We have developed virulence-attenuated strains of Listeria monocytogenes (Lm) that can be used as safe yet effective vaccine carriers for neonatal vaccination. Here we compare the vaccine efficacy of Lm based vaccine carrier candidates after only a single immunization in murine neonates and adults: Lm Delta(trpS actA) based strains that express and secrete multiple copies of the model antigen ovalbumin (OVA) either under the control of a phagosomal (P(hly)) or cytosolic (P(actA))-driven listerial promoter. While both strains induced high levels of antigen-specific primary and secondary CD8 and CD4 T cell responses, both neonatal and adult mice immunized with the phagosomal driven strain were significantly better protected against wildtype Lm challenge as compared to the naïve control group than mice immunized with the cytosolic driven strains. Interestingly, only neonatal mice immunized with the phagosomal driven strains generated high IgG antibody responses against OVA. Our phagosomal driven Lm-based vaccine platform presents the broadest (cellular & humoral response) and most efficient (highly protective) vaccine platform for neonatal vaccination yet described.