The rise of serotype 8 is associated with lineages and mutations in the capsular operon with different potential to produce invasive pneumococcal disease

Despite conjugate vaccine introduction to prevent invasive pneumococcal disease (IPD), serotype replacement by non-vaccine serotypes is a constant concern. In this study, we elucidate the rise of serotype 8 causing IPD in Spain. We evaluated isolates received during the period 2008–2023 including whole genome sequencing characterization and host–pathogen interaction studies. Serotype 8 has emerged as one of the most prevalent serotypes causing IPD in both children and adults. CC53/GPSC3 carrying <i>pspC</i> 6.11 was the dominant lineage in recent years, displaying increased adhesion to lung cells, enhanced biofilm formation, higher factor H recruitment, improved phagocytosis evasion, and greater virulence in a mice pneumonia model than other co-circulating lineages which could explain its predominance. Morphologically, serotype 8 strains exhibit two appearances on blood agar plates: mucoid colonies, and non-mucoid variants. Molecular characterization revealed that non-mucoid variants harbour mutations in the <i>wchA</i> gene and/or others within the capsular operon, leading to increased adhesion and biofilm formation, albeit with reduced immune evasion capacity. Serotype 8 has become a major cause of IPD, with CC53/GPSC3 as the dominant lineage due to its pathogenic advantages. The versatility of the capsular operon contributes to its success in causing IPD. The use of vaccines with broader coverage, such as PCV20 or PCV21, containing this serotype, may offer an effective strategy to ameliorate the impact on IPD by serotype 8.