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Dual-targeting nanoparticle vaccine elicits a therapeutic antibody response against chronic hepatitis B

Nature Nanotechnology volume 15, pages 406–416 (2020)Cite this article

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Abstract

Chronic hepatitis B is caused by prolonged infection with the hepatitis B virus (HBV), which can substantially increase the risk of developing liver disease. Despite the development of preventive vaccines against HBV, a therapeutic vaccine inducing an effective antibody response still remains elusive. The preS1 domain of the large HBV surface protein is the major viral attachment site on hepatocytes and thus offers a therapeutic target; however, its poor immunogenicity limits clinical translation. Here, we design a ferritin nanoparticle vaccine that can deliver preS1 to specific myeloid cells, including SIGNR1+ dendritic cells (which activate T follicular helper cells) and lymphatic sinus-associated SIGNR1+ macrophages (which can activate B cells). This nanoparticle vaccine induces a high-level and persistent anti-preS1 response that results in efficient viral clearance and partial serological conversion in a chronic HBV mouse model, offering a promising translatable vaccination strategy for the functional cure of chronic hepatitis B.

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Fig. 1: Molecular design and characterization of ferritin NP vaccine.
Fig. 2: Protective immunity of ferritin NP–preS1 vaccine against HBV.
Fig. 3: Ferritin NP–preS1 as therapeutic vaccine.
Fig. 4: Ferritin NP vaccine targets distinct APCs.
Fig. 5: Ferritin NP vaccine induces efficient Tfh and GC responses.
Fig. 6: SIGNR1+ macrophages are required for B cell activation and antibody production.

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Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank H. Qi for Cxcr5−/− mice and B. Hou for ΜD4 transgenic mice. We thank K. Fan for technical consultation on ferritin characterization, and X. Shi for mouse breeding and healthcare services. This work was supported by grants from the Strategic Priority Research Programme of the Chinese Academy of Sciences (XDB29040202 to M.Z.), the National Natural Science Foundation of China (81991493 to Q.C.), the National Key R&D Programme of China (2018YF1313000 and 2018YF1313004 to S.W., 2019YFA0905903 to M.Z.) and the Science and Technology Service Network Initiative Programme of the Chinese Academy of Sciences (KFJ-STS-ZDTP-062 to M.Z.).

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Authors and Affiliations

  1. Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Wenjun Wang, Xiaoxiao Zhou, Yingjie Bian, Qian Chai, Hua Peng & Mingzhao Zhu

  2. College of Life Sciences, University of the Chinese Academy of Sciences, Beijing, China

    Wenjun Wang, Xiaoxiao Zhou & Mingzhao Zhu

  3. Department of Pediatric Surgical Oncology, Children’s Hospital, Chongqing Medical University, Chongqing, China

    Shan Wang, Zhenqian Guo & Zhenni Wang

  4. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Ping Zhu

  5. Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Xiyun Yan

  6. National Institute of Biological Sciences, Beijing, China

    Wenhui Li

  7. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Yang-Xin Fu

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  1. Wenjun Wang
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Contributions

W.W. and M.Z. designed the experiments and analysed the data; W.W. and X.Z. conducted most experiments; Y.B., H.P. and Y.-X.F. helped with an AAV–HBV1.3 infection mouse model and in vitro HBV infection assay; S.W. and Z.W. provided human LN samples and helped in the human immune cell targeting assay; Q.C. helped with the immunofluorescence staining; Z.G. and P.Z. performed transmission electron micrography imaging; X.Y. provided technical advice on ferritin preparation and characterization and helped in the iron measuring assay; W.L. provided the HepG2-hNTCP cell line and HBV virus and helped with the in vitro infection assay; W.W. and M.Z. wrote the manuscript; M.Z. conceived and supervised the project.

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Correspondence to Mingzhao Zhu.

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Peer review information Nature Nanotechnology thanks John Kehrl, Daniel Shouval and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Wang, W., Zhou, X., Bian, Y. et al. Dual-targeting nanoparticle vaccine elicits a therapeutic antibody response against chronic hepatitis B. Nat. Nanotechnol. 15, 406–416 (2020). https://doi.org/10.1038/s41565-020-0648-y

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