Evolution of invasive pneumococcal disease by serotype 3 in adults: a Spanish three-decade retrospective study

Background: Invasive pneumococcal disease due to serotype 3 (S3-IPD) is associated with high mortality rates and long-term adverse effects. The introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into the Spanish paediatric immunisation programme has not led to a decrease in the adult S3-IPD. We aimed to analyse the incidence, clinical characteristics and genomics of S3-IPD in adults in Spain. Methods: Adult IPD episodes hospitalized in a Southern Barcelona hospital were prospectively collected (1994–2020). For genomic comparison, S3-IPD isolates from six Spanish hospitals (2008–2020) and historical isolates (1989–1993) were analysed by WGS (Illumina and/or MinION). Findings: From 1994 to 2020, 270 S3-IPD episodes were detected. When comparing pre-PCV (1994–2001) and late-PCV13 (2016–2020) periods, only modest changes in S3-IPD were observed (from 1.58 to 1.28 episodes per 100,000 inhabitants year). In this period, the incidence of the two main lineages shifted from 0.38 to 0.67 (CC180-GPSC12) and from 1.18 to 0.55 (CC260-GPSC83). The overall 30-day mortality remained high (24.1%), though a decrease was observed between the pre-PCV (32.4%; 95.0% CI, 22.0–45.0) and the late-PCV13 period (16.7%; 95.0% CI, 7.5–32.0) (p = 0.06). At the same time, comorbidities increased from 77.3% (95.0% CI, 65.0–86.0) to 85.7% (95.0% CI, 71.0–94.0) (p = 0.69). There were no differences in clinical characteristics or 30-day mortality between the two S3 lineages. Although both lineages were genetically homogeneous, the CC180-GPSC12 lineage presented a higher SNP density, a more open pan-genome, and a major presence of prophages and mobile genetic elements carrying resistance genes. Interpretation: Adult S3-IPD remained stable in our area over the study period despite PCV13 introduction in children. However, a clonal shift was observed. The decrease in mortality rates and the increase in comorbidities suggest a change in clinical management and overall population characteristics. The low genetic variability and absence of clinical differences between lineages highlight the role of the S3 capsule in the disease severity.