Lead Institution: University of South Florida
ICEMR website: https://www.icemr-sea.org/
The central goal of the Southeast Asia ICEMR is to improve understanding of how human mobility, parasite drug resistance, and mosquito biology contribute to continuous malaria transmission at international borders so that innovative control strategies can be developed. The ICEMR achieves this goal by:
- Obtaining detailed knowledge of the malaria epidemiology through surveillance to enable evidence-based and targeted malaria control;
- Identifying the roles of major vector species in malaria transmission and determining genetics of insecticide resistance and biting behavior change;
- Determining the dynamics and mechanisms of antimalarial drug resistance; and,
- Developing point-of-care tools for monitoring antimalarial drug quality to ensure that quality drugs are deployed
Using surveillance to understand transmission patterns in the Greater Mekong sub-region
Malaria in the Greater Mekong sub-region (GMS) is complex and rapidly evolving. The distribution of malaria in this area is very heterogenous, with higher prevalence along international borders and little to no prevalence 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 installing disease surveillance systems, including passive case surveillance, active case surveillance, and cross-sectional surveillance at sentinel sites along international borders (China-Myanmar, Thailand-Myanmar, and Myanmar-Bangladesh), researchers are examining both long-term and short-term trends of malaria incidence, 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. Plasmodium vivax is resilient to control measures and has become the predominant parasite species in most parts of the GMS, and is responsible for many of the outbreaks.
Spatial epidemiology has identified townships near the borders as high-risk areas for malaria. Since the risk is dynamic and changes spatially and temporally, multi-criteria decision analysis is used to create spatial models of risk maps, which provide the foundation for action plans during the pre-elimination period. On the microgeographical scale, malaria cases are clustered in villages at the China-Myanmar and Thailand-Myanmar borders. Together with mosquito surveillance, these data provide the necessary details for targeted malaria control. Studies in multiple sentinel sites along international borders of Myanmar and Thailand have identified risk factors such as school-age children, soldiers, and forest-related occupation as associated with malaria cases and those with repeated episodes of malaria. In areas where malaria is near elimination in southwest China and western Thailand, cross-border travel has been associated with malaria introduction. These findings identify specific human populations in the border areas for targeted and enhanced control activities. Detailed epidemiological and entomological surveys conducted in the Thai-Myanmar border identified outdoor transmission foci (subsistence farm huts and forest), highlighting the 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 have identified high-prevalence asymptomatic and submicroscopic infections, even in areas where clinical cases are rarely detected. Using mosquito feeding assays, researchers have shown that the submicroscopic vivax infections (positive by PCR only, with no clinical symptoms) occurring at the Thailand-Myanmar border are infective to mosquitoes , further corroborating asymptomatic infections as reservoirs sustaining continued malaria infections. These studies have laid the foundation for testing new control strategies such as mass primaquine treatment, which is currently under evaluation in northern Myanmar and southern Thailand, where P. vivax transmission has been persistent or has increased in recent years. Researchers are evaluating 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 trace parasite migration and identify the sources and sinks of the 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 on 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 enables 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 significance in malaria transmission in different areas of malaria endemicity in 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 clearly tied migrant populations to mosquito abundance and infection rates with P. vivax, highlighting local transmission of this parasite species. By tracking 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 is mostly mediated by increased metabolism, whereas in other areas it was associated with mutations in the kdr gene. Using a whole genome sequencing approach, researchers investigated the genetic differences between pyrethroid-resistant and -sensitive strains and identified 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 GMS is an epicenter of drug resistance and 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 falciparum malaria. However, the slower clearance of parasites three days 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 have provided evidence that these mutations are also correlated with day three parasite levels(a proxy for clinical artemisinin resistance), and in vitro resistance. Researchers have also confirmed that some of these mutations mediate artemisinin resistance from in vitro studies. The ICEMR team has 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.
There were 7.9 million confirmed cases of malaria in Southeast Asia in 2018, according to the World Health Organization. Six countries in the Greater Mekong Subregion are aiming to eliminate malaria by 2030 and face many technical challenges. This ICEMR brings together diverse expertise from the United States, China, Myanmar and Thailand to address urgent problems of border malaria that are relevant to both regional and global malaria elimination.
View Associated sites for the Southeast Asia ICEMR in a larger map
Map description: Associated sites in China (Yunan Province), Thailand (Tha Song Yang), Myanmar (Chin State, Mon State, Kayin State, Kachin State)
Co-Principal Investigators: Liwang Cui, Ph.D. and Jetsumon Sattabongkot, Ph.D.
- Myat Phone Kyaw, Myanmar Health Network Organization (Saranath Lawpoolsri - Co-leader, Mahidol University)
- Jetsumon Sattabongkot, Mahidol University (Daibin Zhong – Co-Leader, University of California, Irvine)
- Liwang Cui, University of South Florida
- Baomin Wang, China Agricultural University
- Jaranit Kaewkungwal, Mahidol University
- Myanmar Health Network Organization, Yangon, Myanmar
- Mahidol University, Bangkok, Thailand
- China Agricultural University, Beijing, China
- China Medical University, Shenyang, China
- Kunming Medical University, Yunnan Province, China
- University of California, Irvine, CA