Multi-epitope tick vaccines: From computational design to field deployment, immunoinformatics approaches, validation challenges, and translational pathways.

Ticks are major vectors of pathogens affecting both humans and animals, yet effective and sustainable control strategies remain limited. Conventional vaccines based on the concealed antigen Bm86 provide only partial protection and are often constrained by antigenic variability and strain-specific responses. Recent advances in immunoinformatics have enabled the rational design of multi-epitope vaccines (MEVs), which integrate selected B-cell and T-cell epitopes derived from functionally relevant tick proteins involved in physiology and reproduction. This review synthesizes current approaches to MEV design across the full development pipeline, including antigen selection, epitope prediction, immunoinformatic safety assessment (antigenicity, allergenicity, and toxicity), structural modeling, molecular docking, molecular dynamics simulations, and experimental validation through in vitro and in vivo studies. Key bioinformatic tools commonly used at each stage are discussed, along with their roles in improving epitope selection and construct stability. Despite these advances, several limitations remain, including the redundancy of tick biological systems, genetic variability among tick populations, and the gap between computational predictions and experimental validation. Current evidence highlights that in silico approaches are primarily predictive and must be complemented by experimental studies to confirm immunogenicity and protective efficacy. Emerging strategies, including the integration of artificial intelligence and systems vaccinology, offer opportunities to refine antigen selection and improve predictive accuracy. Additionally, multi-target vaccine designs combining different tick antigens represent a promising direction for enhancing vaccine performance. Overall, integrated computational and experimental approaches provide a strong framework for the development of next-generation anti-tick vaccines, with potential to complement existing control measures and contribute to sustainable vector management within a One Health perspective.