Discovery and structural investigation of Varicella-Zoster virus gE-neutralizing antibodies isolated from a convalescent patient

Varicella-zoster virus (VZV) is a highly contagious human herpesvirus that causes chickenpox upon primary infection and can later reactivate to cause shingles. It is globally widespread, and more than 90% of individuals are infected by adolescence. Glycoprotein E (gE) plays a crucial role in VZV viral infection, serving as the most antigenically potent and abundant glycoprotein present on both the viral envelope and the membranes of infected cells. Owing to its importance, gE is also employed as the key component in recombinant subunit vaccines, which stimulate the production of neutralizing antibodies (nAbs) and help reduce viral transmission between cells. To determine the molecular basis of VZV nAbs after natural infection, we conducted single-cell analysis of VZV gE memory B-cells from a convalescent patient and isolated three noncompeting clusters of gE-specific monoclonal antibodies (mAbs). Using cryo-electron microscopy (cryo-EM), we revealed the structure of the ternary complexes of the nAbs, which target different binding sites on the gI-binding domain of gE (aa 169-325). Structurally, the antibodies bind to opposite sides of the gI-binding domain, which is composed of 9 β-strands and 3 α-helices. Through analysis of the binding epitopes of the antibodies isolated in this study, we found that all of them bind to gE (aa 1-325), suggesting that this region of gE is a critical target for antibody recognition. Therefore, our study not only elucidates the structure of the gI-binding domain of gE but also offers valuable insight for the rational design of next-generation VZV vaccines.