This systematic review and meta-analysis aims to quantify the impact of vaccination on the incidence and prevalence of nonsusceptible infections and investigates the impact of vaccination programs on serotype replacement. We searched a comprehensive set of databases. Identified studies were assessed using the GRADE (Grading of Recommendations Assess-ment, Development and Evaluation) approach and resulting evidence was analyzed using random-effect meta-analyses. Nineteen studies on pneumococcal conjugate vaccines (PCV) met our inclusion criteria. PCV decreases the incidence of nonsusceptible pneumococcal infections (PIs) by 56.91% (95% confidence interval [CI],-50.90% to-62.91%) and the probability of carriage of nonsusceptible pneumococcal bacteria by 28.10% (95% CI,-13.25% to-42.95%). The effect of PCV on PIs becomes higher when only serotypes specifically targeted by the vaccine are taken into account (-80.98%; 95% CI,-70.34% to-91.52%), while it becomes lower when all the PIs, including both susceptible and nonsusceptible PIs, are considered (-48.30%; 95% CI,-31.55% to-65.08%). The effect of PCV is found greater in populations with high prevalence of human immunodeficiency virus and for PCV covering a higher number of serotypes. Findings from this study suggest that vaccination programs may be an effective tool to prevent the spread of PIs and may play a significant role in tackling antimicrobial resistance