Proteolysis-targeting influenza vaccine strains induce broad-spectrum immunity and in vivo protection

IF 20.5 1区生物学 Q1 MICROBIOLOGY Nature Microbiology Pub Date : 2025-01-15 DOI:10.1038/s41564-024-01908-2

Jinying Shen, Jing Li, Quan Shen, Jihuan Hou, Chunhe Zhang, Haiqing Bai, Xiaoni Ai, Yinlei Su, Zihao Wang, Yunfei Zhang, Beibei Xu, Jiawei Hao, Ping Wang, Qisi Zhang, Adam Yongxin Ye, Zhen Li, Tang Feng, Le Li, Fei Qi, Qikai Wang, Yacong Sun, Chengyao Liu, Xuetong Xi, Lei Yan, Hanhui Hong, Yuting Chen, Xin Xie, Jing Xie, Xiaoheng Liu, Ruikun Du, Roberto Plebani, Lihe Zhang, Demin Zhou, George Church, Longlong Si

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Abstract

Generating effective live vaccines from intact viruses remains challenging owing to considerations of safety and immunogenicity. Approaches that can be applied in a systematic manner are needed. Here we created a library of live attenuated influenza vaccines by using diverse cellular E3 ubiquitin ligases to generate proteolysis-targeting (PROTAR) influenza A viruses. PROTAR viruses were engineered to be attenuated by the ubiquitin–proteasome system, which mediates viral protein degradation in conventional host cells, but allows efficient replication in engineered cell lines for large-scale manufacturing. Depending on the degron–E3 ligase pairs, viruses showed varying degrees of attenuation. In animal models, PROTAR viruses were highly attenuated and elicited robust, broad, strain-dependent humoral, mucosal and cellular immunity. In addition, they provided cross-reactive protection against homologous and heterologous viral challenges. This study provides a systematic approach for developing safe and effective vaccines, with potential applications in designing live attenuated vaccines against other pathogens.

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来源期刊

Nature Microbiology Immunology and Microbiology-Microbiology

CiteScore

44.40

自引率

1.10%

发文量

226

期刊介绍： Nature Microbiology aims to cover a comprehensive range of topics related to microorganisms. This includes: Evolution: The journal is interested in exploring the evolutionary aspects of microorganisms. This may include research on their genetic diversity, adaptation, and speciation over time. Physiology and cell biology: Nature Microbiology seeks to understand the functions and characteristics of microorganisms at the cellular and physiological levels. This may involve studying their metabolism, growth patterns, and cellular processes. Interactions: The journal focuses on the interactions microorganisms have with each other, as well as their interactions with hosts or the environment. This encompasses investigations into microbial communities, symbiotic relationships, and microbial responses to different environments. Societal significance: Nature Microbiology recognizes the societal impact of microorganisms and welcomes studies that explore their practical applications. This may include research on microbial diseases, biotechnology, or environmental remediation. In summary, Nature Microbiology is interested in research related to the evolution, physiology and cell biology of microorganisms, their interactions, and their societal relevance.