Innovative Next-Generation Flu Vaccines Using Proteolysis-Targeting Enhance Safety and Cross-Strain Immunity in Animal Studies

Recent advances in influenza vaccine technology have introduced a novel approach utilizing proteolysis-targeting strategies to improve both the safety profile and the breadth of immune protection. Led by Professor Si Longlong from the Shenzhen Institutes of Advanced Technology, researchers have developed a series of live-attenuated influenza A vaccines based on the PROTAR (proteolysis-targeting) system. This innovative method employs E3 ubiquitin ligases to target and degrade viral proteins, effectively attenuating the virus while maintaining its ability to provoke a strong immune response.

The team constructed a diverse library of PROTAR influenza viruses by inserting proteasome-targeting degrons (PTDs) into the viral M1 protein, recognized by various E3 ligases. This modification allows viral proteins to be selectively degraded within host cells, resulting in virus attenuation suitable for vaccine development. These engineered viruses can replicate efficiently in specially designed cell lines, facilitating large-scale vaccine production.

Published research in Nature Microbiology and Nature Chemical Biology detailed how these PROTAR viruses exhibited varying degrees of attenuation depending on PTD–E3 ligase pairing. Crucially, animal studies demonstrated that the PROTAR vaccines stimulated broad-spectrum immune responses, providing protection against both homologous and heterologous influenza strains across different animal models, including mice and ferrets. The vaccines elicited robust humoral, mucosal, and T-cell immunity after a single intranasal dose.

Recognizing limitations in the initial PROTAR approach, particularly its restriction to terminal insertions, the team advanced to PROTAR 2.0. This next-gen strategy enables the insertion of PTDs at multiple sites, including internal regions of viral proteins, boosting adaptability and efficacy. Animal testing confirmed that PROTAR 2.0 vaccines retain their safety and immunogenicity, offering complete cross-protection against various influenza variants.

These cutting-edge developments hold promise for future influenza vaccine design, potentially leading to more effective, broadly protective, and safer vaccines. This innovative use of cellular protein degradation pathways represents a significant step forward in viral vaccine technology.