Live virus vaccination was more effective than VRP based vaccination. The lower level of protection that we observed with ORF2 VRPs in contrast to MNV1.CW3 may be due to many factors, and this study does not provide mechanistic insights into this difference. In comparison to VLPs, VRPs may have advantages in systemic vaccination including targeting dendritic cells and intrinsic adjuvant activities [50] . These properties of VRPs may be responsible for the effectiveness of systemic single protein subunit vaccination against mucosal viral challenge in this case. However, it may be that because VRPs undergo a single round of replication at the site of inoculation they cannot generate the same breadth of immunity that is generated by live replicating virus. While VRP vaccination clearly induces some relevant effector and memory cell responses, vaccination with capsid alone may not sufficient to generate the complete antigenic repertoire required for effective immunity. Interestingly, we found some protection with the non-structural ORF1 polyprotein, suggesting that protective epitopes exist outside of the capsid protein. As the ORF1 polyprotein is expressed early after infection, it may be that these epitopes would be valuable targets for generating an efficient immune response.