Investigating two decades of Streptococcus pneumoniae bacteraemia in the Gelderland area, the Netherlands, using whole-genome sequencing

Abstract

In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV) was introduced to the childhood immunization programme in 2006 and replaced by the 10-valent PCV (PCV10, GSK) in 2011. To describe invasive pneumococcal disease in the era of childhood PCV vaccination on pneumococcal bacteraemia across all ages, we collected and sequenced 979 pneumococcal blood isolates from consecutive patients with pneumococcal bacteraemia in the Gelderland area, the Netherlands, between 2000 and 2020. In total, 58% of the bacteraemia cases (n=563/979) occurred in the elderly population. Compared to the pre-PCV period (2000-2005), the odds ratio for non-PCV10 bacteraemia was 17.5 (CI 9.9-31.6; P<0.001) in the late-PCV10 period, showing an overall increase in the proportion of bacteraemia cases being caused by non-vaccine serotype pneumococci (2016-2020). The increase in non-PCV10 serotypes is mainly driven by an expansion of lineage global pneumococcal sequencing cluster 3 (GPSC3) expressing serotype 8, alongside the emergence of serotype 12F that was mediated by multiple lineages (GPSC32/GPSC26/GPSC55). Both serotypes 8 and 12F were included in the latest PCV20 formulation that is licensed to be used in children and adults in Europe. Over 20 years, we observed a low prevalence of antimicrobial resistance (AMR) as predicted by genome data. There were no significant changes in AMR prevalence after vaccine introduction (P>0.05 for all comparisons). We saw a stably low prevalence of reduced penicillin susceptibility, which was observed in multiple pneumococcal lineages, with GPSC10 being the most common in the Gelderland collection, whilst GPSC1 and GPSC6 were common among the penicillin-resistant pneumococcal blood culture isolates provided by the Netherlands Reference Laboratory for Bacterial Meningitis. Comparison to global collections of GPSC10, GPSC1 and GPSC6 isolates favored the likelihood of separate introductions of penicillin-resistant isolates rather than cloncal expansion. Genomic surveillance of pneumococcal bacteraemia in this unbiased population sample in the Netherlands supports the use of higher valency PCVs, such as PCV20, especially in adults, to prevent future bacteraemia cases caused by Streptococcus pneumoniae in the Gelderland area, the Netherlands, while maintaining a low prevalence of AMR in the pneumococcal population.

Keywords: serotype; antimicrobial resistance; invasive pneumococcal disease (IPD); pneumococcal conjugate vaccine (PCV); pneumococcal lineage; the Netherlands.

Fig. 1.. Coverage of circulating serotypes in Gelderland, Netherlands, by various vaccine formulations. (Top) Serotype coverage over the different vaccine periods: pre-PCV (2000–2005), PCV7 (2006–2010), early-PCV10 (2011–2015) and late-PCV10 (2016–2020). (Bottom) Serotype coverage by age groups over a 20-year time period. At the time of writing, PCV15 and PCV20 were approved to be used in children and adults; PCV21, PCV24 and IVT-25 were not approved to be used in adults and children and were still under development.

Fig. 2.. Changes in bacteraemia cases caused by non-PCV10 serotypes relative to PCV10 serotypes in the Gelderland area, the Netherlands, coloured by statistical significance. Some confidence intervals (marked with hollow squares) extend beyond the range of the x-axis. Odds ratios are not shown where the confidence intervals were infinite due to low numbers of samples. An odds ratio of>1 shows an increase in non-PCV10 serotype samples compared to PCV10 serotype samples. The results are shown for different vaccine periods, defined as pre-PCV (2000–2005), PCV7 (2006–2010), early-PCV10 (2011–2015) and late-PCV10 (2016–2020).

Fig. 3.. Number of pneumococcal serotypes associated with bacteremia across vaccine periods, stratified by age groups in the Gelderland area, the Netherlands, 2000–2020. Red denotes non-PCV10 (GSK) serotypes; blue denotes serotypes covered by PCV7; purple denotes serotypes covered by PCV10, but not PCV7. Significance levels are compared to the same serotype in the previous vaccine period. Significant markers at the x-axis represent significant changes between the pre-PCV and late-PCV10 time periods (*, P<0.05; **, P<0.001; ***, P<0.0001). Serotypes with less than ten isolates were not included in the figure. The>18 years group is not included in the figure because the number of cases in this unbiased population sample was insufficient to reach statistical power for individual serotypes.