Abstract

Severe malaria, primarily caused by Plasmodium falciparum, continues to pose a major threat to global health 
despite substantial progress in control measures. This review synthesizes current understanding of severe malaria 
pathogenesis, with emphasis on adaptive immunity, genetic and epigenetic susceptibility, diagnostic and 
therapeutic advances, and translational research models. The adaptive immune response, particularly T- and B
cell-mediated mechanisms, is central to disease progression and protection, though often dysregulated, 
contributing to immunopathology. Genetic and epigenetic factors, including variants such as sickle cell trait, 
G6PD deficiency, and DARC polymorphisms, modulate host susceptibility and clinical outcomes. Advances in 
biomarker discovery including transcriptional, metabolic, and immunological profiles offer potential for improved 
prognostic precision and personalized care. Despite highly effective antimalarial drugs such as artesunate, high 
mortality persists, underscoring the need for adjunctive and supportive therapies targeting endothelial 
dysfunction, coagulopathy, and multi-organ failure. Translational research using rodent and primate models 
continues to elucidate host–parasite interactions and guide the design of next-generation vaccines and 
immunotherapies. The review highlights critical knowledge gaps, including the need for integrated models linking 
host genetics, immune dysregulation, and clinical outcomes. Addressing these challenges through 
multidisciplinary research will advance diagnostic innovation, improve clinical management, and accelerate 
vaccine development to reduce the global burden of severe malaria.