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Nat Chem Biol
. 2025 Jan 15.
doi: 10.1038/s41589-024-01813-z. Online ahead of print. PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins
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
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.
. 2025 Jan 15.
doi: 10.1038/s41589-024-01813-z. Online ahead of print. PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins
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
- PMID: 39814992
- DOI: 10.1038/s41589-024-01813-z
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.