Abstract Many vaccines against childhood diseases are administered early after birth. Despite the fact that neonatal-infant immunity differs from adult immunity, vaccine development studies frequently test efficacy in adult rather than in neonatal animal models. A good example of this scenario is Bacillus Calmette-Guerin (BCG). BCG is the only vaccine available against tuberculosis (TB). The vaccine lacks efficacy against child and adulthood pulmonary disease or reactivation of latent TB but prevents disseminated TB in children and is thus widely used in countries with endemic TB as part of the neonatal vaccine regimen. There are several new vaccines that have shown efficacy against TB in adult animal models yet fail to protect infants from TB disease in clinical trials. In this novel approach, we used the minipig as a neonatal animal model for evaluation of immune responses to BCG vaccination. The longitudinal immune responses of neonatal mini-piglets vaccinated with BCG were followed until adolescence, with the same monitoring applied to a group of unvaccinated mini-piglets. We characterized the memory and activation phenotype of T cells, cytokine profile, and monocyte activation in response to BCG stimulation from 4 weeks of age into adolescence- age of 24 weeks. Further, we challenged both vaccinated and non-vaccinated animals via aerosol route with a low dose aerosol of Mycobacterium tuberculosis strain HN878 and we characterized changes between the two groups in the course of immune responses following challenge. Based on comparison of immune responses to BCG in minipigs with similar studies in infants, our findings suggest that minipigs have the potential to serve as an effective neonatal animal model for vaccine development.