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Genome-Wide Codon Reprogramming Enables a Multifactorially Attenuated Influenza Vaccine with Broad Cross-Protection.

Yang Wang^1,2,3, Tianxin Ma¹, Yujiao He^4,5

¹State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510370, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)

|November 30, 2025

Summary

This summary is machine-generated.

Scientists developed a new live attenuated influenza vaccine (LAIV) using genome-wide codon reprogramming. This safe and effective vaccine provides broad protection against influenza A virus strains.

Keywords:

cross‐protective immunity host antiviral restriction factors influenza A virus live attenuated vaccines synonymous codon reprogramming

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Area of Science:

Virology
Vaccinology
Molecular Biology

Background:

Live attenuated influenza vaccines (LAIVs) offer broad immunity but have limited rational attenuation strategies.
Developing safer and more effective LAIVs is crucial for influenza prevention.

Purpose of the Study:

To establish genome-wide codon reprogramming as a versatile platform for developing safe and broadly protective LAIVs.
To investigate the mechanisms of attenuation and protective immunity induced by the novel LAIV.

Main Methods:

Generation of PR8rp, an influenza A virus with reprogrammed synonymous codons and elevated CpG content.
In vitro and in vivo assessment of PR8rp attenuation and immunogenicity in mice.
Analysis of immune responses, including neutralizing antibodies and T cell responses, following vaccination.

Main Results:

PR8rp exhibited profound attenuation and significantly reduced virulence in mice while maintaining vaccine yields.
A single intranasal dose conferred sterilizing homologous protection and cross-protection against heterologous and heterosubtypic influenza strains.
Attenuation mechanisms included defective NA genome packaging, reduced NS1 protein accumulation, enhanced host antiviral responses, and increased susceptibility to zinc-finger antiviral protein restriction.

Conclusions:

Genome-wide codon reprogramming is a viable strategy for creating stable, attenuated influenza viruses for vaccine development.
This approach yields LAIVs with multiple attenuation mechanisms, ensuring safety and broad protective immunity.
The developed LAIV platform demonstrates potential for generating next-generation influenza vaccines against diverse strains.