2. Academic Validation
  3. A potent protective bispecific nanobody targeting Herpes simplex virus gD reveals vulnerable epitope for neutralizing

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

  • Nat Commun. 2025 May 6;16(1):4196. doi: 10.1038/s41467-025-58669-7.
Jing Hu # 1,  Haoyuan Tan # 2,  Meihua Wang 3,  Shasha Deng 3,  Mengyao Liu 3,  Peiyi Zheng 3,  Anmin Wang 2,  Meng Guo 2,  Jin Wang 3,  Jiayin Li 3,  Huanwen Qiu 3,  Chengbing Yao 4,  Zhongliang Zhu 3 4,  Chaolu Hasi 5,  Dongli Pan 6,  Hongliang He 1,  Chenghao Huang 7,  Yuhua Shang 4,  Shu Zhu 8 9,  Tengchuan Jin 10 11 12 13 14 15 16 17
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China.
  • 2 National Key Laboratory of immune response and immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
  • 3 Laboratory of Structural Immunology, National Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
  • 4 Anhui Genebiol Biotech. LTD, Hefei, 230000, China.
  • 5 Sonid Suoqi Animal Husbandry Workstation, Xilinhot City, Inner Mongolia Xilin Gol League, Xilinhot, China.
  • 6 Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 7 State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China.
  • 8 National Key Laboratory of immune response and immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. zhushu@ustc.edu.cn.
  • 9 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China. zhushu@ustc.edu.cn.
  • 10 Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Hefei, Anhui, 230001, P.R. China. jint@ustc.edu.cn.
  • 11 National Key Laboratory of immune response and immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. jint@ustc.edu.cn.
  • 12 Laboratory of Structural Immunology, National Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. jint@ustc.edu.cn.
  • 13 Anhui Genebiol Biotech. LTD, Hefei, 230000, China. jint@ustc.edu.cn.
  • 14 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China. jint@ustc.edu.cn.
  • 15 Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, 230027, China. jint@ustc.edu.cn.
  • 16 Biomedical Sciences and Health Laboratory of Anhui Province, University of Science & Technology of China, Hefei, 230027, China. jint@ustc.edu.cn.
  • 17 Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China. jint@ustc.edu.cn.
  • # Contributed equally.
PMID: 40328740 DOI: 10.1038/s41467-025-58669-7
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.

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