Abstract
Zika virus (ZIKV) is an arbovirus with single-stranded RNA that has become a major health concern worldwide, particularly in tropical and subtropical areas where it is transmitted by Aedes aegypti mosquitoes. Infection can leads to severe neurological complications, including microcephaly in infants and Guillain-Barré syndrome in adults. Due to the absence of a licensed vaccine, the current study was conceived to design a novel circular mRNA vaccine, capable of inducing an effective immune response by targeting the ZIKV proteins. Total 26 top-ranked epitopes (IC(50) ≤ 100 nM) were prioritized from the conserved regions of ZIKV proteins. A multi-epitope construct was designed by incorporation of prioritized epitopes and β-defensin III adjuvant sequences to enhance immune activation. Molecular docking analysis revealed significant molecular interactions between the designed vaccine molecule and Toll-like receptors (TLRs), predicting an effective immune capability of the model vaccine. Molecular dynamics simulation validated the molecular and structural stability of the vaccine structure under physiological conditions. Immune simulations analysis predicted that the vaccine molecule could boost antibody production and is capable of achieving a global population coverage of 93.22%. Additionally, the circular mRNA vaccine design exhibited stability, with a minimum free energy (MFE) of - 1515.60 kcal/mol and a secondary centroid structure of - 1181.42 kcal/mol, speculating a resilient vaccine framework for potential ZIKV immunity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00362-0.