Proteomic signatures of vaccine-induced immunity in teleost fish: from antigen discovery to correlates of protection

Fish-vaccine efficacy in teleosts is still established primarily through pathogen-challenge experiments, which determine whether a formulation protects but provide limited insight into the antigens and immune mechanisms responsible. Proteomics addresses part of this limitation by measuring pathogen proteins and host responses induced by vaccination. This critical narrative review evaluates pathogen-focused and host-response proteomics from antigen discovery through biomarker validation and translational decision-making. We assess quantitative mass spectrometry, immunoproteomics, surfaceome and secretome profiling, and their integration with reverse and systems vaccinology. Across the limited teleost evidence base, vaccination-associated changes involve complement and acute-phase pathways, antigen processing, redox regulation, hemostasis, tissue repair and exosome-associated antigen presentation. Cross-study replication remains weak, and the reported proteins largely represent study-specific vaccine-responsive profiles. More importantly, most studies do not test whether pre-challenge signatures predict subsequent survival, pathogen control or tissue protection. Within the literature reviewed here, no candidate proteomic signature has yet been prospectively replicated in an independent teleost vaccination cohort; therefore, none currently meets the requirements of a validated, transferable correlate of protection. The main obstacles include heterogeneous study designs, incomplete reference proteomes, teleost-specific protein-inference challenges, small cohorts, limited longitudinal sampling and scarce external validation. We argue that the principal bottleneck is now study design and validation rather than mass-spectrometric capability alone. We therefore outline a development sequence that begins with infection relevant antigen selection and proceeds through longitudinal profiling, targeted verification, predictive modeling, independent validation and field evaluation. This framework separates vaccine responsiveness, protection association, prediction and mechanism, using proteomics to support vaccine-development decisions while retaining challenge testing.