A potent protective bispecific nanobody targeting Herpes simplex virus gD reveals vulnerable epitope for neutralizing

Jing Hu, Haoyuan Tan, Meihua Wang, Shasha Deng, Mengyao Liu, Peiyi Zheng, Anmin Wang, Meng Guo, Jin Wang, Jiayin Li, Huanwen Qiu, Chengbing Yao, Zhongliang Zhu, Chaolu Hasi, Dongli Pan, Hongliang He, Chenghao Huang, Yuhua Shang, Shu Zhu () and Tengchuan Jin ()
Additional contact information
Jing Hu: University of Science and Technology of China
Haoyuan Tan: University of Science and Technology of China
Meihua Wang: University of Science and Technology of China
Shasha Deng: University of Science and Technology of China
Mengyao Liu: University of Science and Technology of China
Peiyi Zheng: University of Science and Technology of China
Anmin Wang: University of Science and Technology of China
Meng Guo: University of Science and Technology of China
Jin Wang: University of Science and Technology of China
Jiayin Li: University of Science and Technology of China
Huanwen Qiu: University of Science and Technology of China
Chengbing Yao: Anhui Genebiol Biotech. LTD
Zhongliang Zhu: University of Science and Technology of China
Chaolu Hasi: Inner Mongolia Xilin Gol League
Dongli Pan: Zhejiang University School of Medicine
Hongliang He: University of Science and Technology of China
Chenghao Huang: Xiamen University
Yuhua Shang: Anhui Genebiol Biotech. LTD
Shu Zhu: University of Science and Technology of China
Tengchuan Jin: University of Science and Technology of China

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Herpes simplex virus (HSV) causes significant health burden worldwide. Currently used antiviral drugs are effective but resistance can occur. Here, we report two high-affinity neutralizing nanobodies, namely Nb14 and Nb32, that target non-overlapping epitopes in HSV gD. Nb14 binds a neutralization epitope located in the N-A’ interloop, which prevents the interaction between gD and gH/gL during the second step of conformational changes during membrane fusion after virus attachment. The bispecific nanobody dimer (Nb14-32-Fc) exhibits high potency in vitro and in vivo. Mechanistically, Nb14-32-Fc neutralizes HSVs at both the pre-and post-attachment stages and prevents cell-to-cell spread in vitro. Administration of Nb14-32-Fc at low dosage of 1 mg/kg provides 100% protection in an HSV-1 infection male mouse model and an HSV-2 infection female mouse model. Our results demonstrate that Nb14-32-Fc could serve as a promising drug candidate for treatment of HSV infection, especially in the cases of antiviral drug resistance and severe herpes encephalitis.

Date: 2025
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DOI: 10.1038/s41467-025-58669-7

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