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

Abstract

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.

Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) "PI18/00339", "PI21/01000", "INT22/00096", "FI22/00279", CIBER "CIBERES-CB06/06/0037", "CIBERINFEC-CB21/13/00009" and MSD grant "IISP 60168".

Keywords: Genomics; Serotype 3; Streptococcus pneumoniae.

Fig. 1

Evolution of serotype 3 lineages that cause IPD in adults. The black line (right axis) represents the overall incidence (episodes/100,000) of IPD in adults. The bars represent the incidence of S3-IPD by periods (left axis) caused by different STs. Other-CC180 includes ST8561, ST9420 and ST18057. Other-CC260 includes ST1377, ST18059 and ST18060. Other Lineages represents isolates belonging to ST113 (GPSC50), ST458 (GPSC458), ST717 (GPSC3), ST6193 (GPSC309) and ST18058.

Fig. 2

Genetic diversity of CC180-GPSC12. Heatmap displaying differences in the SNPs, using the oldest isolate HUB-01001 as a reference. The phylogenetic tree groups genomes into different clades based on the SNPs, with their origins shown as black triangles in the tree. Circles at the end of the branches represent hospitals. The other information displayed includes the ST (shown as squares) and the period, as well as the presence of transposons and phages (shown as dots).

Fig. 3

Genetic diversity of CC260-GPSC83. Heatmap displaying differences in the SNPs, using the oldest isolate HUB-01990 (1991) as a reference. The phylogenetic tree groups genomes into different clades based on the SNPs, with their origins shown as black triangles in the tree. Circles at the end of the branches represent hospitals. The other information displayed includes the ST (shown as squares) and the period, as well as the presence of transposons and phages (shown as dots).

Fig. 4

Analysis of the overall serotype 3 pangenome and major lineages. (a) The X-axis shows the number of genomes included in the analysis, while the Y-axis presents the number of genes in the pan-genome analysis for each added genome. The squares display the conserved genes of the genome, whereas the dots represent the accessory genes. (b) Representation of the pan-genome according to the core genome (in dark green), the soft-core genome (in light green), the shell genome (in orange) and the cloud genome (in beige). The grey line represents the core genome (core plus soft-core genome) and the dark purple line represents the accessory genome (shell plus cloud genome). (c) Differences in the genes between the conserved genome and the accessory genome of GPSC12 (red line) and GPSC83 (blue line) are shown.