Integrative Computational Modeling of a Multi-Epitope Vaccine to Fight Periodontal Diseases, Oral and Extra-Oral Malignancies

The expanding clinical relevance of Fusocbacterium nucleatum, spanning common oral infections and cancer to extra-oral cancer, coupled with its antibiotic resistance, warrants the exploration of new therapeutic avenues. Herein, immunoinformatics approaches were employed to predict immunogenic B-cell and T-cell (CD8[Formula: see text] and CD4[Formula: see text] epitopes from ten virulence-associated proteins of F. nucleatum for the design of a multi-epitope vaccine candidate (MEVC). The selected epitopes were antigenic, nonallergenic, nonhomologous to human proteins and conserved across various strains. A chimeric MEVC was designed by integrating a resuscitation-promoting factor (adjuvant), PADRE sequence, epitopes and linkers (AAY, GPGPG, GGGS and KK) to enhance immunogenicity and structural stability. Structural modeling and molecular docking revealed strong binding affinities of T-cell epitopes with human and mouse MHC receptors. The vaccine construct showed favorable immunological properties, thermostability, solubility and wide population coverage. Docking of the vaccine construct with innate immune receptors, namely TLR2 and TLR4 via HADDOCK 2.4 revealed strong interactions, indicating their possible involvement in triggering immune activation. Strong binding affinities (MEVC-TLR2: –31.41 ± 6.89 kcal/mol; MEVC–TLR4: –52.22 ± 1.71 kcal/mol), as well as structural stability, compactness and flexibility of the proposed vaccine in complex with innate immune receptors, were validated through molecular dynamics simulations. In silico immune simulation revealed strong and sustained humoral and cellular responses, including high IgM/IgG titers, elevated CD8[Formula: see text] and CD4[Formula: see text] T cell activity, and robust cytokine induction, suggesting durable and coordinated immune protection by the MEVC. Further, in vitroand in vivo trials are required to affirm the effectiveness of the constructed vaccine against F. nucleatum.