Generation of a live attenuated influenza A vaccine by proteolysis targeting

Longlong Si; Quan Shen; Jing Li; Li Chen; Jinying Shen; Xue Xiao; Haiqing Bai; Tang Feng; Adam Yongxin Ye; Le Li; Chunhe Zhang; Zhen Li; Ping Wang; Crystal Yuri Oh; Atiq Nurani; Siwen Niu; Chengxin Zhang; Xiaoqiong Wei; Wanqiong Yuan; Hao Liao; Xiaojie Huang; Ning Wang; Wen-Xia Tian; Hongwei Tian; Li Li; Xiaoheng Liu; Roberto Plebani

doi:10.1038/s41587-022-01381-4

Generation of a live attenuated influenza A vaccine by proteolysis targeting

Nat Biotechnol. 2022 Sep;40(9):1370-1377. doi: 10.1038/s41587-022-01381-4. Epub 2022 Jul 4.

Authors

Longlong Si^#¹, Quan Shen^#², Jing Li^#², Li Chen², Jinying Shen², Xue Xiao², Haiqing Bai³, Tang Feng⁴, Adam Yongxin Ye⁵, Le Li², Chunhe Zhang^{2

4}, Zhen Li², Ping Wang², Crystal Yuri Oh⁶, Atiq Nurani⁷, Siwen Niu⁸, Chengxin Zhang⁹, Xiaoqiong Wei⁹, Wanqiong Yuan^{10

11

12}, Hao Liao¹³, Xiaojie Huang¹⁴, Ning Wang¹⁴, Wen-Xia Tian¹⁵, Hongwei Tian¹⁶, Li Li⁵, Xiaoheng Liu⁴, Roberto Plebani¹⁷

Affiliations

¹ CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. ll.si@siat.ac.cn.
² CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
³ Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA.
⁴ Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China.
⁵ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁶ Rare Disease Research Unit, Pfizer Inc., Cambridge MA, USA.
⁷ Jnana Therapeutics, Boston, MA, USA.
⁸ Third Institute of Oceanography, State Oceanic Administration, Xiamen, China.
⁹ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Orthopedics, Peking University Third Hospital, Beijing, China.
¹¹ Beijing Key Laboratory of Spinal Disease, Beijing, China.
¹² Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China.
¹³ Department of Clinical Laboratory, Shenzhen Third People's Hospital, Southern University of Science and Technology, National Clinical Research Center for Infectious Diseases, Shenzhen, China.
¹⁴ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
¹⁵ College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China.
¹⁶ National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
¹⁷ Center on Advanced Studies and Technology (CAST), Department of Medical, Oral and Biotechnological Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Ferrets
Humans
Influenza Vaccines* / genetics
Influenza, Human* / prevention & control
Mice
Orthomyxoviridae Infections* / prevention & control
Proteasome Endopeptidase Complex
Proteolysis
Vaccines, Attenuated / genetics

Substances

Influenza Vaccines
Vaccines, Attenuated
Proteasome Endopeptidase Complex