9XYB

Crystal structure of a ZIKV E glycoprotein DI-DIII vaccine candidate in complex with human neutralizing antibody MZ4

Summary for 9XYB

• Entry DOI: 10.2210/pdb9xyb/pdb
• Descriptor: Human MZ4 Fab heavy chain, Human MZ4 Fab light chain, Envelope protein E, ... (5 entities in total)
• Functional Keywords: envelope protein, vaccine candidate, recombinant protein, zika virus, human antibody, neutralizing antibody, viral protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 75766.55

Authors

Jensen, J.L.,Joyce, M.G. (deposition date: 2025-08-25, release date: 2026-04-15, Last modification date: 2026-04-29)

Primary citation

Dussupt, V.,Jensen, J.L.,Rosado, A.P.,Donofrio, M.,Pflugheber, J.,Mendez-Rivera, L.,Sankhala, R.S.,Chen, W.H.,Slike, B.M.,Schmid, A.,Tran, U.,Metzger, L.,Peterson, C.E.,Pinto, A.K.,Vasan, S.,Collins, N.D.,Farmer, A.,Michael, N.L.,Joyce, M.G.,Brien, J.D.,Krebs, S.J.
Targeting the Zika virus envelope domains I and III as a recombinant vaccine protects mice from lethal challenge.
Npj Vaccines, 2026

PubMed Abstract: Zika virus (ZIKV) vaccine candidates developed through Phase I clinical trials are based on the full-length envelope glycoprotein (E), which presents both desirable and undesirable antigenic determinants. Among the latter, the conserved fusion loop epitope (FLE) within domain II is a major target for flavivirus cross-reactive and poorly neutralizing responses. To eliminate unwanted FLE targeting, we redesigned ZIKV E using a reverse vaccinology approach, excising domain II and allowing domains I and III (DI-DIII) to fold into an independent subunit harboring key neutralizing epitopes. Ifnar1 mice vaccinated with ZIKV DI-DIII elicited high ZIKV neutralizing antibodies and were protected from weight loss and death. In addition, sera from DI-DIII vaccinated mice demonstrated a reduced capacity to enhance DENV 1-4 infection in vitro, compared to mice vaccinated with full-length E. This study identifies DI-DIII as a promising immunogen, focusing antibody responses to protective epitopes on ZIKV and minimizing the elicitation of unwanted responses.

PubMed: 41980974
DOI: 10.1038/s41541-026-01442-8

Experimental method

X-RAY DIFFRACTION (2.85 Å)