor collections, suggesting that they are potential vectors for outdoor transmission. Further studies conducted at the Thai-Myanmar border tied migrant populations to mosquito abundance and infection rates of P. vivax, highlighting local transmission of this parasite species. By tracing residual transmission to outdoor farming activities in the forest, our study identified the places where outdoor transmission occurs. These studies emphasize the importance of outdoor control measures to eliminate malaria.
The development of insecticide resistance in primary vector species is a concern for vector management. Though pyrethroid resistance in western Thailand was not detected in the past, there is clear evidence that it is emerging. In comparison, most vector species in the China-Myanmar border area have developed high-level resistance to pyrethroid insecticides. While these studies have linked resistance to agricultural uses of insecticides, they also revealed drastically different mechanisms of resistance in different geographical regions. In the China-Myanmar border, the pyrethroid resistance was mostly mediated by increased metabolism, whereas in other areas it was associated with mutations in the kdr gene. Using whole genome sequencing, researchers investigated the genetic differences between pyrethroid-resistant and -sensitive strains and identified resistance markers, including in genes involved in detoxification, that may be used in future resistance surveillance.
Investigating Antimalarial Drug Resistance in the Greater Mekong Sub-Region
The emergence of resistance in P. falciparum to artemisinin-based combination therapies (ACTs) is a major concern for both regional and global malaria control. To deter the spread of multidrug resistant parasites, research has focused on the understanding of molecular mechanisms of resistance, monitoring frontline drug efficacy, and molecular surveillance of resistance-associated markers.
Artemisinin resistance differs greatly between the eastern and western GMS. At sentinel sites of Myanmar bordering China in the east and Bangladesh in the west, ICEMR researchers confirmed the efficacy of ACTs for treating uncomplicated P. falciparum malaria. However, the slower clearance of parasites after treatment suggests potential emergence of artemisinin resistance.
Artemisinin resistance is associated with mutations in the propeller domain of the pfK13 gene. Though the predominant pfK13 mutations in the western GMS differ from those in the eastern GMS, ICEMR studies provided evidence that these mutations are also correlated with day-three parasite levels (a proxy for clinical artemisinin resistance), and in vitro resistance. In laboratory studies, researchers have also confirmed that some of these mutations mediate artemisinin resistance. The ICEMR team studied clinical parasites and followed the evolution of drug resistance longitudinally, providing complementary information on development of resistance in field parasite populations. Conducting genome-wide association studies to identify additional markers associated with artemisinin resistance, researchers genetically validated decreased hemoglobin digestion as a mechanism of artemisinin resistance. These studies provide additional markers for molecular epidemiological studies.
Continued surveillance of the molecular markers in sentinel sites of Myanmar provides updated information of drug resistance. As parasite populations shrink with intensified control efforts, studies reveal that even geographically proximal pockets of parasites may diverge significantly in drug resistance, highlighting the necessity of continued drug surveillance.
Regional Impact
There were approximately five million confirmed cases of malaria in the WHO South-East Asia in 2022. Six countries in the GMS are aiming to eliminate malaria by 2030 but face many technical challenges. This ICEMR brings together a diverse set of expertise from Thailand, Malaysia, Japan, and the United States, to address urgent problems of border malaria and zoonotic malaria that are relevant to both regional and global malaria elimination.
Collaborating Institutions
- University Malaya, Malaysia
- University of California, Irvine
- Ehime University, Japan
Staff
Principal Investigator: Jetsumon Sattabongkot Prachumsri, Ph.D.
Project Leads
- Project 1: Wang Nguitragool, Ph.D, Mahidol University;Yee Ling Lau, Ph.D. - Co-leader, Universiti Malaya
- Project 2: Daibin Zhong, Ph.D, University of California, Irvine; Jetsumon Sattabongkot Prachumsri, Ph.D.,Co-leader, Mahidol University
- Admin Core: Jetsumon Sattabongkot Prachumsri, Ph.D., Mahidol University
- Data Core: Amnat Khamsiriwatchara, Mahidol University