Computational Design of a Novel Multi-Epitope Vaccine Against <i>Aggregatibacter actinomycetemcomitans</i>: A Potential Intervention for Periodontitis and Systemic Diseases

Aggregatibacter actinomycetemcomitans is a key cause of periodontitis in young individuals and is linked to systemic diseases like endocarditis, atherosclerosis, arthritis, brain abscesses and oral cancer. Its virulence and rising antimicrobial resistance highlight the urgent need for new therapeutic strategies. Herein, a multi-epitope vaccine candidate (MVAA) was designed to offer a novel therapeutic approach for mitigating A. actinomycetemcomitans-induced pathogenesis. Adhesins and surface proteins were analyzed to identify immunodominant epitopes– seven CD8[Formula: see text], six CD4[Formula: see text] and eight B-cell epitopes — fused using appropriate linkers (LRMKLPKS, GPGPG and KK), a DC targeting peptide (FYPSYHSTPQRP) and Cholera toxin subunit B as an adjuvant, forming a 531-aa chimeric antigen. The construct was predicted to be soluble, stable, antigenic, nonallergenic and to possess favorable physicochemical properties. Notably, the selected alleles are expected to cover [Formula: see text]96% of the global population. The tertiary structure of MVAA was modeled, refined and validated through computational approaches. The chosen CD8[Formula: see text] and CD4[Formula: see text] cell epitopes were found to possess strong binding affinity for the predicted HLA class I and class II alleles, respectively. Molecular docking revealed high binding affinity for MVAA–TLR2–TLR1 (–208.5 kcal/mol) and MVAA–TLR4–MD2 (–232.2 ± 2.8 kcal/mol) complexes. Molecular dynamics simulation demonstrated the stability and strong binding affinity of MVVA for immune receptors in a biological environment. Additionally, codon adaptation and in silico cloning were performed to ensure the reliability and optimal expression of MVAA in the Escherichia coli system. In silico immune simulations suggested its ability to stimulate innate and adaptive immunity. The designed MVAA could be a promising therapeutic candidate for mitigating the A. actinomycetemcomitans-associated pathologies, and warrants experimental validation studies.