Understanding, Tracking, and Eliminating Malaria Transmission in the Asia-Pacific Region
Lead Institution: Walter and Eliza Hall Institute of Medical Research (WEHI)
Tackling malaria in the Asia-Pacific region requires addressing a number of key challenges related to increasingly strong variations in malaria transmission, the presence of a large reservoir of infected but asymptomatic individuals, and the development of drug resistance. The predominance of P. vivax infections also poses the challenge of relapsing malaria caused by P. vivax hypnozoites (dormant parasites). The Asia-Pacific ICEMR is conducting a coordinated set of field studies in Cambodia and Papua New Guinea that span a range of transmission intensities in the Asia-Pacific region.
- The Epidemiology Project employs rigorous cross-sectional and longitudinal cohort studies, state-of-the-art molecular detection and genotyping of Plasmodium parasites, and an assessment of host immune responses to investigate spatio-temporal patterns of malaria risk. These studies inform improved surveillance strategies.
- The Transmission Project tracks human movement, especially time spent in forests, detailed studies of mosquito host seeking, and measurements of antibodies to anopheline salivary gland proteins to establish variations in human-vector contact. Studies of mosquito ecology are conducted to determine patterns of mosquitos’ host seeking behavior. The combined human and vector studies will help researchers better understand transmission in forest settings and the impact of sustained control on the vector population and community structure.
These interconnected, multi-disciplinary studies aim to identify and characterize critical parasite, vector, and host features that contribute to continued transmission despite intensive national malaria control and elimination programs. A detailed understanding, not only of where people with malaria infections and disease are living, but also where they may have acquired infections and where they could spread them, is crucial to eliminating malaria from the Asia-Pacific region.
In Cambodia, transmission risk is associated with forest-related activities. Epidemiological and molecular data from a community cross-sectional study revealed that 8.3 percent of inhabitants in Kaev Seima are infected with Plasmodium parasites, with 68 percent of infections due to P. vivax. Prevalence was found to range widely across villages with a trend towards very high levels of infections in villages inside the forest where all inhabitants were at risk of malaria infection. In villages outside the forest or on the fringe, the risk of infection was highly associated with work in and travel to the forest and highest in working age men. The vast majority of infections (96 percent) were asymptomatic and/or undetectable by standard microscopy or rapid diagnostic tests.
To better quantify human-vector contact patterns resulting in residual malaria transmission, global positioning system (GPS) trackers were used to capture motion patterns of humans in endemic areas and human-vector contact was quantified using geospatial information system (GIS) technology and spatial analysis methods. Follow-ups of 200 forest-goers (at-risk group, males aged between 13 and 60 years old) were carried out in the dry season from February to April 2019. All blood samples were typed for Plasmodium species. Overall, 41.4 percent of the participants were malaria positive at least once during the follow-up. Most infections were due to P. vivax (35.6 percent P. vivax, 2.5 percent mixed infections, 1.7 percent P. falciparum and 1.7 percent undetermined species).
In parallel with these epidemiological studies, intensive vector studies reveal the following:
- An entomological inoculation rate (number of infectious bites per person per unit of time) that is 6 times higher in the forest compared to the other sampled sites
- A daytime biting rate of approximately 20 percent with infectious mosquitoes collected both during day and night
- High diversity of malaria vectors with 27 different mosquito species identified by molecular species typing, of which 14 were found to be infected by Plasmodium
Altogether, these results strengthen the hypothesis that the forests are the main risk areas for human malaria transmission in Cambodia and highlight the importance of daytime biting behavior as a potential source for transmission.
Results also highlight the high burden of mostly asymptomatic P. vivax infections and the importance of specific control efforts aimed at this parasite. The only licensed drug with hypnozoiticidal effect for the treatment of P. vivax infections is Primaquine, which is part of the national treatment guidelines but not yet implemented because of concerns over the drug’s safety in patients with G6PD deficiency. New advances in the use of multiple antigens to detect antibodies as serological markers for recent exposure and for potential hypnozoite carriers are promising. Approaches targeted at risk groups only (based on forest proximity) may be more cost effective for the national malaria control program.
Understanding the epidemiology of ongoing malaria transmission in Papua New Guinea
The intensification of malaria control measures was associated with marked reductions in malaria-related infection and illness in Papua New Guinea (PNG) between 2005 and 2014. Since 2015, malaria in PNG has resurged significantly. A suite of cross-sectional surveys, longitudinal cohorts and entomological surveillance conducted throughout this period of time has provided critical insights into the epidemiology of ongoing transmission.
In communities of East Sepik Province, the prevalence of P. falciparum decreased from 55 percent (2005) to 9 percent (2013) and and P. vivax from 36 percent to 6 percent. The mean multiplicity of infection (MOI) decreased from 1.8 to 1.6 for P. falciparum (p = 0.08) and from 2.2 to 1.4 for P. vivax (p < 0.001). The reductions led to a more equal distribution of infections and illness across age groups, but increased spatial heterogeneity, i.e., larger differences between villages and among households within villages.
In more recent years, the prevalence of P. falciparum increased to 22 percent in 2016 and remained relatively stable in 2019 (20 percent) in the same communities. For P. vivax, however, prevalence increased to 12 percent in 2016 and to more than 30 percent in 2019. Population genetic analysis of P. falciparum and P. vivax with microsatellite markers identified a modest decrease in diversity for P. falciparum, but no change for P. vivax.
Surveillance of P. falciparum haplotypes for artemisinin resistance associated mutation C580Y revealed mixing between Wewak and West Papuan isolates, suggesting these mutants may have originated elsewhere on the island of New Guinea.
Long-lasting insecticidal nets (LLINs) are the only vector control tool implemented by the national malaria control program (NMCP) in PNG on a nationwide level. Between 2010 and 2019, 12.8 million LLINs were delivered to the country, with approximately 10.2 million since 2013. In close collaboration with NMCP, the ICEMR tested the bioefficacy of LLINs manufactured between 2013 and 2019 collected from villages and LLIN distributors. Reduced bioefficacy was observed, with only 16 percent of LLINs manufactured after 2013 fulfilling the required WHO bioefficacy standards. In contrast, all LLINs manufactured prior to 2013 met the WHO bioefficacy standards. These results suggest that decreased bioefficacy of LLINs may be contributing to the malaria resurgence in PNG and increased scrutiny of LLIN quality is warranted.
ICEMR investigators have completed the development of a new amplicon-sequencing (AmpSeq)-based assay for tracking parasite clones over time and measuring multiplicity of infection at high resolution for P. falciparum. Using this assay, researchers have shown that P. falciparum infections in PNG are genetically more diverse than those in Cambodia.
In parallel, the ICEMR has developed long-read amplicon assays to genotype P. falciparum drug resistance as well as host polymorphisms involved in the safety and efficacy of primaquine treatment of P. vivax infection. In addition, the ICEMR has developed rapid multiplex SNP barcoding assays for genotyping large numbers of polymorphisms (including panels of SNPs). Barcodes have been developed for both P. falciparum and P. vivax and are being applied to PNG and Cambodian ICEMR samples to investigate changes in parasite relatedness, population structure, and geneflow with transmission.
ICEMR researchers have also developed a number of high-throughput Luminex assays for measuring IgG, IgG subclass, and IgM antibodies to P. falciparum and P. vivax antigens. These studies show that IgM responses are prominent for some antigens and can persist for an extended time following exposure. New advances in the use of multiple antigens to detect antibodies as serological markers for recent exposure and thus for potential hypnozoite carriers are promising. These multiplex serological assays are being used to map transmission, identify pockets of exposure, and predict at-risk groups in Cambodia and PNG.
The Asia-Pacific ICEMR maintains very close contacts with the National Malaria Control Programs in PNG and Cambodia and aims to provide insights that support evidence-based policy making and program implementation. Any knowledge gained is leveraged regionally through its close links with the Asia-Pacific Malaria Elimination Network (APMEN, including its Vivax and vector working groups) as well as the Australian Centre of Excellence in Malaria Elimination.
View Associated sites for the Asia-Pacific ICEMR in larger map.
Map description: Associated sites in PNG (East Sepik, Madang) and Cambodia (Mondulkiri)
Co-Principal Investigators: Ivo Mueller, Ph.D. & Leanne Robinson Ph.D.
- Ivo Mueller, WEHI, Australia
- Leanne Robinson, Burnet Institute and WEHI, Australia
- Benoit Witkowski, Institut Pasteur Cambodia, Cambodia
- Amelie Vantaux, Institut Pasteur Cambodia, Cambodia
- Stephan Karl, PNG Institute of Medical Research, PNG & AITHM James Cook University, Australia
- Moses Laman, PNG Institute of Medical Research, PNG
- Alyssa Barry, Burnet Institute and Deakin University, Australia
- James Beeson, Burnet Insititute, Australia
- Michael White, Institut Pasteur Paris, France
- Papua New Guinea Institute of Medical Research, Madang, PNG
- Institut Pasteur Cambodia, Phnom Penh, Cambodia
- Case Western Reserve University, Cleveland, USA
- The Walter And Eliza Hall Institute of Medical Research (WEHI), Melbourne, Australia
- Swiss Tropical & Public Health Institute, Basel, Switzerland
- Burnet Insititute, Melbourne, Australia