Decoding early life exposure and immunity to Streptococcus pyogenes (360G-Wellcome-340466_Z_25_Z)

Streptococcus pyogenes (Strep A) causes 500,000 deaths annually, largely through immune sequelae leading to Rheumatic Heart Disease (RHD) in low- and middle-income countries (LMIC). Vaccine development is hindered by limited understanding of natural immunity and correlates of protection. How infant exposure patterns common in LMICs (skin infections, high antigenic diversity, intense early-life exposure) shape protective and maladaptive immunity remains unclear. We will address three fundamental questions: What antibody responses correlate with protection against Strep A skin and pharyngeal events? Why does intense early-life exposure in high-burden settings fail to generate early protective immunity? Does priming for RHD begin in infancy, and which exposure patterns drive these pathological immune profiles? We will leverage multiple well-characterised cohorts and establish a new birth cohort in The Gambia with an embedded azithromycin intervention altering early colonisation, to define how distinct exposure profiles shape immune development. Whole-proteome multiplex serology combined with statistical and machine-learning approaches will reconstruct individual immune trajectories, identify early biomarkers linked to RHD risk, and map how cumulative Strep A exposures shape protective and pathological immunity. Our programme will transform understanding of early-life Strep A immunity in high-burden settings, generating insight to inform vaccination and prevention strategies against RHD worldwide.