Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and other serious infections, particularly affecting vulnerable populations such as young children and the elderly. However, comprehensive real-world data on the epidemiology, disease burden, and clinical outcomes of pneumococcal infections in Hong Kong are limited. This study addresses these gaps by investigating serotype distribution, lineage patterns, antibiotic resistance, and molecular characteristics of predominant S. pneumoniae serotypes in Hong Kong, particularly in the context of pneumococcal vaccines and the COVID-19 pandemic, with a focus on the persistence mechanisms of serotype 3.