Enhanced immunogenicity of an mRNA vaccine against dengue virus serotype 2 with modified key residue

Despite intensive efforts to develop different types of vaccines against dengue virus (DENV), safe and effective products are still lacking. Progress toward this goal has been especially hindered by a pathological phenomenon known as antibody-dependent enhancement (ADE). In our previous study, we demonstrated that the N8 epitope within the envelope (E) protein of DENV2 plays a role in cross-reactivity and infection enhancement. Building on these findings, we designed mRNAs encoding structurally modified DENV2 E proteins (E_1-394-N8R) to assess their antibody neutralization activity and infection-enhancing effects in comparison to wild-type E proteins (E_1-394-WT). Mice were immunized using mRNA-containing lipid nanoparticles (mRNA-LNPs), carrying either the modified (N8R-mRNA-LNP) or wild-type (WT-mRNA-LNP) DENV2 mRNA vaccines. Animals immunized with N8R-mRNA-LNP exhibited higher antibody titers and enhanced neutralizing activity, along with a reduced ADE burden compared to those immunized with WT-mRNA-LNP. Furthermore, sera from N8R-mRNA-LNP-immunized animals demonstrated superior protective effects in vivo compared to sera from WT-mRNA-LNP-immunized animals. Based on these findings, mRNA vaccines with enhancing epitope modification may allow for the generation of highly effective dengue tetravalent mRNA vaccines with low potential for ADE.