A Jennerian approach using live animal viruses to immunize humans is the current lead strategy for developing rotavirus vaccines. This strategy has been modified by incorporating human rotavirus VP7 genes into vaccine strains to induce serotype-specific neutralizing antibodies to human strains. However, the role of homotypic versus heterotypic immunity in protection is unclear. To investigate the importance of serotype-specific immunity in a mouse model, mice were immunized with rhesus rotavirus (RRV: G3, P5[3]), RRV-based modified Jennerian vaccine strains D×RRV (Gl, P5[3]), DS1×RRV (G2, P5[3]), or ST3×RRV (G4, P5[3]), or bovine rotavirus NCDV (G6, P6[1]) and challenged with murine rotavirus ECw (G3, P[16]). Mice immunized with modified Jennerian vaccines exhibited complete to near-complete protection from challenge. NCDV-immunized mice also showed partial protection. The protection was correlated with fecal IgA levels to VP6, not serum IgG responses. Modified Jennerian vaccines induce both heterotypic and homotypic immunity in mice.