Decoding yellow fever virus immunogenicity: Targeting highly effective epitopes of YFV for next-generation vaccine design.

Yellow fever (YF) remains a significant public health concern despite the success of the live-attenuated YF-17D vaccine. While YF-17D serves as a benchmark for durable protection, its inherent drawbacks, including cold-chain dependence, contraindications for vulnerable populations, and rare severe adverse events, necessitate the development of safer, more deployable alternatives. The core of next-generation vaccine design lies in the systematic identification and functional validation of highly effective YFV epitopes. The robust immunogenicity of YF-17D is characterized by a polyfunctional, multilineage immune response sustained by high-quality CD8+ T cells (targeting NS3 and NS4B) and neutralizing antibodies (targeting the E protein domains EDII and EDIII). Advanced analyses reveal that precise epitope selection within these proteins is the foundational principle for next-generation platforms. Rather than offering a merely historical literature recap, this review provides a critical, methodologically driven synthesis that bridges computational tools, such as immunoinformatics, molecular dynamics simulations, and systems biology, with biological validation pipelines. By establishing this 'prediction-to-proof' framework, next-generation platforms (including peptide-based, genetic, and chimeric constructs) can be rationally engineered to minimize reactogenicity while retaining the robust immunological signature defined by YF-17D. Ultimately, this approach provides an actionable blueprint to translate high-resolution immunopeptidomic data into precision tools for yellow fever control and broader flavivirus vaccine design.