Natural carriage of Streptococcus pneumoniae is associated with increased experimental pneumococcal carriage but reduced conjugate vaccine efficacy in a human challenge model.

We investigated the relationship between natural and experimental pneumococcal carriage, focusing on the impact of natural carriage on vaccine efficacy. Statistical analyses were carried out according to a pre-specified Statistical Analysis Plan using R v.4.2.2 (R Development Core Team, Vienna, Austria) and GraphPad Prism v9.0.0 (Graph-Pad Software, San Diego, California, USA). Two key findings emerged: firstly, individuals with natural carriage were more likely to become experimental carriers, and secondly, the efficacy of the PCV-13 vaccine in preventing experimental carriage was reduced in those with natural carriage. Serotype exchange as well as co-colonisation with experimental carriage was observed in 15 participants. We concluded that natural carriage could impact vaccine efficacy in high-prevalence settings, emphasizing the importance of vaccine design targeting reductions in natural carriage. The use of carriage reduction as a trial endpoint was encouraged, along with the adoption of batched samples and molecular diagnostics to enhance trial efficiency.