Resurfaced ZIKV EDIII nanoparticle immunogens elicit neutralizing and protective responses in vivo

George I. Georgiev, Ryan J. Malonis, Ariel S. Wirchnianski, Alex W. Wessel, Helen S. Jung, Sean M. Cahill, Elisabeth K. Nyakatura, Olivia Vergnolle, Kimberly A. Dowd, David Cowburn, Theodore C. Pierson, Michael S. Diamond, Jonathan R. Lai

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Zika virus (ZIKV) is a flavivirus that can cause severe disease, but there are no approved treatments or vaccines. A complication for flavivirus vaccine development is the potential of immunogens to enhance infection via antibody-dependent enhancement (ADE), a process mediated by poorly neutralizing and cross-reactive antibodies. Thus, there is a great need to develop immunogens that minimize the potential to elicit enhancing antibodies. Here we utilized structure-based protein engineering to develop “resurfaced” (rs) ZIKV immunogens based on E glycoprotein domain III (ZDIIIs), in which epitopes bound by variably neutralizing antibodies were masked by combinatorial mutagenesis. We identified one resurfaced ZDIII immunogen (rsZDIII-2.39) that elicited a protective but immune-focused response. Compared to wild type ZDIII, immunization with resurfaced rsZDIII-2.39 protein nanoparticles produced fewer numbers of ZIKV EDIII antigen-reactive B cells and elicited serum that had a lower magnitude of induced ADE against dengue virus serotype 1 (DENV1) Our findings enhance our understanding of the structural and functional determinants of antibody protection against ZIKV.

Original languageEnglish
Pages (from-to)811-823.e7
JournalCell Chemical Biology
Issue number5
StatePublished - May 19 2022


  • DENV
  • ZIKV
  • combinatorial mutagenesis
  • flavivirus
  • immune focusing
  • immunogen resurfacing
  • nanoparticle
  • phage display
  • protein engineering
  • vaccine


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