Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes
CP: Immunology; X-ray crystallography; Zika virus; dengue virus; flavivirus; monoclonal antibodies; neutralizing antibodies; rhesus macaque; structural biology
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.
Sankhala, Rajeshwer S.; Dussupt, Vincent; Donofrio, Gina; Gromowski, Gregory D.; De La Barrera, Rafael A.; Larocca, Rafael A.; Mendez-Rivera, Letzibeth; Lee, Anna; Choe, Misook; Zaky, Weam; Mantus, Grace; Jensen, Jaime L.; Chen, Wei-Hung; Gohain, Neelakshi; Bai, Hongjun; McCracken, Michael K.; Mason, Rosemarie D.; Leggat, David; Slike, Bonnie M.; Tran, Ursula; Jian, Ningbo; Abbink, Peter; Peterson, Rebecca; Mendes, Eric Araujo; Freitas de Oliveira Franca, Rafael; Calvet, Guilherme Amaral; Bispo de Filippis, Ana Maria; McDermott, Adrian; Roederer, Mario; Hernandez, Mayda; Albertus, Amie; and Davidson, Edgar, "Zika-specific neutralizing antibodies targeting inter-dimer envelope epitopes" (2023). GW Authored Works. Paper 3199.
Microbiology, Immunology, and Tropical Medicine