Systems Vaccinology-Integrated Proteomics to Develop a Novel Prophylactic and Therapeutic Vaccine Against Human Papillomavirus 16.

Cervical cancer remains a major global health burden, with high-risk human papillomavirus (HPV), particularly HPV-16, responsible for most cases. While licensed prophylactic HPV vaccines are effective, their type-restricted coverage and lack of therapeutic activity highlight the need for next-generation vaccine strategies. In this study, a systems vaccinology-based approach was used to design a multi-epitope vaccine with both prophylactic and therapeutic potential against HPV-16. Immunodominant epitopes eliciting immune responses from HPV-16 E5, E6, E7, and L2 proteins were identified using immunoinformatics methods. Transcriptomic and pathway enrichment analysis of cervical cancer data sets identified interleukin-17A (IL-17A) signaling as a favorable immune axis, supporting its inclusion as a cytokine adjuvant. Population coverage evaluation demonstrated broad global applicability, with a predicted coverage of 99.98% across MHC class I and II alleles. Among 7 designed constructs, 1 candidate (model D) exhibited favorable physicochemical and structural properties, including high predicted solubility (73%), strong model quality, and antigenic potential. Docking analyses indicated strong correlations between native complexes and the corresponding vaccine-IL-17 receptor A and C complexes (Pearson r = .98 and .88, respectively). Molecular dynamics simulations over 500 ns confirmed structural stability, with favorable MM/PBSA binding free energies (ΔG_total ≈ -31 kJ/mol). Immune response simulations demonstrated activation of CD4+ and CD8+ T-cells, memory B-cell formation, and a predominantly IFN-γ immune response. These findings demonstrate that the proposed construct is a promising HPV-16 vaccine candidate; nevertheless, targeted in vitro and in vivo studies are essential to confirm its immunogenicity, efficacy, and safety prior to further clinical developments.