Researchers have developed a promising new strategy for generating live-attenuated viral vaccines. Their strategy, which uses PROTAC technology to prompt host cells to degrade viral proteins, was shown to elicit strong immune responses in animal models.

The findings are published in the journal Nature Biotechnology in a paper titled “Generation of a live attenuated influenza A vaccine by proteolysis targeting.”

Live-attenuated viral vaccines use a weakened form of the virus that causes the disease. But the utility of these vaccines has been limited by safety concerns, suboptimal immunogenicity, and inefficient manufacturing processes. These limitations have prompted some researchers, including Longlong Si, PhD, from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences, to explore alternative strategies for generating live-attenuated vaccines.

Si’s team recognized that viral replication—and the spread of infection—depend on the stability of virally encoded proteins. They postulated that utilizing the protein-degradation machinery of the host cell to manipulate the stability of viral proteins after infection may represent a potential new strategy for developing live-attenuated viral vaccines.

The team engineered influenza A viruses in such a way that after infecting host cells, the viral proteins were degraded—or live attenuated—by the host. In mouse and ferret models, the engineered viruses were shown to elicit robust and broad immune responses.

The success of their strategy is based on proteolysis targeting chimeric (PROTAC) technology, an effective protein-degradation tool developed in recent years. It harnesses the normal ubiquitin-proteasome system of the cell to degrade unwanted proteins.

Si’s team designed PROTAC viruses in which influenza viral proteins were fused to a conditionally removable proteasome-targeting domain (PTD). When these viruses infected conventional cells, they were live attenuated by the host protein degradation machinery.

The researchers also generated stable cell lines that maintain the reproductive potential of the PROTAC viruses during vaccine production. These cell lines express an enzyme that removes the PTD from the viral proteins, thus sparing them from degradation.

“This PROTAC vaccine technology could be a promising and universal strategy for creating safer and more effective vaccines,” wrote the researchers. “It is a simple and general method, potentially applicable to many other viruses, and accessible to most laboratories.”


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