New vaccine strategies targeting cellular and trained immunity against intracellular bacteria in fish.

The rapid growth of global aquaculture has led to an increase in infectious diseases, including intracellular bacterial pathogens such as Piscirickettsia salmonis and Edwardsiella spp., which threaten the industry's sustainability. These microbial agents evade humoral immunity by replicating inside host cells, making traditional inactivated vaccines largely ineffective because they do not generate strong cell-mediated immunity (CMI) or trained immunity. Here, we revisit and analyze emerging strategies aimed at stimulating CMI and inducing trained immunity in fish, explaining their mechanisms and their potential to control intracellular infections. We also examine the use of in silico platforms to identify antigens that activate cellular pathways, followed by advanced delivery and expression methods such as nanolipids (LNPs) and recombinant bacteria such as Bacillus Calmette-Guérin (BCG). Additionally, we explore trained immunity, the epigenetic and metabolic reprogramming of innate immune cells, as a complementary approach for broad-spectrum protection. Lastly, we highlight the need to redefine vaccine efficacy by including functional memory parameters beyond traditional antibody titers and survival rates. By integrating these advances, this review assesses innovative platforms that could transform disease control and decrease reliance on antibiotics in modern aquaculture.