A computationally designed multi-epitope vaccine (V4) targeting major HFMD-causing enteroviruses demonstrated strong TLR4 binding (-801.3 kcal/mol) and robust predicted immune responses in silico.
An in silico designed multi-epitope vaccine (V4) against major HFMD-causing enteroviruses shows promising structural stability, TLR4 binding, and predicted immunogenicity, providing a framework for experimental validation.
Hand, Foot, and Mouth Disease (HFMD) presents a serious public health concern, especially in children below five years of age and is predominantly caused by Coxsackievirus A16 (CV-A16) and Enterovirus 71 (EV-A71). Despite the availability of supportive treatments and strain-specific protection offered by existing monovalent vaccines, there is an urgent need for a broadly effective, widely accessible multivalent vaccine. This study implements reverse vaccinology to design a multiepitope vaccine targeting key immunogenic regions of CV-A6, CV-A16 and EV-A71. From 18,278 VP1 capsid protein sequences, redundancy was eliminated using CD-HIT (90% identity threshold), yielding 4,309 non-redundant sequences. Further screening for antigenic potential, non-allergenicity, non-toxicity, resulted in 306 qualified candidates for epitope prediction analysis. Highly immunogenic B-cell (BCPred score > 0.8, specificity > 75%), CTL (MHC-I binding IC50 < 200 nM), and HTL (MHC-II binding IC50 < 200 nM) epitopes were predicted from these sequences and integrated into four chimeric vaccine constructs. Among these the Vaccine 4 (V4) construct exhibited optimal structural stability. Molecular docking of the V4 construct with human Toll-Like Receptor 4 (TLR4) revealed a strong complex with a ClusPro-weighted score of −801.3 kcal/mol. Molecular dynamics simulations over 120 ns showed V4-TLR4 complex stabilization with RMSD values of 0.3–0.4 nm. C-ImmSim immune simulation predicted a predominant Th1/Th17 immune response, characterized by robust B-cell activation with peak IgG1 antibody titres, progressive memory B-cell formation, and effective antigen clearance upon repeated exposure. Epitopes of the designed construct projected a broad global HLA coverage (99.06%), including 92.71% in India. The V4 construct was codon-optimized for expression in E. coli achieving a Codon Adaptation Index (CAI) of 0.95. This computationally validated V4 multi-epitope vaccine candidate offers a promising, cross-protective strategy against major HFMD-causing enteroviruses, providing a robust preclinical framework that warrants subsequent experimental validation.
Desai et al. (Mon,) conducted a other in Hand, Foot, and Mouth Disease (HFMD). V4 multi-epitope vaccine was evaluated. A computationally designed multi-epitope vaccine (V4) targeting major HFMD-causing enteroviruses demonstrated strong TLR4 binding (-801.3 kcal/mol) and robust predicted immune responses in silico.
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