Johne’s disease or paratuberculosis is a condition of significant economic impact globally. The pathogen, Mycobacterium avium subspecies paratuberculosis (Mptb) causes a chronic enteropathy and wasting disease in ruminants. Vaccination and on-farm management strategies are commonly used control measures. Disease progression is slow and it can take many years for animals to develop clinical signs. While vaccines are protective they are not effective in all animals. In addition, animals with subclinical infection are not easily detected by current diagnostic tests and can continue to spread Mptb in their faeces. Therefore, it was imperative to study changes in the host during the long duration of disease progression to identify biomarkers indicative of protection, in both non-vaccinated and vaccinated animals. Immune parameters (lymphocyte proliferation, interferon gamma, interleukin 10 and serum antibodies) and shedding of viable mycobacteria in faeces were monitored for 14 months in 20 control and 38 exposed sheep. Disease outcomes were determined at the end of the trial by culture of intestinal tissues for detection of viable mycobacteria and histopathology for detection of granulomatous infiltrates. Some early (16 weeks post exposure) host responses were predictive of eventual disease outcomes. Similarly, in a trial of vaccinated sheep (with 8 controls and 17 exposed to Mptb) we identified early (13-21 weeks post exposure) host immune responses associated with lack of vaccine protection. Thus, on farms with a history of Johne’s disease, monitoring these parameters in young animals could be used to inform management strategies to identify animals most likely to become highly infectious and to succumb to disease. These early markers can also be used to screen vaccine candidates to develop more effective vaccines.