Vaccine approaches for controlling Fasciola hepatica present a promising avenue, particularly considering increasing resistance to anthelmintic treatments and concerns over chemical residues. Targeting vaccine candidates that are expressed and secreted during the early infective stage of F. hepatica could offer an effective alternative. This approach aims to inhibit the invasion and migration of juvenile parasites, which have not yet fully developed their immune evasion mechanisms, thereby preventing parasite establishment and development in the host. In this study, we evaluated the host immune response and the protective efficacy of a vaccine cocktail comprising four antigens -KTSPIDP, VGHC1, CRTA, and CAL- in sheep infected with F. hepatica. These parasitic antigens were selected based on a proteomic analysis coupled with an "in vitro" interaction model between newly excysted juvenile worms and mouse intestinal epithelial cell cultures. Despite inducing a strong IgG1 response, vaccination did not reduce liver fluke burden nor faecal egg counts. However, it reduced liver pathology caused by the parasite. Our findings highlight the need for further research into early-stage interactions between F. hepatica and the host. Understanding these interactions could facilitate the progress of vaccines capable of disrupting parasite development and transmission in livestock, potentially reducing the economic and health impacts associated with fasciolosis.