In conclusion, our studies support the now wellaccepted scheme of cellular internalization involving initial binding to cell surface glycosaminoglycans, endocytosis and entrapment within cytoplasmic vesicles. Most of the material unfortunately remains segregated in endocytic vesicles even for the most active of our conjugates and efforts should now be geared at improving endosomal escape. Model systems described here might turn rather useful in future SAR studies if pH-dependent liposome destabilization can be correlated with splicing correction efficiency. The most active conjugates will also have to be monitored for their biodisponibility, metabolic stability and biological activity in animal models. Immune Mechanisms Responsible for Vaccination against and Clearance of Mucosal and Lymphatic Norovirus Infection Two cardinal manifestations of viral immunity are efficient clearance of acute infection and the capacity to vaccinate against secondary viral exposure. For noroviruses, the contributions of T cells to viral clearance and vaccination have not been elucidated. We report here that both CD4 and CD8 T cells are required for efficient clearance of primary murine norovirus (MNV) infection from the intestine and intestinal lymph nodes. Further, long-lasting protective immunity was generated by oral live virus vaccination. Systemic vaccination with the MNV capsid protein also effectively protected against mucosal challenge, while vaccination with the capsid protein of the distantly related human Lordsdale virus provided partial protection. Fully effective vaccination required a broad immune response including CD4 T cells, CD8 T cells, and B cells, but the importance of specific immune cell types varied between the intestine and intestinal lymph nodes. Perforin, but not interferon gamma, was required for clearance of MNV infection by adoptively transferred T lymphocytes from vaccinated hosts. These studies prove the feasibility of both mucosal and systemic vaccination against mucosal norovirus infection, demonstrate tissue specificity of norovirus immune cells, and indicate that efficient vaccination strategies should induce potent CD4 and CD8 T cell responses. More than 90% of epidemic nonbacterial gastroenteritis worldwide can be attributed to human noroviruses (HuNV) [1] [2] [3] . Infection is transmitted fecal-orally, and symptomatic infection is characterized by nausea, vomiting and/or diarrhea lasting 24-48 hours within 24 hours of exposure [4] . Despite the significant costs and morbidity of HuNV infections, no vaccine is currently available. The elderly and individuals in long-term care facilities may be more susceptible to either norovirus infection or norovirusinduced disease [5] and would be an important target population for a norovirus vaccine. The reasons for increased incidence and/ or susceptibility to HuNV disease are unknown. This is due in part to our incomplete understanding of norovirus immunity. The potential to vaccinate against these and related viruses has been demonstrated in gnotobiotic piglets, cats and rabbits [6] [7] [8] , but the immune mechanisms responsible have not been identified. The challenges for vaccine efficacy may be very different between different caliciviruses. For example, variation in MNV strains is significantly less than between HuNV strains [9] . Human volunteer studies demonstrate short-term, but not long-term, protection against homologous, but not heterologous, viral challenge [10] [11] [12] . Since HuNV belong to 3 genogroups (GI, GII and GIV) with many strains in each genogroup [4] , this lack of cross-protection is a challenge for vaccine development. Frequent exposure to noroviruses within short time periods stimulates sustained immunity and resistance to norovirus induced illness [13, 14] . Serum antibody levels in adults reflect susceptibility to infection and do not always correlate with protection [13, 14] . In children, however, serum antibody levels correlate with protection, likely reflecting short-term immunity and recent exposure [15] [16] [17] . A nonfunctional fucosyl transferase gene (FUT2) accounts for a significant proportion, though not all, of resistance to Norwalk virus infection, suggesting that other factors, yet undiscovered, may contribute to norovirus resistance [18, 19] .