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

Cell Chem Biol. 2022 May 19;29(5):811-823.e7. doi: 10.1016/j.chembiol.2022.02.004. Epub 2022 Feb 28.


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.

Keywords: DENV; ZIKV; combinatorial mutagenesis; flavivirus; immune focusing; immunogen resurfacing; nanoparticle; phage display; protein engineering; vaccine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Dengue Virus* / chemistry
  • Humans
  • Nanoparticles*
  • Viral Envelope Proteins / chemistry
  • Viral Envelope Proteins / genetics
  • Zika Virus Infection* / prevention & control
  • Zika Virus*


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Viral Envelope Proteins