Varicella-zoster virus (VZV) is a highly contagious human herpesvirus responsible for chickenpox upon primary infection and shingles upon viral reactivation. While Varicella-zoster immune globulin (VZIG) can offer post-exposure protection for high-risk individuals, structural insights into neutralizing antibodies (nAbs) derived from natural infection remain limited. Glycoprotein E (gE), the most abundant and immunogenic envelope protein of VZV, plays an essential role in viral infection and is the sole antigen in the recombinant zoster vaccine.
In this study, gE was used as the target antigen to isolate three classes of potent human monoclonal antibodies (mAbs) from convalescent individual. Using cryo-electron microscopy, the structure of the Fab WLL-1/Fab WLL-28/gE (gI-binding domain) complex was determined. Structural analysis revealed that Fab WLL-1 mainly interacts with a loop formed by residues 191–
195, situated between β2 and β3, as well as another loop encompassing the α1 helix formed by residues 251–261. Fab WLL-28 binds to multiple loop regions on gE (gI-binding domain), including residues 273–276 located between β5 and β6, a loop region containing the α3 helix formed by residues 290–294, loops between β1 and β2 (aa 178–179) and between β3 and β4 (aa 206–209). These data define key antigenic sites on gE and offer mechanistic insights into antibody-mediated neutralization.
Additionally, the gE N-terminal region (aa 1–188), which interacts with the host receptor IDE, was found to be an immunodominant domain. Neutralizing antibodies targeting this domain were identified exclusively in convalescent individuals, not in vaccine recipients. Competitive ELISA demonstrated that these antibodies effectively block the gE–IDE interaction despite recognizing distinct epitopes, suggesting a common neutralization mechanism via interference with receptor engagement.
Taken together, this work provides structural and functional characterization of human anti-gE antibodies elicited by natural infection. These findings highlight the therapeutic potential of gE-targeting mAbs and offer a foundation for the development of antiviral biologics, particularly for immunocompromised or vaccine-ineligible individuals.
This study presents the isolation of gE-specific antibodies from convalescent patient followed by functional and structural characterization, providing insights into antibody recognition and guiding next-generation vaccine development.
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