Lineage dynamics and risk factors underlying serotype 4 invasive pneumococcal disease in Spain.

BACKGROUND: The emergence of vaccine-covered serotypes causing invasive pneumococcal disease (IPD) is a serious concern worldwide. METHODS: We characterized all national serotype 4 IPD isolates from children and adults received at the Spanish Pneumococcal Reference Laboratory (2009-24). RESULTS: We investigated the unexpected rise of serotype 4 causing IPD in young adults after the COVID-19 pandemic, affecting elderly population in recent years. Epidemiological and genomic analysis confirmed that the rise started as an abrupt cluster of cases in Seville (Andalusia) in the year 2022 due to the ST15063 within GPSC12 lineage. This outbreak initially affected non-vaccinated young individuals associated with high rates of tobacco smoking, alcohol, and inhaled drugs followed by a general distribution through the country in the following years that affected adults ≥ 65 years old. Moreover, ST15063 serotype 4 strains displayed enhanced infection rates of human lung cells that significantly increased in the presence of cigarette smoke exposure and by influenza H3N2 coinfection. CONCLUSIONS: These findings highlight the need for targeted vaccination strategies, molecular surveillance, and focused interventions in high-risk populations.