title: Host immunity toPlasmodium falciparumand the assessment of emerging artemisinin resistance in a multinational cohort.
abstract: Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence ofkelch13mutants, has emerged in the Greater Mekong Subregion. Naturally acquired immunity to malaria clears parasites independent of antimalarial drugs. We hypothesized that between- and within-population variations in host immunity influence parasite clearance after artemisinin treatment and the interpretation of emerging artemisinin resistance. Antibodies specific to 12Plasmodium falciparumsporozoite and blood-stage antigens were determined in 959 patients (from 11 sites in Southeast Asia) participating in a multinational cohort study assessing parasite clearance half-life (PCt1/2) after artesunate treatment andkelch13mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt1/2.P. falciparumantibodies were lowest in areas where the prevalence ofkelch13mutations and slow PCt1/2were highest [Spearman ρ = -0.90 (95% confidence interval, -0.97, -0.65), and Spearman ρ = -0.94 (95% confidence interval, -0.98, -0.77), respectively].P. falciparumantibodies were associated with faster PCt1/2(mean difference in PCt1/2according to seropositivity, -0.16 to -0.65 h, depending on antigen); antibodies have a greater effect on the clearance ofkelch13mutant compared with wild-type parasites (mean difference in PCt1/2according to seropositivity, -0.22 to -0.61 h faster inkelch13mutants compared with wild-type parasites). Naturally acquired immunity accelerates the clearance of artemisinin-resistant parasites in patients with falciparum malaria and may confound the current working definition of artemisinin resistance. Immunity may also play an important role in the emergence and transmission potential of artemisinin-resistant parasites.
authors.affiliation: Disease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia.
authors.forename: Ricardo
authors.identifier: 0000-0002-1014-0432
authors.initials: R
authors.lastname: Ataide
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.affiliation: Disease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Powell
authors.affiliation: Disease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Chan
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.|Victorian Cytology Service Ltd., Melbourne, VIC 3002, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Malloy
authors.affiliation: Disease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: O'Flaherty
authors.affiliation: Division of Malaria Research, Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan.
authors.forename: Eizo
authors.initials: E
authors.lastname: Takashima
authors.affiliation: Disease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Langer
authors.affiliation: Division of Malaria Research, Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Tsuboi
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom.|Worldwide Antimalarial Resistance Network, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford OX3 7FZ, United Kingdom.|Howard Hughes Medical Institute, Malaria Group, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201-1559.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dhorda
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.|National Center for Parasitology, Entomology and Malaria Control, Phnom Penh 12101, Cambodia.
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Chanaki
authors.initials: C
authors.lastname: Amaratunga
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Sasithon
authors.initials: S
authors.lastname: Pukrittayakamee
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom.|Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Quan 5, Ho Chi Minh City, Vietnam.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Department of Medical Research, Lower Myanmar, Yangon 11191, Myanmar.
authors.forename: Ye
authors.initials: Y
authors.lastname: Htut
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom.|Lao-Oxford-Mahosot Hospital-Wellcome Trust-Research Unit, Mahosot Hospital, Vientiane, Lao PDR.|Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Lao PDR.
authors.forename: Mayfong
authors.initials: M
authors.lastname: Mayxay
authors.affiliation: Malaria Research Group & Dev Care Foundation, Chittagong, Bangladesh.
authors.forename: M Abul
authors.initials: MA
authors.lastname: Faiz
authors.affiliation: Disease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom.|Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Tak 63110, Thailand.
authors.forename: Francois
authors.identifier: 0000-0002-7951-0745
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Simpson
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Disease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia; fowkes@burnet.edu.au.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.|Department of Epidemiology and Preventive Medicine, Department of Infectious Diseases, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Freya J I
authors.initials: FJ
authors.lastname: Fowkes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage*; D001208:Asia; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000276:immunology* / Q000469:parasitology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins
keywords: artemisinin; drug resistance; immunity; malaria; serology