Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes

Rajeshwer S. Sankhala, Vincent Dussupt, Gina Donofrio, Gregory D. Gromowski, Rafael A. De La Barrera, Rafael A. Larocca, Letzibeth Mendez-Rivera, Anna Lee, Misook Choe, Weam Zaky, Grace Mantus, Jaime L. Jensen, Wei Hung Chen, Neelakshi Gohain, Hongjun Bai, Michael K. McCracken, Rosemarie D. Mason, David Leggat, Bonnie M. Slike, Ursula TranNingbo Jian, Peter Abbink, Rebecca Peterson, Eric Araujo Mendes, Rafael Freitas de Oliveira Franca, Guilherme Amaral Calvet, Ana Maria Bispo de Filippis, Adrian McDermott, Mario Roederer, Mayda Hernandez, Amie Albertus, Edgar Davidson, Benjamin J. Doranz, Morgane Rolland, Merlin L. Robb, Rebecca M. Lynch, Dan H. Barouch, Richard G. Jarman, Stephen J. Thomas, Kayvon Modjarrad, Nelson L. Michael, Shelly J. Krebs*, M. Gordon Joyce*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Zika virus (ZIKV) is an emerging pathogen that causes devastating congenital defects. The overlapping epidemiology and immunologic cross-reactivity between ZIKV and dengue virus (DENV) pose complex challenges to vaccine design, given the potential for antibody-dependent enhancement of disease. Therefore, classification of ZIKV-specific antibody targets is of notable value. From a ZIKV-infected rhesus macaque, we identify ZIKV-reactive B cells and isolate potent neutralizing monoclonal antibodies (mAbs) with no cross-reactivity to DENV. We group these mAbs into four distinct antigenic groups targeting ZIKV-specific cross-protomer epitopes on the envelope glycoprotein. Co-crystal structures of representative mAbs in complex with ZIKV envelope glycoprotein reveal envelope-dimer epitope and unique dimer-dimer epitope targeting. All four specificities are serologically identified in convalescent humans following ZIKV infection, and representative mAbs from all four groups protect against ZIKV replication in mice. These results provide key insights into ZIKV-specific antigenicity and have implications for ZIKV vaccine, diagnostic, and therapeutic development.

Original languageEnglish
Article number112942
JournalCell Reports
Volume42
Issue number8
DOIs
StatePublished - 29 Aug 2023
Externally publishedYes

Keywords

  • CP: Immunology
  • X-ray crystallography
  • Zika virus
  • dengue virus
  • flavivirus
  • monoclonal antibodies
  • neutralizing antibodies
  • rhesus macaque
  • structural biology

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