A Multiplex Serological Assay to Evaluate the Antibody Responses to a Set of Plasmodium falciparum Antigens and Their Protective Role Against Malaria in Children Aged 1.5 to 12 Years Living in a Highly Seasonal Malaria Transmission Area of Burkina Fa

<b>Background/Objectives:</b> Understanding the seroepidemiology of <i>P. falciparum</i> antibody responses is essential for assessing the acquisition of natural immunity and may guide interventions that impact the acquisition of immunity against malaria in endemic areas. This study assessed the association between antigen-specific IgG responses and protection against <i>P. falciparum</i> infection in children from Burkina Faso. <b>Methods</b>: Children aged 1.5 to 12 years were followed using cross-sectional and longitudinal approaches. IgG responses to 16 <i>P. falciparum</i> antigens were measured using a multiplex assay and analyzed by age group and malaria infection status. Associations between antibody levels and clinical malaria risk were assessed using incidence rate ratios (IRRs), and predictive performance of antibody combinations was evaluated using ROC analysis. <b>Results</b>: IgG responses to AMA1, CSP, and MSP2 CH150 showed weak but significant positive correlation with age. Children aged 5-12 years had higher antibody levels than younger children aged 1.5-5 years. Uninfected children had higher levels of antibodies to EBA181 RIII-V, Rh5.1, and SEA1, while infected children had elevated AMA1 and MSP2 CH150. Anti-GLURP R2 and anti-Rh5.1 antibodies were associated with reduced malaria risk (adjusted IRR = 0.52 and 0.40, respectively). The antibody combination of AMA1, GLURP R2, and Etramp5 Ag1 showed the best predictive performance (AUC = 0.70). <b>Conclusions</b>: This study underlines the value of less-studied antibodies (Etramp5 Ag1, Rh5.1, HSP40 Ag1) for diagnosing and protecting against malaria, opening up prospects for the development of more effective tests and targeted vaccine approaches. The variability of responses according to age and infection status calls for further studies to optimize prevention strategies.