Researchers propose a new live attenuated influenza A vaccine

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Schematic illustration of the generation of PROTAC viruses (VP, viral protein; Ub, ubiquitin). Posted by Si Longlong

A promising strategy to reduce the impact of viral infectious diseases such as influenza is the use of live attenuated viruses as vaccines.

However, the utility of traditional live attenuated virus vaccines has often been limited by suboptimal immunogenicity, safety concerns, or cumbersome manufacturing processes and techniques. In addition, immune escape due to the rapid evolution of the virus poses another challenge for traditional flu vaccines.

Recently, a research team led by Professor Xi Longlong from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences proposed a new live attenuated influenza virus vaccine approach— creation of a proteolysis-targeted chimeric influenza A virus (PROTAC) as a live attenuated vaccine by using the endogenous ubiquitin-proteasome system of host cells to degrade viral proteins.

The results are published in Biotechnology of nature July 4.

Provided virus replication depends on virus-encoded proteins, manipulation of viral protein stability by exploiting the host cell’s protein degradation machinery may represent a potential approach to turning the viral life cycle on and off for vaccine development. Therefore, the researchers developed proteolysis-targeting chimeric viruses (PROTACs) by fusing a conditionally deleted proteasome-targeting domain (PTD) to influenza virus proteins.

The PTD was designed to contain a proteasome-targeting peptide and a tobacco etch virus (TEVcs) cleavage site linker. It has been used to selectively induce proteasomal degradation of viral proteins of interest; however, the TEVcs linker can be selectively cleaved by tobacco toxin virus protease (TEVp) to separate viral proteins from PTD, saving them from degradation.

Accordingly, the researchers constructed the genome the flu A viruses in stable TEVp-expressing cell lines were engineered for virus production to introduce a conditionally deleted PTD, generating fully infectious PROTAC viruses that were live attenuated by the host’s protein degradation machinery after infection.

In mouse and ferret models, PROTAC viruses were sufficiently attenuated but capable of eliciting robust and broad humoral, mucosal, and cellular immunity. As a result, they provided broad protection against homologous and heterologous virus challenges.

“This is PROTAC vaccine the technology may also be useful for creating live attenuated vaccines against other types of pathogens,” said Professor Xi.


New universal flu vaccine provides broad protection against influenza A virus infections, researchers say


Additional information:
Longlong Si, Development of a Live Attenuated Influenza A Vaccine by Proteolytic Targeting, Biotechnology of nature (2022). DOI: 10.1038/s41587-022-01381-4. www.nature.com/articles/s41587-022-01381-4

Citation: Researchers propose new live attenuated influenza A vaccine (2022, July 5) Retrieved July 5, 2022, from https://medicalxpress.com/news/2022-07-live-attenuated-influenza-vaccine-approach.html

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