Outburst of serotype 4 IPD after COVID-19 is driven by ST15063/GPSC162 lineage associated with high-risk behaviors and greater virulence linked to influenza H3N2 virus coinfection and cigarette smoke

The emergence of vaccine covered serotypes causing invasive pneumococcal disease (IPD) is a serious concern worldwide. We investigated the unexpected rise of serotype 4 causing IPD primarily in non-vaccinated young adults after the COVID-19 pandemic that further spread to adults ≥ 65 years in recent years. For this purpose, we conducted a retrospective study of serotype 4 IPD cases (n=827) reported in Spain between 2009 and 2024. Whole-genome sequencing was performed to assess clonal lineages and phylogenetic relationships. Clinical and epidemiological data were compared between serotype 4 and all other serotypes causing IPD. Epidemiological and genomic analysis confirmed that the rise started as an abrupt cluster of IPD cases in Seville (Andalusia) in the year 2022 due to the ST15063 within GPSC12 lineage. This outbreak initially caused pneumonia episodes that required hospitalization in young individuals associated with high rates of tobacco smoking, alcohol, and inhaled drugs such as cannabis and cocaine, followed by a general distribution pattern throughout the country in the following years, affecting the elderly population. Experimental studies to evaluate potential underlying mechanisms confirmed that 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 virus coinfection, but not with H1N1. These findings highlight the need for targeted vaccination strategies not only against pneumococcus but also against respiratory viruses such as influenza, RSV and COVID-19 and demonstrate the importance of molecular surveillance to establish effective interventions in high-risk populations.