ICEMR-SEA-MaTH
International Centers of Excellence for Malaria Research - South East ASIA -Malaysia and Thailand
The changing landscape of human and zoonotic malaria in Southeast Asia
Lead institution: Mahidol University, Thailand
Background
The epidemiology of malaria in Southeast Asia (SEA) is multifaceted and rapidly evolving, marked by immense spatial heterogeneity in disease distribution across different regions and countries. As SEA countries strive to eliminate malaria, they encounter unique challenges, including the transition from Plasmodium falciparum to P. vivax and persistent malaria-endemic areas that are remote and exhibit rich ecological diversity. Additionally, the emergence and rapid spread of human P. knowlesi infections in Malaysia and Thailand are serious concerns that necessitate integration into the elimination program. This new iteration of the International Centers of Excellence for Malaria Research (ICEMR) program builds on the groundbreaking scientific discoveries of its predecessors (ICEMR 1&2), which has fostered international collaborations among researchers from academic institutions in Thailand, Malaysia, Japan, and the United States.
The program's primary aim 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 meticulously selected to encompass diverse landscapes and malaria transmission patterns.
The research program consists of two interdependent projects, with Project 1 probing the epidemiology of malaria in Thailand and Malaysia, and Project 2 scrutinizing the impact of vector biology on the transmission dynamics of both human and zoonotic malaria in these countries. By analyzing malaria parasite distribution and transmission dynamics in human populations, Project 1 seeks to glean insights into disease heterogeneity, clinical outcomes, and to identify new antigens for improved diagnostic tests. Project 2 seeks to improve our understanding of the vectorial system and its role in malaria transmission in SEA, by examining vector community structure, population genetics, vector-parasite interactions, and vector control tools related to human and zoonotic malaria.
Both projects will be executed concurrently at selected study sites across two countries in SEA (Thailand and Malaysia), focusing on border regions where active malaria transmission is ongoing. The program's multidisciplinary approach, which blends epidemiology, vector biology, and advanced diagnostic tools, aims to devise integrated control strategies tailored to SEA's distinctive 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.
Research Goal
The program’s primary goal is to comprehend the intricate interplay between malaria epidemiology and vector biology in Southeast Asia (SEA), with a particular emphasis on the dynamics of human and zoonotic malaria transmission, to inform strategies for malaria elimination
Study sites
Research sites across Thailand and Malaysia have been meticulously selected to encompass diverse landscapes and malaria transmission patterns.
The preparatory activities varied from site to site, depending on the context and the types of specimen or data collection. Regional authorities were engaged before activities began. Extensive training was provided to project staff, including local health authorities (malaria clinic staff and vector-borne disease control unit staff), local health workers (hospital staff and village health volunteers), and local hires (villagers). The training covered all aspects of field activities, from human subject research and participant enrollment to data entry and query. Furthermore, the central study database and the logistics of travel, supply management, sample collection have now been set up.
Project 1
Parasite and epidemiology
Malaria in Southeast Asia (SEA) is undergoing significant changes, with decreasing Plasmodium falciparum cases, increasing P. vivax dominance, and the emergence of P. knowlesi infections, particularly in Malaysia and Thailand. The project-1 aims to address these challenges by understanding transmission dynamics, identifying diagnostic tools, and exploring disease mechanisms.
Specific Aims
1. To understand the epidemiology of complex and changing malaria: This aim focuses on understanding how malaria transmission is evolving. Using molecular tools, case detection, and surveys, the study will analyze disease dynamics and risk factors in diverse settings in Thailand and Malaysia. Parasite genetics will also be conducted to understand the evolving population genetics.
2. To identify seromarkers of P. knowlesi infection and evaluate cross-species protection: The study seeks to identify P. knowlesi-specific seromarkers and assess whether prior P. vivax exposure offers immunity against this parasite. High-throughput immunoscreening will help identify antibodies for these purposes.
3. To identify new parasite antigens to enhance point-of-care diagnosis: Current rapid diagnostic tests (RDTs) underperform for non-falciparum species. The project will use proteomic analysis to identify new antigens and develop new antibodies for more reliable RDTs, enabling better patient management.
4. To understand the role of cytoadhesion, rosetting, and multiplication rates in severe P. knowlesi malaria: By investigating cytoadherence, rosetting, and rapid multiplication, the study seeks to uncover mechanisms driving severe disease. Transcriptome analysis and functional assays will be used to identify genes linked to virulence, aiding the development of prognostic tools.
Planned field-based activities include
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Cross-sectional surveys (CSS). CSS were conducted to assess the prevalence of malaria infection and identify risk factors associated with it.
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Passive Case Detections (PCD). PCD, the collection and analysis of blood samples from patients suspected of malaria, was used to further gather demographic information and samples from patients who visited local health facilities. Considering the relatively low transmission rates in Thailand and Malaysia, we expect that PCD would offer a more efficient approach to obtaining parasite specimens compared to CSS. The collected samples underwent PCR to detect and identify the malaria parasite species.
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Reactive Case Detections (RCD). RCD were conducted to identify additional malaria infections in ~10 households (50 villagers) around clinical malaria cases (index cases). This is part of the Thai malaria control program’s 1-3-7 strategy, which aims to identify and treat additional infections to suppress transmission. In this study, we leverage the existing government activity to supplement the routine microscopic/RDT detection with PCR. The results will provide valuable data to assess the need and the effectiveness of routine reactive case detection.
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Project 2
Vector and Transmission
Although considerable progress has been made in the prevention and control of malaria globally, the marked increase in zoonotic malaria cases caused by Plasmodium knowlesi poses a major obstacle to malaria control in SEA. Human cases of knowlesi malaria have been reported across SEA, yet knowledge on the distribution, population dynamics, and bionomics of P. knowlesi vectors remains sparse. The occurrence of zoonotic malaria in humans has been linked to activities such as deforestation, landscape modification, and agriculture, but the underlying mechanisms are not yet fully understood. P. knowlesi vectors are typically described as forest-dwelling mosquitoes belonging to the Leucosphyrus group of the genus Anopheles. However, some Leucosphyrus species have become dominant in agricultural villages that have undergone extensive land use changes and deforestation. The emergence and spread of insecticide resistance in SEA present additional challenges in the management and control of P. knowlesi malaria in endemic areas. Widespread use of indoor residual spraying and insecticide-treated nets has led to shifts in the species composition, abundance, susceptibility to insecticides, and biting behaviors of mosquitoes. The effects of these interventions on P. knowlesi vectors and disease transmission are currently unknown. Therefore, the overarching objectives of this project are to 1) investigate how environmental changes affect human and zoonotic malaria transmission in Southeast Asia; and 2) enhance understanding of vector behavioral ecology, population dynamics, vector competence, insecticide resistance, and the genetic basis underlying these factors.
Specific Aims
1. To examine the impact of anthropogenic environmental changes on malaria vector ecology, bionomics, and transmission of human and zoonotic malaria. Environment changes caused by human activities can modify the ecology and composition of vector communities, thereby increasing the risk of exposure to zoonotic malaria vectors. We will examine the impact of deforestation and agricultural activities on the complexity of the malaria vectorial system in malaria endemic regions in SEA. We aim to determine how changes in landscape structure, vector abundance, and vector community structure affect the transmission of human and zoonotic malaria. This Aim will enhance our understanding of the impact of environmental changes and intervention strategies on the distribution of vector species and their role in transmitting human and zoonotic malaria.
2. To determine the effects of environmental modifications on the vector population genetics and vector competence for Plasmodium infection. Environmental changes alter vector genetic diversity and population structure. Genotype-by-genotype interactions between haplotypes of Plasmodium parasites (e.g., P47) and resistant alleles (e.g., TEP1) of Anopheles host mosquitoes impact vector competence. We will examine genetic diversity and vector competence of the Anopheles mosquitoes by membrane feeding and molecular genotyping. This Aim will significantly improve our comprehension of the genetic mechanisms underlying human and zoonotic malaria transmission by exploring the impact of host factors on population evolution and vector competence.
3. To assess insecticide resistance of vectors and novel vector control methods targeting Anopheles malaria vectors in controlled environments. The extensive use of insecticides in vector control programs results in the emergence of resistance through selection pressure. Spatial repellents can hinder human biting by adult mosquitoes, while the autodissemination approach with pyriproxyfen can target both immature and adult mosquitoes, resulting in a decrease in the incidence of malaria transmission in both indoor and outdoor settings. We will examine vector insecticide resistance using standard bioassay and evaluate novel vector control tools in the controlled environment. This aim will provide important management information on outdoor vector control and intervention and reduction of both human and zoonotic transmission.
Anthropogenic activities create new breeding habitats for Anopheles mosquitoes, which can lead to alterations in their behavior and ecology. To develop appropriate control measures, it is crucial to understand the bionomics of Anopheles vectors and how environmental changes affect their transmission dynamics. This project aims to analyze the effects of environmental changes and vector control programs on mosquito species composition, dynamics, biting behavior, insecticide resistance, and vector competence, which in turn affect the dynamics of human and zoonotic malaria transmission. By analyzing the ecological and genetic mechanisms underlying these changes, this project will provide the important knowledge base for more effective vector control tools.
Planned field-based activities include
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Two adult mosquito surveillance: CDC light traps (with and without CO₂ bait), and Human Landing Catch (HLC),
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Larval sampling using standard 350 mL dippers.
Dashboard
Impact
The forests and plantations of Southeast Asia form a complex and rich ecology that is home to all major malaria parasite species of public health importance. This study will use state-of-the-art tools in genetics, serology, parasitology, and vector biology to tackle current challenges confronting the malaria-elimination effort in this region, focusing on the factors underlying disease transmission and the rapid spread of Plasmodium knowlesi, a malaria parasite of monkeys that often causes severe and fatal infections in humans. The expected outputs of this project range from fundamental knowledge underlying parasite virulence and transmission to new diagnostic tools for point-of-care and surveillance applications.
Research Personnel
Key investigators
Program director
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Prof. Jetsumon Prachumsri, Mahidol University, Thailand
Project leads
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Project 1: Assoc. Prof. Wang Nguitragool, Mahidol University, Thailand
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Project 2: Dr. Daibin Zhong, University of California, Irvine, USA
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Data core: Mr. Amnat Khamsiriwatchara, Mahidol University, Thailand
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Administrative core: Prof. Jetsumon Prachumsri, Mahidol University, Thailand
Other investigators
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Prof. Jaranit Kaewkungwal, Mahidol University, Thailand
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Prof. Kesinee Chotivanich, Mahidol University, Thailand
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Dr. Saranath Lawpoolsri Niyom, Mahidol University, Thailand
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Dr. Patchara Sriwichai, Mahidol University, Thailand
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Dr. Wanlapa Roobsoong, Mahidol University, Thailand
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Dr. Chawarat Rotejanaprasert, Mahidol University, Thailand
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Dr. Lokachet Tanasugran, Mahidol University, Thailand
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Dr. Anuwat Wiratsudakul, Mahidol University, Thailand
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Dr. Sarin Suwanpakdee, Mahidol University, Thailand
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Dr. Onrapak Reamtong, Mahidol University, Thailand
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Dr. Sirasate Bantuchai, Mahidol University, Thailand
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Dr. Saduudee Chotirat, Mahidol University, Thailand
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Dr. Pyae Linn Aung, Mahidol University, Thailand
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Prof. Yee Ling Lau, University of Malaya, Malaysia
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Prof. Indra Vythilingham, University of Malaya, Malaysia
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Prof. Mun Yik Fong, University of Malaya, Malaysia
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Prof. Eizo Takashima, Ehime University, Japan
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Prof. Takafumi Tsubo, Ehime University, Japan
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Prof. Guiyun Yan, University of California, Irvine, USA
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Dr. Ming-Chieh Lee, University of California, Irvine, USA
