Malaria parasite population genomics during an elimination program in Eastern Myanmar

BackgroundWe investigated parasite population genomics during an intensive malaria elimination program in Kayin State (Myanmar), in which malaria posts were used for rapid detection and treatment of malaria cases, while mass drug administration (MDA) was used in villages with high submicroscopic reservoirs. MethodsWe collected 5014 dried blood spots from Plasmodium falciparum infected patients from 413 malaria posts, over 58-months (November 2015 - August 2020), and sequenced 2270 parasite genomes, each with geographic references (latitude and longitude). We used identity-by-descent (IBD) relationships to examine how control efforts impact parasite population structure. FindingsParasites were genetically depauperate: 1726 single-genotype infections comprised 166 unique genomes ([≥]90% IBD), while nine families ([≥]45% IBD) accounted for 62{middle dot}5% of parasites sampled. We observed localized, temporally stable transmission of unique parasite genotypes, identifying transmission chains. Parasite relatedness was positively correlated up to approximately 20 km revealing the scale of parasite subpopulations. Kelch13 diversity was stable from 2016-2019, but only one predominant clonal genotype (kelch13-R561H) remained in 2020. MDA resulted in parasite founder effects, providing genomic evidence for the efficacy of this malaria control tool. InterpretationOur genomic data show that parasite population size decreased over the study period, and we observed regional distribution of parasite genotypes, which can define operational units for parasite control. One parasite genotype (kelch13-R561H) from the north rose to high frequency in 2020, because transmission was halted elsewhere in the control area. Future surveillance will reveal whether this genotype spreads to neighboring regions. Genetic drift may have a stronger impact on parasite population structure than selection in low-transmission elimination settings. FundingNational Institutes of Health; Wellcome Trust; Global Fund to Fight against AIDS, Tuberculosis and Malaria; The Bill and Melinda Gates Foundation. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThis study describes the genomic analysis of malaria parasites collected during a malaria elimination program targeting four townships (Myawaddy, Kawkareik, Hlaingbwe, and Hpapun) in Kayin State, eastern Myanmar. We searched PubMed on May 10, 2025, using the terms: "malaria", "transmission", "drug resistance", "southeast Asia" and "genetic surveillance" without any date or language restrictions. Our search yielded 58 publications, including reports on declined immunity to malaria and increased drug resistance in southeast Asia; genetic diversity and population structure shaped by mass drug administration, transmission intensity, human movement and mosquito ecology; and the spread of kelch13 and pfcrt mutations conferring dihydroartemimsinin-piperaquine resistance in east southeast Asia countries. Added value of this studyWe sequenced and analyzed 2270 Plasmodium falciparum whole genomes (each with geographic location) collected between November 2015 and August 2020 in Kayin State. We described fine-scale molecular epidemiology changes during intense malaria elimination interventions. We observed localized, temporally stable transmission of parasite genotypes, with different parasite families and kelch13 haplotypes predominating in different subregions over the 5-year period. We found kelch13 haplotypes with local or regional origin, but none originating from eastern southeast Asia. The genomic data indicated decreasing parasite population size, but we observed no selection towards drug-resistance parasites. In 2020, only one predominant lineage (kelch13-R561H) remained in our studying region, consistent with genetic drift in a pre-elimination setting. Implications of all the available evidenceThe parasite population was genetically depauperate, with a spatially localized and temporally stable distribution of parasite lineages, and declining population size. In this situation genetic drift may play a heightened role in parasite epidemiology. Consistent with this, parasites carrying kelch13-R561H rose to high frequency in 2020, because transmission was eliminated in all regions except the north of Kayin State, where parasites bearing this kelch13 genotype have predominated since 2017. Future surveillance will determine whether this parasite genotype is transmitted to neighboring regions, and thus related to changes in P. falciparum drug resistance dynamics on the Thailand Myanmar border. These data illustrate how genetic drift in small populations can result in instantaneous changes in the resistance status of parasite populations in near elimination settings.