Mucosal IgA to pre-fusion F protein predicts protection from RSV infection in a high burden setting

Respiratory syncytial virus (RSV) causes over 100,000 annual deaths, predominantly in low-and middle-income countries, yet immunological correlates of protection remain poorly defined in high-burden settings. We conducted an intensively sampled prospective household cohort study in The Gambia, following 342 participants over 12 months with weekly PCR testing and longitudinal serum and nasal sampling. Using a Bayesian hierarchical framework jointly modelling antibody kinetics, household transmission dynamics, and imperfect PCR ascertainment, we characterised humoral immunity to RSV-A antigens across systemic and mucosal compartments. Mucosal IgA to the pre-fusion F (pre-F) protein was the strongest predictor of protection against infection (AUC = 0.72), outperforming serum anti-Pre-F IgG (AUC = 0.66). Serum and mucosal responses were largely compartment-independent (r = 0.02–0.28), with a combined serum and mucosal anti-Pre-F model outperforming either alone, and both biomarkers correlating with RSV-A neutralising titres. These findings have direct implications for designing RSV infection preventing vaccine strategies.