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journal article·2026-02Open access

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

Yang Wang, Tianxin Ma, Yujiao He, Qinming Li, Kailin Mai, Minying Mo, Chenyang Cao, Jiahui Li, Pei Feng, Jiaojiao Peng, Jing Sun, Weiqi Pan, Zifeng Yang, Ling Chen

Advanced Science· Volume 13· Issue 9
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Source abstract

Abstract

Abstract Live attenuated influenza vaccines (LAIVs) can elicit broad immunity, but rational attenuation strategies are limited. PR8 rp , a prototype influenza A virus with five segments extensively reprogrammed to use the least‐preferred synonymous codons is generated, introducing 1956 silent mutations and elevating CpG content. PR8 rp exhibits profound attenuation in vitro and ≈20 000‐fold lower virulence in mice, yet maintains vaccine‐level yields. A single intranasal dose confers sterilizing homologous protection and dose‐dependent cross‐protection against heterologous H1N1pdm and heterosubtypic H3N2 challenge, mediated by homologous neutralizing antibodies, cross‐reactive non‐neutralizing antibodies, and IFN‐γ–biased T cell responses. Mechanistic analyses reveal that attenuation resulted from defective NA genome packaging, loss of NS1 protein accumulation, augment of host antiviral responses, and heightened susceptibility to zinc‐finger antiviral protein–mediated restriction, rather than impaired RNA or protein synthesis. Applying this approach to a contemporary H1N1 strain yielded similar stable attenuation. These findings establish genome‐wide codon reprogramming as a versatile platform for safe, broadly protective LAIVs with multiple attenuation mechanisms.
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Research context

OpenAlex topics: Influenza Virus Research Studies · interferon and immune responses · Respiratory viral infections research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

State 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

Guangzhou National Laboratory Guangzhou 510005 China

Respiratory Disease AI Laboratory on Epidemic and Medical Big Data Instrument Applications Faculty of Innovation Engineering Macau University of Science and Technology Macau SAR 999078 China

Guangdong Cardiovascular Institute Medical Research Institute Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou 510080 China

Institute of Biochemistry & Molecular Biology School of Basic Medical Sciences Guangdong Medical University Dongguan 523808 China

Guangdong Laboratory of Computational Biomedicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou 510530 China

Funding

National Natural Science Foundation of China

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