Abstract

Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence of kelch13 mutants, 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 12 Plasmodium falciparum sporozoite 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 and kelch13 mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt1/2.P. falciparum antibodies were lowest in areas where the prevalence of kelch13 mutations and slow PCt1/2 were 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. falciparum antibodies were associated with faster PCt1/2 (mean difference in PCt1/2 according to seropositivity, -0.16 to -0.65 h, depending on antigen); antibodies have a greater effect on the clearance of kelch13 mutant compared with wild-type parasites (mean difference in PCt1/2 according to seropositivity, -0.22 to -0.61 h faster in kelch13 mutants 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.

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We thank all the patients for their participation in these studies; TRAC study investigators; Bongkot Soonthornsata and Daniel Blessborn for their assistance in specimen management; Annie Mo (NIH) for providing EBA175RII; Robin Anders (La Trobe University) for providing MSP2; Alistair McLean, Jack Richards, and Andrew Guy for technical support; and Paul Newton and colleagues in Laos and TRAC investigators and colleagues in Cambodia for their efforts in support of this work. Antibody work and analysis was supported by the National Health and Medical Research Council of Australia [Project Grant 1060785 (to F.J.I.F., J.A.S., and F.N.), Program Grant APP637406 (to J.G.B.), training fellowship 637396 (to F.J.I.F.), and senior research fellowships APP1077636 (to J.G.B.) and 1104975 (J.A.S.)], the Australian Research Council [Future Fellowships FT130101122 (to F.J.I.F.) and FT0992317 (to J.G.B.)], Ramaciotti Establishment Grant 3245/2011 and Ian Potter Foundation Grant (to F.J.I.F.), and a Victorian State Government Operational Infrastructure Support grant. The clinical trials were funded by the UK Department for International Development, with additional support from the Worldwide Antimalarial Resistance Network and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. The trials were part of the Wellcome Trust Mahidol Oxford Tropical Medicine Research Programme funded by the Wellcome Trust of Great Britain.