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Abstract Predicting how pathogen populations will change over time is challenging. Such has been the case with Streptococcus pneumoniae , an important human pathogen, and the pneumococcal conjugate vaccines (PCVs), which target only a fraction of the strains in the population. Here, we use the frequencies of accessory genes to accurately predict changes in the pneumococcal population after vaccination, hypothesizing that these frequencies reflect negative frequency-dependent selection (NFDS) on the gene products. We find that the standardized fitness of a strain estimated by an NFDS-based model at the time the vaccine is introduced accurately predicts the direction of the strain’s prevalence change observed after vaccine introduction. Further, we are able to accurately predict the equilibrium post-vaccine population composition and assess the migration and invasion capacity of emerging lineages. In general, we provide a method for predicting the impact of an intervention on pneumococcal populations and other bacterial pathogens for which NFDS is a driving force. One Sentence Summary We develop estimates of pneumococcal strain fitness based on the frequencies of accessory genes in a population, and test them using our ability to predict the impact of vaccination.

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