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<p>Generating effective live vaccines from intact viruses remains challenging owing to considerations of safety and immunogenicity. Approaches that can be applied in a systematic manner are needed. Here we created a library of live attenuated influenza vaccines by using diverse cellular E3 ubiquitin ligases to generate proteolysis-targeting (PROTAR) influenza A viruses. PROTAR viruses were engineered to be attenuated by the ubiquitin–proteasome system, which mediates viral protein degradation in conventional host cells, but allows efficient replication in engineered cell lines for large-scale manufacturing. Depending on the degron–E3 ligase pairs, viruses showed varying degrees of attenuation. In animal models, PROTAR viruses were highly attenuated and elicited robust, broad, strain-dependent humoral, mucosal and cellular immunity. In addition, they provided cross-reactive protection against homologous and heterologous viral challenges. This study provides a systematic approach for developing safe and effective vaccines, with potential applications in designing live attenuated vaccines against other pathogens.</p>

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Proteolysis-targeting influenza vaccine strains induce broad-spectrum immunity and in vivo protection

  • 期刊论文

  • 发表日期：

    2025年1月15日

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  • Jinying Shen,
  • Jing Li,
  • Quan Shen,
  • Jihuan Hou,
  • Chunhe Zhang,
  • Haiqing Bai,
  • Xiaoni Ai,
  • Yinlei Su,
  • Zihao Wang,
  • Yunfei Zhang,
  • Beibei Xu,
  • Jiawei Hao,
  • Ping Wang,
  • Qisi Zhang,
  • Adam Yongxin Ye,
  • Zhen Li,
  • Tang Feng,
  • Le Li,
  • Fei Qi,
  • Qikai Wang,
  • Yacong Sun,
  • Chengyao Liu,
  • Xuetong Xi,
  • Lei Yan,
  • Hanhui Hong,
  • Yuting Chen,
  • Xin Xie,
  • Jing Xie,
  • Xiaoheng Liu,
  • Ruikun Du,
  • Roberto Plebani,
  • Lihe Zhang,
  • Demin Zhou,
  • George Church,
  • Longlong Si

摘要

Generating effective live vaccines from intact viruses remains challenging owing to considerations of safety and immunogenicity. Approaches that can be applied in a systematic manner are needed. Here we created a library of live attenuated influenza vaccines by using diverse cellular E3 ubiquitin ligases to generate proteolysis-targeting (PROTAR) influenza A viruses. PROTAR viruses were engineered to be attenuated by the ubiquitin–proteasome system, which mediates viral protein degradation in conventional host cells, but allows efficient replication in engineered cell lines for large-scale manufacturing. Depending on the degron–E3 ligase pairs, viruses showed varying degrees of attenuation. In animal models, PROTAR viruses were highly attenuated and elicited robust, broad, strain-dependent humoral, mucosal and cellular immunity. In addition, they provided cross-reactive protection against homologous and heterologous viral challenges. This study provides a systematic approach for developing safe and effective vaccines, with potential applications in designing live attenuated vaccines against other pathogens.