Quantifying the mechanisms of vaccine-induced serotype replacement in Streptococcus pneumoniae using genome-informed modelling

Streptococcus pneumoniae is a colonizer of the child’s nasopharynx and a leading cause of invasive pneumococcal disease (IPD). Despite widespread use of pneumococcal conjugate vaccines (PCV), recent rebounds in IPD incidence have coincided with serotype replacement. The relative contribution of the replacement of serotypes within lineages and the replacement of the lineages themselves to this phenomenon is unclear. Yet these two evolutionary mechanisms may affect differently the fitness of S. pneumoniae and have distinct consequences on vaccination strategies. Here, we quantified the relative contribution of these two mechanisms to serotype replacement in carriage and their consequences for IPD. We combined nationwide longitudinal surveillance of carriage in children with acute otitis media and IPD in children from 2002 to 2023 with whole-genome sequencing. Observed lineage-specific carriage rates across PCV-related periods were fitted with polynomial logistic regression and compared with two counterfactual scenarios, each isolating one mechanism with: (i) fixed serotype composition within varying lineages and (ii) serotype shifts within fixed lineage carriage rates over time. Carriage dynamics were consistent with an 82% contribution of serotype shifts within persistent lineages. Estimates of serotype-specific IPD incidence derived from this predominant scenario correlated with observed IPD trends. These findings quantify the dominant role of serotype replacement within persistent lineages, disentangling the vaccine-driven adaptive history of S. pneumoniae.