Identification of the seven critical residues that control ZIKV-DENV cross-reactivity to engineer a non-cross-reactive ZIKV vaccine

Identification of the seven critical residues that control ZIKV-DENV cross-reactivity to engineer a non-cross-reactive ZIKV vaccine

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...

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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-08-01
Series:Cell Reports
Subjects:
CP: Immunology
CP: Microbiology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725008691
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Summary: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.
ISSN:2211-1247

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