These studies leave several important questions unanswered. Firstly, we used a homologous virus challenge. In nature, it is likely that hosts are repeatedly challenged with antigenically distinct noroviruses. However, the mouse norovirus strains identified so far fall into a single genogroup, GV, which likely represents a single serotype [9] . In this way murine noroviruses identified to date may present less of a challenge for the immune system than HuNV, which are distributed across 3 genogroups and appear to evolve under antibody selection [51] . In addition, we selected a strain of MNV that is cleared by WT mice. Other strains persist for prolonged periods of up to 35 days [9] . It remains to be determined whether vaccination will be effective against persistent MNV strains. It is interesting that human noroviruses can persist beyond the time frame of usual clinical symptoms [52] [53] [54] [55] . Longterm persistence might contribute to explaining the sporadic epidemics of infection in the absence of an animal reservoir. Antigenic and pathogenetic complexity will likely be a major issue for the development of norovirus vaccines. The lack of comparable variation in MNV strains limits the utility of the MNV model for assessing immunity to antigenically distinct strains. Perhaps this limitation will be overcome as additional strains of MNV are identified, sequenced, and studied. However, the fact that we observed partial cross protection between MNV and one HuNV, and the demonstration that vaccination with many different VLPs can enhance generation of cross reactive antibodies [56] provide some encouragement.