Comparative Analysis of Pneumococcal Serotypes for 10 Years (2014–2024) in the Comunidad Valenciana Region, Spain, and How They Are Correlated with PCV13, PCV20, and PCV21

<b>Background/Objectives</b>: This study analyzes the epidemiology of invasive pneumococcal disease (IPD) and the dynamics of <i>Streptococcus pneumoniae</i> (SP) serotypes in the Comunidad Valenciana (CV) region, Spain, over a 10-year period (2014-2024), with particular focus on vaccine coverage of PCV13 compared to the newer PCV20 and PCV21 formulations. <b>Methods</b>: A total of 2.014 isolates of SP obtained from sterile fluids were included, with available serotype, demographic data, and vaccination status, which were collected from the Epidemiological Surveillance System (AVE) and the Microbiological Surveillance Network of the CV region (RedMIVA). <b>Results</b>: Overall vaccination coverage was low (22.4%), with the highest rates observed in children under 10 years (78%) compared to only 16% in those aged 10-64 years and 22% in those over 64. Serotype distribution revealed 120 distinct serotypes, with serotype 8 (17.6%) and serotype 3 (14.7%) being the most frequent. Serotype 8 predominated among unvaccinated individuals, while serotype 3 remained highly prevalent despite inclusion in PCV13. Other relevant serotypes included 22F, 9N, 19A, 6C, and 23A. Temporal analysis showed that serotype 3 has continued to increase in recent years, whereas serotype 8 rose during the pandemic period but has remained stable in the most recent interval, while 19A, 15A, and 11A significantly declined. Among serotypes with <2% incidence, some, such as 4, 24F, and 38, showed upward trends. <b>Conclusions</b>: The findings suggest that PCV20 currently provides broad coverage of dominant serotypes, but PCV21 may offer advantages should serotypes like 23A, 9N, or 15A increase further due to serotype replacement. Continuous epidemiological surveillance is essential to guide evidence-based vaccine policy and anticipate future vaccine reformulations.