Single-cell analysis of memory B cells from top neutralizers reveals multiple sites of vulnerability within HCMV Trimer and Pentamer.

Human cytomegalovirus (HCMV) can cause severe diseases in fetuses, newborns, and immunocompromised individuals. Currently, no vaccines are approved, and treatment options are limited. Here, we analyzed the human B cell response of four HCMV top neutralizers from a cohort of 9,000 individuals. By single-cell analyses of memory B cells targeting the pentameric and trimeric HCMV surface complexes, we identified vulnerable sites on the shared gH/gL subunits as well as complex-specific subunits UL 128/130/131A and gO. Using high-resolution cryogenic electron microscopy, we revealed the structural basis of the neutralization mechanisms of antibodies targeting various binding sites. Moreover, we identified highly potent antibodies that neutralized a broad spectrum of HCMV strains, including primary clinical isolates, that outperform known antibodies used in clinical trials. Our study provides a deep understanding of the mechanisms of HCMV neutralization and identifies promising antibody candidates to prevent and treat HCMV infection. [Display omitted] • Analysis of HCMV-reactive memory B cells in top neutralizers identifies potent nAbs • Epitope mapping uncovers vulnerable sites on the HCMV Trimer and Pentamer • A gO-targeting nAb prevents infection of fibroblasts, epithelial, and endothelial cells • Cryo-EM structures provide functional understanding of antibody neutralization Vaccines against HCMV are not available, and treatment options are limited. By dissecting the B cell response of HCMV top neutralizers, Zehner et al. reveal key epitopes for the neutralization of HCMV. Structural analyses elucidate HCMV neutralization mechanisms, and highly potent and cross-neutralizing antibodies were identified. These data provide a basis for developing antibody-mediated approaches to effectively prevent and treat HCMV infection. [ABSTRACT FROM AUTHOR]