Design of Hyperglycosylated Zika Virus E Proteins that Focus Antibody Recognition on the Complex E Dimer Epitope

Zika virus (ZIKV) and dengue virus serotypes 1–4 (DENV1–4) are flaviviruses spread by Aedes mosquitoes. ZIKV infection can cause Guillain–Barré syndrome and microcephaly, while severe dengue can lead to hemorrhagic fever and death. DENV infection of ZIKV-immune individuals is linked to severe clinical outcomes due to antibody-dependent enhancement (ADE) of infection. Thus, the development of broadly protective vaccines is an important objective. We focus on the E dimer epitope (EDE) of ZIKV, which is targeted by broadly neutralizing antibodies that protect against ZIKV and DENV1–4. We engineered ZIKV E dimer variants containing non-native asparagine-linked glycosylation sites to block antibody responses to regions outside the EDE using a structure-based iterative design approach. One candidate, SC30m53, bound EDE mAbs but not other mAbs and induced a potently neutralizing response against ZIKV and moderately cross-neutralizing responses against DENV1–3 in mice. These findings suggest that hyperglycosylation provides a promising approach to focusing the immune response on key epitopes.