In 2016, 33 Tasmanian devils were given an experimental immunisation against devil facial tumour disease (DFTD) prior to their wild release on the Tasmanian north coast. The devils were monitored for 2.5 years post release to determine the efficacy of the vaccination protocol and the longevity of the induced responses. The vaccine was not protective in the majority of devils trapped during this period. However, the immunised devils that succumbed to natural DFTD challenges showed signs of immune activation which contrasts with the “immune deserts” typical of DFT’s in incumbent (unvaccinated) devils. Immunohistochemical analysis of the vaccinated devils’ tumour biopsies identified the functional immune molecules associated with antigen presenting cells (MHC-II) and T cells (CD3), and the immune checkpoint molecule PD-1, all associated with anti-tumour immunity in other species. Serum samples from immunised and incumbent devils were tested for antibody against unmanipulated cultured DFT cells not expressing MHC-I, and cultured DFT cells treated with the cytokine interferon gamma (IFNg) to upregulate MHC-I expression. Serum antibodies against both cell types persisted in all immunised devils for up to two years post vaccination. A handful of incumbent devils had serum antibodies against both cell types, or against MHC-I upregulated cells only. A further study was the first to interrogate the relevance of the MHC-I molecule for the development of serum antibody against DFT cells. Using CRISPR modified DFT cells, we showed that in those devils with serum antibody against MHC-I upregulated cells only, the antibody targets the MHC-I molecule rather than other molecules upregulated by IFNg treatment. This finding is important given an apparent association between DFT regression and serum antibody against MHC-I upregulated DFT cells.