BACKGROUND Enterovirus 71 (EV71) is the pathogen most likely to cause HFMD in young children (1-5 years old). A small number of virion protein (VP) vaccine candidates are considered as the protective molecules in EV71 models. This study aimed to observe comprehensive immunogenicity for a promising EV71 vaccine depending on VP1 in neonatal mouse EV71 models. MATERIAL AND METHODS VP1 was isolated from patients and associated peptides were synthesized. EV71 particles were inactivated and mixed with Freund's complete adjuvant to prepare peptide vaccines. An EV71 vaccine was administered to establish the mouse model and the mice were infected with EV71. Hematoxylin and eosin staining was used to examine inflammatory response in EV71-infected neonatal mice. A semi-quantitative reverse transcription-polymerase chain reaction assay was performed to evaluate the levels of EV71 virus in skeletal muscle, small intestines, and brain tissues. RESULTS Three peptides were selected from 20 VP1 peptides due to their exhibition of the highest immunogenicity. The peptide injection improved inflammation and decreased EV71 particle levels in muscle, small intestines, and brain tissues. The injection also decreased lesions in the small intestines of EV71-infected mice and protected brain tissues from the EV71 infection. CONCLUSIONS The present study confirmed the immuno-protective effects of VP1 vaccine transplantation in mice infected with EV71 virus. Our results provide valuable information that can be used in further studies investigating the specific mechanism of the anti-EV71 vaccine.