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.

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