In conclusion, the present study showed that (1) Immunization of turkeys against CD, using ATX as a target vaccine antigen, can effectively prevent mortality and reduce disease severity; (2) Of the two non-toxic antigenic domains of ATX, the ntATX-D2 seems to offer the most efficacious vaccine antigen platform in achieving protective immunity against CD in turkeys; and (3) The immune mechanisms of immunization-driven protection may include an effective antibody response along with enhanced CD4+ and CD8+ T cell functions, which collectively can control infection-induced inflammation. Here, CD8A is linked to infection.