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Addressing the Genetic Dynamics of Plasmodium falciparum under Emerging Partial Resistance to Artemisinin and its Derivatives in a Low Transmission Setting

par Fankem Noukimi, Sandra
Président du jury Vanhamme, Luc
Promoteur Souopgui, Jacob
Publication Non publié, 2026-06-01

Thèse de doctorat

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Résumé :

Malaria control in sub-Saharan Africa is increasingly challenged by the emergence of artemisinin partial resistance, threatening the long-term efficacy of Artemisinin-based Combination Therapies (ACTs) , such as Artemether-Lumefantrine (AL). Sustaining progress toward elimination requires a deeper understanding of the multifactorial drivers of treatment failure, alongside strategies for effective resistance monitoring and the development of alternative therapies. In Rwanda, validated Pfkelch13 mutations associated with delayed parasite clearance have been reported, underscoring the need for integrated clinical and molecular surveillance. This thesis investigated the clinical performance of AL in Kigali, characterized the molecular landscape of drug resistance and vaccine-relevant polymorphisms, and evaluated Artemisia afra as a complementary therapeutic strategy. Clinical evaluation of recurrent Plasmodium falciparum infections following AL treatment revealed persistent parasitemia in a subset of patients. After first treatment, 56.5% remained microscopy-positive and 83.3% qPCR-positive, with continued positivity after retreatment. Genotyping confirmed recrudescence, indicating true treatment failure. Molecular analysis showed high prevalence of resistance-associated polymorphisms, including pfmdr1 Y184F (86.9%) and pfdhfr IRNI (73.9%). Sequencing of Pfkelch13 identified validated artemisinin resistance mutations such as R561H (13.05%) alongside a novel BTB/POZ domain mutation, H384R (13.05%). Importantly, a proportion of treatment failures occurred in the absence of kelch13 mutations, suggesting alternative resistance mechanisms. Increased gametocyte-specific Pfs25 expression following treatment (P = 0.0014) further indicated potential enhancement of transmission among persistent infections.Population-level genomic surveillance confirmed widespread persistence of multidrug resistance markers and expansion of artemisinin resistance associated variants, with non-synonymous Pfkelch13 mutations detected in 50.4% of isolates. Concurrent analysis of the circumsporozoite protein (CSP) gene demonstrated high haplotype diversity and substantial variability in vaccine-relevant epitopes, with fewer than 1% of isolates matching the 3D7 reference haplotype. These findings raise important considerations regarding allele-specific vaccine efficacy in endemic settings. In parallel, Artemisia afra demonstrated measurable in vitro anti-plasmodial activity against both drug-sensitive and multidrug-resistant strains, comparable to Artemisia annua. Preparation and storage conditions significantly influenced efficacy, and standardized lyophilized formulations retained bioactivity. A preliminary community-based trial suggested potential reduction of asymptomatic parasite carriage when infusions were correctly prepared, with no evidence of renal or hepatic toxicity. Collectively, this work demonstrates the coexistence of Kelch13 propeller domain dependent and independent mechanisms of AL treatment failure, a dynamic and expanding resistance landscape, significant vaccine antigen diversity, and the translational potential of standardized Artemisia afra preparations. These findings support sustained therapeutic efficacy monitoring, expanded genomic surveillance, adaptive vaccine implementation, and rigorous evaluation of complementary strategies to preserve malaria control gains and inform elimination efforts in Rwanda.