We next assessed vaccination with heterologous ORF2 proteins. Mice were vaccinated and boosted with VRPs expressing ORF2 from Chiba Virus or Lordsdale virus and challenged with MNV1.CW3. Vaccination with Lordsdale virus capsid led to statistically significant protection against MNV infection in the distal ileum, (p = 0.0007, Figure 1B ) but not the MLN ( Figure 1C ). No significant reduction in MNV titers was seen after immunization with Chiba virus capsid ( Figure 1B and 1C ). Protection after Lordsdale ORF2 VRP vaccination did not correlate with generation of cross-reactive serum IgG in these mice, measured by ELISA, despite the potential for such cross-reactivity revealed by western blot ( Figure S1B ). Fecal extracts from immunized mice yielded no measurable homotypic or heterotypic IgG or IgA (data not shown). Taken together, these data show that there is measurable functional immunologic cross protection between Lordsdale virus and MNV in the distal ileum. The lack of a correlation between serum or fecal antibody responses and protection suggested that protection may be T cell mediated.