Abstract

Malaria remains a leading cause of pediatric morbidity and mortality in sub-Saharan Africa, with Plasmodium 
falciparum accounting for over 90% of cases in high-transmission regions. The RTS, S/AS01 vaccine represents the 
first licensed malaria vaccine, targeting the circumsporozoite protein to prevent sporozoite invasion of hepatocytes. 
This review critically synthesizes evidence on RTS, S/AS01 implementation in high-transmission sub-Saharan 
African pediatric populations, focusing on molecular mechanisms, clinical efficacy, and programmatic challenges. A 
systematic literature search was conducted in PubMed, Embase, and Web of Science databases (2015–2024), 
selecting randomized controlled trials, implementation studies, immunological analyses, and systematic reviews. 
Phase III clinical trials demonstrated modest efficacy of 36% against clinical malaria and 32% against severe malaria 
in children aged 5–17 months following a four-dose regimen, with waning immunity requiring booster doses. 
Immunological studies reveal that RTS, S/AS01 induces anti-circumsporozoite antibodies and CD4+ T-cell 
responses, though protection is incomplete and variant-dependent. Pilot implementation programs in Ghana, Kenya, 
and Malawi have vaccinated over 2 million children, confirming feasibility and acceptable safety profiles, yet 
coverage gaps, logistical barriers, and interaction with seasonal malaria chemoprevention persist. Cost-effectiveness 
analyses support integration into existing vaccination schedules in high-burden settings, though long-term 
population-level impact requires ongoing surveillance. RTS, S/AS01 represents a significant advance in malaria 
control but requires complementary interventions and next-generation vaccine development to achieve elimination 
targets in endemic regions.