tetano
Editor, Senior Moderator
Nat Biotechnol
. 2022 Jul 4.
doi: 10.1038/s41587-022-01381-4. Online ahead of print.
Generation of a live attenuated influenza A vaccine by proteolysis targeting
Longlong Si[SUP] #[/SUP][SUP] 1 [/SUP], Quan Shen[SUP] #[/SUP][SUP] 2 [/SUP], Jing Li[SUP] #[/SUP][SUP] 2 [/SUP], Li Chen[SUP] 2 [/SUP], Jinying Shen[SUP] 2 [/SUP], Xue Xiao[SUP] 2 [/SUP], Haiqing Bai[SUP] 3 [/SUP], Tang Feng[SUP] 4 [/SUP], Adam Yongxin Ye[SUP] 5 [/SUP], Le Li[SUP] 2 [/SUP], Chunhe Zhang[SUP] 2 4 [/SUP], Zhen Li[SUP] 2 [/SUP], Ping Wang[SUP] 2 [/SUP], Crystal Yuri Oh[SUP] 6 [/SUP], Atiq Nurani[SUP] 7 [/SUP], Siwen Niu[SUP] 8 [/SUP], Chengxin Zhang[SUP] 9 [/SUP], Xiaoqiong Wei[SUP] 9 [/SUP], Wanqiong Yuan[SUP] 10 11 12 [/SUP], Hao Liao[SUP] 13 [/SUP], Xiaojie Huang[SUP] 14 [/SUP], Ning Wang[SUP] 14 [/SUP], Wen-Xia Tian[SUP] 15 [/SUP], Hongwei Tian[SUP] 16 [/SUP], Li Li[SUP] 5 [/SUP], Xiaoheng Liu[SUP] 4 [/SUP], Roberto Plebani[SUP] 17 [/SUP]
Affiliations
Abstract
The usefulness of live attenuated virus vaccines has been limited by suboptimal immunogenicity, safety concerns or cumbersome manufacturing processes and techniques. Here we describe the generation of a live attenuated influenza A virus vaccine using proteolysis-targeting chimeric (PROTAC) technology to degrade viral proteins via the endogenous ubiquitin-proteasome system of host cells. We engineered the genome of influenza A viruses in stable cell lines engineered for virus production to introduce a conditionally removable proteasome-targeting domain, generating fully infective PROTAC viruses that were live attenuated by the host protein degradation machinery upon infection. In mouse and ferret models, PROTAC viruses were highly attenuated and able to elicit robust and broad humoral, mucosal and cellular immunity against homologous and heterologous virus challenges. PROTAC-mediated attenuation of viruses may be broadly applicable for generating live attenuated vaccines.
. 2022 Jul 4.
doi: 10.1038/s41587-022-01381-4. Online ahead of print.
Generation of a live attenuated influenza A vaccine by proteolysis targeting
Longlong Si[SUP] #[/SUP][SUP] 1 [/SUP], Quan Shen[SUP] #[/SUP][SUP] 2 [/SUP], Jing Li[SUP] #[/SUP][SUP] 2 [/SUP], Li Chen[SUP] 2 [/SUP], Jinying Shen[SUP] 2 [/SUP], Xue Xiao[SUP] 2 [/SUP], Haiqing Bai[SUP] 3 [/SUP], Tang Feng[SUP] 4 [/SUP], Adam Yongxin Ye[SUP] 5 [/SUP], Le Li[SUP] 2 [/SUP], Chunhe Zhang[SUP] 2 4 [/SUP], Zhen Li[SUP] 2 [/SUP], Ping Wang[SUP] 2 [/SUP], Crystal Yuri Oh[SUP] 6 [/SUP], Atiq Nurani[SUP] 7 [/SUP], Siwen Niu[SUP] 8 [/SUP], Chengxin Zhang[SUP] 9 [/SUP], Xiaoqiong Wei[SUP] 9 [/SUP], Wanqiong Yuan[SUP] 10 11 12 [/SUP], Hao Liao[SUP] 13 [/SUP], Xiaojie Huang[SUP] 14 [/SUP], Ning Wang[SUP] 14 [/SUP], Wen-Xia Tian[SUP] 15 [/SUP], Hongwei Tian[SUP] 16 [/SUP], Li Li[SUP] 5 [/SUP], Xiaoheng Liu[SUP] 4 [/SUP], Roberto Plebani[SUP] 17 [/SUP]
Affiliations
- PMID: 35788567
- DOI: 10.1038/s41587-022-01381-4
Abstract
The usefulness of live attenuated virus vaccines has been limited by suboptimal immunogenicity, safety concerns or cumbersome manufacturing processes and techniques. Here we describe the generation of a live attenuated influenza A virus vaccine using proteolysis-targeting chimeric (PROTAC) technology to degrade viral proteins via the endogenous ubiquitin-proteasome system of host cells. We engineered the genome of influenza A viruses in stable cell lines engineered for virus production to introduce a conditionally removable proteasome-targeting domain, generating fully infective PROTAC viruses that were live attenuated by the host protein degradation machinery upon infection. In mouse and ferret models, PROTAC viruses were highly attenuated and able to elicit robust and broad humoral, mucosal and cellular immunity against homologous and heterologous virus challenges. PROTAC-mediated attenuation of viruses may be broadly applicable for generating live attenuated vaccines.