Host immunity to <i>Plasmodium falciparum</i> and the assessment of emerging artemisinin resistance in a multinational cohort

Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence of <i>kelch13</i> 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 <i>Plasmodium falciparum</i> 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 (PCt_1/2) after artesunate treatment and <i>kelch13</i> mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt_1/2.<i>P. falciparum</i> antibodies were lowest in areas where the prevalence of <i>kelch13</i> mutations and slow PCt_1/2 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]. <i>P. falciparum</i> antibodies were associated with faster PCt_1/2 (mean difference in PCt_1/2 according to seropositivity, -0.16 to -0.65 h, depending on antigen); antibodies have a greater effect on the clearance of <i>kelch13</i> mutant compared with wild-type parasites (mean difference in PCt_1/2 according to seropositivity, -0.22 to -0.61 h faster in <i>kelch13</i> 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.