Yue Sun, Jianbo Liu, Shi‐Jia Xu, Meng‐Xin Wang, Hongliang Zhang, Yanhe Zhang, Zhi‐Jun Tian, Jin‐Mei Peng, Xin Yin, Tong‐Qing An, Xue‐Hui Cai, Yan‐Dong Tang
Pseudorabies virus (PRV), an α‑herpesvirus, has recently been recognized as a potentially significant zoonotic pathogen, causing severe encephalitis and endophthalmitis in humans with high mortality and disability rates. Despite its growing public‑health threat, no effective therapeutics are available for human PRV infection. Here, we isolated a broadly neutralizing monoclonal antibody, designated 6F7, which targets the PRV glycoprotein D (gD) and neutralizes all tested PRV lineages. Mechanistic studies reveal that 6F7 does not impede viral attachment or internalization; instead, it specifically blocks the fusion of the viral envelope with cellular membranes, thereby preventing viral replication. Moreover, the antibody also potently suppresses cell‑to‑cell spread of PRV. We demonstrate that the interaction between gD and the PRV receptor Nectin‑1 is blocked by 6F7. Last, a humanized version of 6F7 confers complete protection in mice challenged with a lethal PRV variant and blocks the establishment of latency at a dose of 15 mg/kg per mouse. Overall, the humanized broadly neutralizing antibody represents a promising therapeutic candidate for human PRV infection.