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Aim: Dengue and Zika viruses cause significant mortality globally. Considering high sequence similarity between the viral proteins, we designed common multi-epitope vaccine candidates against these pathogens. Methods: We identified multiple T and B cell epitope-rich conserved ‘immunogenic hotspots’ from highly antigenic and phylogenetically related viral proteins and used these to design the multi-epitope vaccine (MEV) candidates, ensuring high global population coverage. Results: Four MEV candidates containing conserved immunogenic hotspots from E and NS5 proteins with the highest structural integrity could favorably interact with TLR4-MD2 complex in molecular docking studies, indicating activation of TLR-mediated immune responses. MEVs also induced memory responses in silico, hallmarks of a good vaccine candidate. Conclusion: Conserved immunogenic hotspots can be utilized to design cross-protective MEV candidates.

Diseases caused by Dengue (DENV) and Zika (ZIKV) viruses cause significant mortality and illness globally. Due to the high sequence similarity of the viral proteins and the purported cross-reactive immune responses against the viruses, we envisioned a common multi-epitope vaccine (MEV) against both viruses by adopting a novel approach of identifying “immunogenic hotspots”. These stretches of the structural and non-structural proteins are enriched with MHC class I and class II supertype-restricted T cell epitopes, and B cell epitopes, in addition to being highly conserved between different DENV serotypes and ZIKV. Such an approach ensures inclusion of multiple overlapping T and B cell epitopes common to both viruses, and also warrants high population coverage. Importantly, epitopes known to cause antibody-dependent-enhancement of infection have been excluded. These immunogenic hotspots have then been stitched together with linkers in-silico along with an adjuvant, CTxB to develop the MEV candidate. Four structural models of the MEV were selected on the basis of conformational preservation of CTxB, and their biophysical parameters, which also conserved the immunogenicity of the multiple epitopes. Importantly, each of the MEV candidates were found to interact with TLR4-MD2 complex by molecular docking studies, indicative of their ability to induce TLR-mediated immune responses.