HuNV infection and disease is rapid, with symptoms developing within 24-48 hours of infection and lasting for a few days. Thus, we selected three days after challenge as a readout for infection in our studies, since relevant vaccine-generated immune responses would have to act very early after challenge. Lack of any of the three components of the adaptive response: B cells, CD4 T cells, or CD8 T cells significantly diminished vaccine effects generated by either live virus or VP1 capsid protein immunization, and delayed viral clearance during primary infection. This indicates that VP1 has antibody epitopes as well as MHC H-2b restricted CD4 and CD8 T cell epitopes. These data suggest that it may be necessary to engage the concerted actions of an intact immune response including both MHC Class I and MHC Class II restricted T cells and antibody responses to efficiently vaccinate against HuNV infection.