TY - JOUR
T1 - Malaria outbreak in Laos driven by a selective sweep for Plasmodium falciparum kelch13 R539T mutants
T2 - a genetic epidemiology analysis
AU - Wasakul, Varanya
AU - Disratthakit, Areeya
AU - Mayxay, Mayfong
AU - Chindavongsa, Keobouphaphone
AU - Sengsavath, Viengphone
AU - Thuy-Nhien, Nguyen
AU - Pearson, Richard D.
AU - Phalivong, Sonexay
AU - Xayvanghang, Saiamphone
AU - Maude, Richard J.
AU - Gonçalves, S. nia
AU - Day, Nicholas P.
AU - Newton, Paul N.
AU - Ashley, Elizabeth A.
AU - Kwiatkowski, Dominic P.
AU - Dondorp, Arjen M.
AU - Miotto, Olivo
N1 - Funding Information: This study was funded by the Bill & Melinda Gates Foundation (grant numbers OPP11188166, OPP1204268, INV-001927) and by The Global Fund to Fight AIDS, Tuberculosis and Malaria (grant number 20864-007-44). This research was funded in part by the Wellcome Trust (grant number 204911). The authors wish to thank all the patients and guardians who generously agreed to provide blood samples. We wish to thank all public health and medical staff who participated in the collection of samples; a full list of sites and local collaborators is included in appendix 2 (pp 15–18 ). Genome sequencing and genotyping was performed by the Wellcome Sanger Institute (WSI), and sequencing data processing was supported by the MalariaGEN Resource Centre. We thank the staff of the WSI Sample Logistics, Sequencing, and Informatics facilities for their contribution; Eleanor Drury for support in the sample processing pipeline; and Victoria Simpson and Kim Johnson for coordinating the MalariaGEN Resource Centre. Funding Information: This study was funded by the Bill & Melinda Gates Foundation (grant numbers OPP11188166, OPP1204268, INV-001927) and by The Global Fund to Fight AIDS, Tuberculosis and Malaria (grant number 20864-007-44). This research was funded in part by the Wellcome Trust (grant number 204911). The authors wish to thank all the patients and guardians who generously agreed to provide blood samples. We wish to thank all public health and medical staff who participated in the collection of samples; a full list of sites and local collaborators is included in appendix 2 (pp 15–18). Genome sequencing and genotyping was performed by the Wellcome Sanger Institute (WSI), and sequencing data processing was supported by the MalariaGEN Resource Centre. We thank the staff of the WSI Sample Logistics, Sequencing, and Informatics facilities for their contribution; Eleanor Drury for support in the sample processing pipeline; and Victoria Simpson and Kim Johnson for coordinating the MalariaGEN Resource Centre. Publisher Copyright: © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2023/5
Y1 - 2023/5
N2 - Background: Malaria outbreaks are important public health concerns that can cause resurgence in endemic regions approaching elimination. We investigated a Plasmodium falciparum outbreak in Attapeu Province, Laos, during the 2020–21 malaria season, using genomic epidemiology methods to elucidate parasite population dynamics and identify its causes. Methods: In this genetic analysis, 2164 P falciparum dried blood spot samples were collected from southern Laos between Jan 1, 2017, and April 1, 2021, which included 249 collected during the Attapeu outbreak between April 1, 2020, and April 1, 2021, by routine surveillance. Genetic barcodes obtained from these samples were used to investigate epidemiological changes underpinning the outbreak, estimate population diversity, and analyse population structure. Whole-genome sequencing data from additional historical samples were used to reconstruct the ancestry of outbreak strains using identity-by-descent analyses. Findings: The outbreak parasite populations were characterised by unprecedented loss of genetic diversity, primarily caused by rapid clonal expansion of a multidrug-resistant strain (LAA1) carrying the kelch13 Arg539Thr (R539T) mutation. LAA1 replaced kelch13 Cys580Tyr (C580Y) mutants resistant to dihydroartemisinin–piperaquine (KEL1/PLA1) as the dominant strain. LAA1 inherited 58·8% of its genome from a strain circulating in Cambodia in 2008. A secondary outbreak strain (LAA2) carried the kelch13 C580Y allele, and a genome that is essentially identical to a Cambodian parasite from 2009. A third, low-frequency strain (LAA7) was a recombinant of KEL1/PLA1 with a kelch13 R539T mutant. Interpretation: These results strongly suggest that the outbreak was driven by a selective sweep, possibly associated with multidrug-resistant phenotypes of the outbreak strains. Established resistant populations can circulate at low frequencies for years before suddenly overwhelming dominant strains when the conditions for selection become favourable—eg, when front-line therapies change. Genetic surveillance can support elimination by characterising key properties of outbreaks such as population diversity, drug resistance marker prevalence, and the origins of outbreak strains. Funding: Bill & Melinda Gates Foundation; The Global Fund to Fight AIDS, Tuberculosis and Malaria; Wellcome Trust. Translation: For the Lao translation of the abstract see Supplementary Materials section.
AB - Background: Malaria outbreaks are important public health concerns that can cause resurgence in endemic regions approaching elimination. We investigated a Plasmodium falciparum outbreak in Attapeu Province, Laos, during the 2020–21 malaria season, using genomic epidemiology methods to elucidate parasite population dynamics and identify its causes. Methods: In this genetic analysis, 2164 P falciparum dried blood spot samples were collected from southern Laos between Jan 1, 2017, and April 1, 2021, which included 249 collected during the Attapeu outbreak between April 1, 2020, and April 1, 2021, by routine surveillance. Genetic barcodes obtained from these samples were used to investigate epidemiological changes underpinning the outbreak, estimate population diversity, and analyse population structure. Whole-genome sequencing data from additional historical samples were used to reconstruct the ancestry of outbreak strains using identity-by-descent analyses. Findings: The outbreak parasite populations were characterised by unprecedented loss of genetic diversity, primarily caused by rapid clonal expansion of a multidrug-resistant strain (LAA1) carrying the kelch13 Arg539Thr (R539T) mutation. LAA1 replaced kelch13 Cys580Tyr (C580Y) mutants resistant to dihydroartemisinin–piperaquine (KEL1/PLA1) as the dominant strain. LAA1 inherited 58·8% of its genome from a strain circulating in Cambodia in 2008. A secondary outbreak strain (LAA2) carried the kelch13 C580Y allele, and a genome that is essentially identical to a Cambodian parasite from 2009. A third, low-frequency strain (LAA7) was a recombinant of KEL1/PLA1 with a kelch13 R539T mutant. Interpretation: These results strongly suggest that the outbreak was driven by a selective sweep, possibly associated with multidrug-resistant phenotypes of the outbreak strains. Established resistant populations can circulate at low frequencies for years before suddenly overwhelming dominant strains when the conditions for selection become favourable—eg, when front-line therapies change. Genetic surveillance can support elimination by characterising key properties of outbreaks such as population diversity, drug resistance marker prevalence, and the origins of outbreak strains. Funding: Bill & Melinda Gates Foundation; The Global Fund to Fight AIDS, Tuberculosis and Malaria; Wellcome Trust. Translation: For the Lao translation of the abstract see Supplementary Materials section.
UR - http://www.scopus.com/inward/record.url?scp=85149663737&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S1473-3099(22)00697-1
DO - https://doi.org/10.1016/S1473-3099(22)00697-1
M3 - Article
C2 - 36462526
SN - 1473-3099
VL - 23
SP - 568
EP - 577
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 5
ER -