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

Significance Slow-clearing artemisinin-resistant malaria parasites are now well established in the Greater Mekong Subregion. This large multinational therapy efficacy study incorporating clinical data, molecular drug-resistance markers, and immune profiling aimed to understand how variations in population levels of naturally acquired malarial immunity affect the slow-clearing phenotype, emergence of artemisinin resistance-associated mutations, and assessment of the geographical spread of artemisinin resistance. We found that slow-clearing mutant parasites occur at higher frequencies in areas where immunity is lowest, patients with higher immunity have faster clearance times, and immunity has the greatest effect on clearance in patients with slow-clearing mutant parasites. Immunity plays an important role in the emergence of resistant parasites and can confound the World Health Organization’s phenotype and genotype definitions of artemisinin resistance.