B cells and MNV specific antibody are important in the clearance of primary MNV infection [39] , but the role of T cells in clearance and the potential and mechanisms of vaccination against mucosal norovirus challenge are unknown. We show here that vaccination with either live MNV or Venezuelan Equine Encephalitis replicon particles (VRPs) expressing the MNV capsid protein VP1 protect the intestine against re-challenge for at least six months. Live virus was more effective than VRP-mediated vaccination. There was partial cross protection against MNV infection after vaccination with a HuNV capsid protein. We found that both the clearance of primary infection and vaccination require the concerted efforts of CD4 T cells, CD8 T cells, B cells, and that T cells required the effector molecule perforin for maximal impact on MNV infection. The effects of specific immune cell types were tissue specific, differing between ileum and mesenteric lymph nodes. These are the first studies to demonstrate immune mechanisms responsible for norovirus clearance and vaccination.