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April 30, 2025 – In a breakthrough that could reshape the fight against seasonal and pandemic influenza, researchers from the Shenzhen Institutes of Advanced Technology (SIAT) at the Chinese Academy of Sciences have unveiled a new generation of live-attenuated flu vaccines. These vaccines, developed using innovative proteolysis-targeting strategies, have demonstrated enhanced safety and broad cross-strain immunity in animal studies.
The Science Behind PROTAR Vaccines
Led by Prof. Si Longlong, the SIAT team has constructed a library of influenza A vaccines using the body’s own protein-degrading machinery-the ubiquitin-proteasome system (UPS). By engineering viral proteins to be selectively degraded in conventional host cells, the new vaccines (called PROTAR, for PROteolysis TARgeting) are rendered harmless, yet still capable of stimulating the immune system.
The initial PROTAR technology, first published in Nature Biotechnology in 2022, involved attaching proteasome-targeting degrons (PTDs) to the viral protein M1. These PTDs act as “tags” that signal for the protein’s destruction, attenuating the virus. The latest research, published in Nature Microbiology and Nature Chemical Biology, expands on this approach, introducing PROTAR 2.0-a more versatile version that allows PTDs to be placed at multiple positions within viral proteins.
What Makes PROTAR 2.0 Different?
While the original PROTAR system could only tag the ends of viral proteins, PROTAR 2.0 enables PTDs to be inserted at the N-terminal, C-terminal, or even internal regions. This flexibility means that multiple viral proteins can be targeted for degradation, further reducing the risk of the vaccine virus causing illness.
In laboratory and animal studies-including tests on mice and ferrets-PROTAR 2.0 vaccines showed:
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Excellent safety profiles: The vaccines did not cause disease in the test animals.
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Strong immune responses: A single intranasal dose induced robust antibody, mucosal, and T-cell immunity.
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Broad protection: Animals were protected against both matching (homologous) and different (heterologous) flu virus strains.
Why Is This Important?
Traditional flu vaccines, especially inactivated and cold-adapted live-attenuated types, can sometimes fail to match circulating strains, reducing their effectiveness. The PROTAR approach allows for the creation of vaccines that closely mimic the natural virus, potentially offering better protection and easier adaptation to new strains.
Moreover, by using the UPS to control viral protein stability, the PROTAR vaccines can be manufactured efficiently in engineered cell lines, but remain safe in humans and animals.
What’s Next?
Although these results are highly promising, the research is still in the animal testing phase. Further studies, including human clinical trials, will be needed to confirm safety and effectiveness in people. If successful, this technology could lead to more reliable, broadly protective flu vaccines in the future.
Disclaimer
This article is based on preclinical research findings published in peer-reviewed journals (Nature Microbiology and Nature Chemical Biology) and summarized by Medical Xpress on April 29, 2025. The PROTAR and PROTAR 2.0 vaccine technologies have so far only been tested in animal models. Their safety and efficacy in humans have not yet been established. Readers should consult healthcare professionals for current flu vaccination recommendations.
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