The differences between immune responses in red deer with either low-grade or high-grade histopathology were profiled following vaccination with a killed whole cell Map vaccine with mineral oil adjuvant and experimental challenge with Mycobacterium avium subspecies paratuberculosis (Map). Immune responses generated were monitored using a Map-specific IgG1 antibody ELISA, an interferon gamma ELISA and flow cytometry. The initial 24 animals in the study were divided into 6 outcome groups on the basis of histological and culture data available post-mortem. Animals mounted a mixed immune response to both vaccination and experimental challenge characterised by high levels of interferon gamma and significant antibody responses. The profile of the Map-specific IgG1 response in the unvaccinated and challenged group showed marked differences between animals with low-grade and high-grade histopathology. Unvaccinated animals with low-grade histopathology tended to show cross-reactive interferon gamma responses. No significant differences were observed in the circulating cell populations. Vaccination eliminated immunological differences between the low and high-grade histopathology groups and affected Johne's disease diagnosis. These profiles provide information on the different immune processes that affect Johne's disease progression in red deer.