Live Attenuated Influenza Vaccine Can Generate PROTAC Influenza A Virus to Destroy Viral Protein and Address Traditional Versions' Limitation

Researchers from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences proposed a strategy to reduce the impact of influenza viruses, such as influenza A, by using a novel live-attenuated influenza vaccine. It aims to address limitations of traditional versions, such as suboptimal immunogenicity, safety, and cumbersome manufacturing processes.

Lead author Professor Si Longlong explained in their study titled "Generation of a Live Attenuated Influenza A Vaccine by Proteolysis Targeting," published in Nature Biotechnology, that the novel live-attenuated influenza vaccine approach generates proteolysis-targeting chimeric (PROTAC) influenza A virus that uses an endogenous ubiquitin-proteasome system to destroy viral proteins.

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Novel Live-Attenuated Influenza A Vaccine Approach Addresses Limitation of Traditional Versions

Degrading Viral Proteins to Prevent Viral Replication

Researchers think manipulating the stability of viral protein using protein degradation of the host cell is a potential mechanism to create vaccines for the influenza virus. According to Medical Xpress, the team designed PROTAC viruses by fusing removable proteasome-targeting domain (PTD) to viral proteins.

The PTD contains proteasome-targeting peptide and tobacco etch virus cleavage sites (TEVcs) linker used to selectively trigger the degradation of influenza virus proteins. However, they also found that tobacco etch virus protease (TEVp) could selectively cleave the TEVcs linker of viral proteins and separate them. That means they are spared from the degradation process.

So, the team developed a genome of the influenza A virus in TEVp-expressing cell lines for virus production and added conditionally removable PTD that generates PROTAC viruses that were live-attenuated using host protein degradation machinery activated upon infection.

For instance, PROTAC viruses mouse and ferret models successfully attenuated, but can still release a robust and broad cellular immunity that provided broad protection against homologous and heterogenous virus problems. Professor Si noted that the PROTAC vaccine technology is used to generate live-attenuated vaccines for other diseases and pathogens and not just influenza A.

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About Live Attenuated Vaccines

According to the History of Vaccines of the College of Physicians of Philadelphia, the attenuated vaccine can be developed in many ways, but the common methods involve testing pathogens on a series of cell cultures or animal embryos. Scientists would use chick embryos and with each passage, the virus would replicate in the chick cells until it lost its ability to replicate in human cells.

Live attenuated vaccines go through up to 200 different embryos or cell cultures to make the virus unable to replicate and be used in a vaccine. It is first tested in animal studies that usually produce a virus that can still be recognized by the immune system of humans but cannot replicate in a human host.

When humans receive this type of vaccine, it will replicate enough in the body to trigger an immune response but not cause illness. In other words, it trains the immune system to recognize the virus to provide protection in the future.

The only concern with live-attenuated vaccines is that the vaccine virus can return to being a virus that can cause disease since mutations could occur that may result in a more virulent strain. But limiting its ability to replicate could solve the problem.

An example of this type of vaccine is the oral polio vaccine (OPV), which is ingested and not injected. Although it gives protection, the virus can mutate into a virulent form and lead to paralytic polio and other rare cases. That is why the US no longer uses OPV and has replaced it with the inactivated polio vaccine (IPV).