Identification of the seven critical residues that control ZIKV-DENV cross-reactivity to engineer a non-cross-reactive ZIKV vaccine
2025
Ariadna Grinyo-Escuer | Srikar Reddy | Agnes L. Chenine | J. Charles Whitbeck | Sonya Jacobsen | Allison Sheetz | Kyle Doolan | Diana M. Norden | Nolan Frey | Frederick W. Holtsberg | M. Javad Aman | Katja Fink | Michael S. Diamond | John S. Schieffelin | James E. Crowe, Jr. | Edgar Davidson | Benjamin J. Doranz
Summary: The development of a Zika virus (ZIKV) vaccine is complicated by the high homology between ZIKV and dengue virus (DENV) envelope (E) proteins, resulting in immunological cross-reactivity that can exacerbate disease through antibody-dependent enhancement (ADE). Here, we screen 121 anti-DENV monoclonal antibodies (mAbs) for cross-reactivity with ZIKV E proteins. We identify 70 cross-reactive mAbs, 66 of which have epitopes that included at least one of seven E protein residues conserved among DENV1–DENV4 and ZIKV (R73, E79, W101, L107, F108, K110, and W212), establishing these residues as the key determinants of DENV-ZIKV cross-reactivity. Using these data, we engineer a ZIKV E protein variant with 10 mutations (“ZIKVm10”) that reduces cross-reactivity with DENV mAbs in vitro and minimizes the induction of anti-DENV antibodies in immunized mice. Passive serum transfer from ZIKVm10-immunized mice confers near-complete protection against lethal ZIKV challenge and reduced ADE for DENV infection, providing a pathway for improved ZIKV vaccine design.
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