2. Academic Validation
  3. PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins

PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins

  • Nat Chem Biol. 2025 Jan 15. doi: 10.1038/s41589-024-01813-z.
Chunhe Zhang # 1,  Jihuan Hou # 1,  Zhen Li # 1,  Quan Shen # 1 2,  Haiqing Bai # 3 4,  Li Chen # 1,  Jinying Shen # 1,  Ping Wang # 1,  Yinlei Su 1,  Jing Li 1,  Qisi Zhang 1,  Chengyao Liu 1,  Xuetong Xi 1 2,  Fei Qi 1,  Yuting Chen 1,  Xin Xie 3 4,  Adam Yongxin Ye 5,  Xiaoheng Liu 6,  Roberto Plebani 7,  George Church 5,  Longlong Si 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Xellar Biosystems, Boston, MA, USA.
  • 4 Henan Academy of Innovations in Medical Science, Xinzheng, China.
  • 5 Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • 6 Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
  • 7 Center for Advanced Studies and Technology (CAST), Department of Medical, Oral and Biotechnological Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
  • 8 State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. ll.si@siat.ac.cn.
  • 9 University of Chinese Academy of Sciences, Beijing, China. ll.si@siat.ac.cn.
  • # Contributed equally.
PMID: 39814992 DOI: 10.1038/s41589-024-01813-z
Abstract

Manipulating viral protein stability using the cellular ubiquitin-proteasome system (UPS) represents a promising approach for developing live-attenuated vaccines. The first-generation proteolysis-targeting (PROTAR) vaccine had limitations, as it incorporates proteasome-targeting degrons (PTDs) at only the terminal ends of Viral Proteins, potentially restricting its broad application. Here we developed the next-generation PROTAR vaccine approach, referred to as PROTAR 2.0, which enabled flexible incorporation of PTDs at various genomic loci of influenza viruses, including internal regions and terminal ends. The PROTAR 2.0 influenza viruses maintained efficient replication in UPS-deficient cells for large-scale production but were attenuated by PTD-mediated proteasomal degradation of Viral Proteins in conventional cells. Incorporation of multiple PTDs into one virus generated optimized PROTAR 2.0 vaccine candidates. In animal models, PROTAR 2.0 vaccine candidates were highly attenuated and a single-dose intranasal immunization induced robust and broad immune responses that provided complete cross-reactive protection against both homologous and heterologous viral challenges.

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