Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-09-25 DOI:10.1016/j.xcrm.2025.102369

Tiffany M Styles, Akil Akhtar, Chunyang Gu, Gabriele Neumann, Hiromi Muramatsu, Justine S McPartlan, Poulami Talukder, Derrik Gratz, Kasey Stokdyk, Hannah L Turner, James A Ferguson, Alesandra J Rodriguez, Madhumathi Loganathan, Benjamin Francis, Anass Abbad, Ghania Chikh, Ying K Tam, Zhaohui S Qin, Julianna Han, Juan Manuel Carreño, Andrew B Ward, Jasdave S Chahal, Christian W Mandl, Norbert Pardi, Yoshihiro Kawaoka, Florian Krammer, Rafi Ahmed, Rama R Amara

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引用次数: 0

Abstract

A universal influenza vaccine that elicits a strong and lasting stalk-specific antibody response is advantageous. We utilize nucleoside-modified mRNA in lipid nanoparticles (mRNA-LNP) and unmodified self-amplifying mRNA in modified dendritic nanoparticles (sam-MDNP), expressing chimeric hemagglutinin (cHA) antigens to induce stalk-specific humoral immunity in non-human primates with pre-existing influenza virus immunity. mRNA-LNP immunization induces strong stalk-specific binding antibodies capable of protecting mice from lethal heterologous influenza virus challenges and bone marrow plasma cells (BMPCs) that persist for up to 8 months. sam-MDNP vaccine induces lower humoral immunity, despite showing strong innate activation. Transcriptomic and cytokine analyses reveal a more persistent induction of interferon responses, interleukin (IL)-1β signaling, and IL-6 production in the mRNA-LNP group, correlating with the induction of serum antibody responses and BMPCs. These results identify a transcriptional signature associated with induction of BMPCs following mRNA vaccination and highlight the utility of cHA-based mRNA-LNP vaccines in inducing persistent stalk-directed protective antibody responses.

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基于嵌合血凝素的通用流感mRNA疫苗诱导恒河猴保护性免疫和骨髓浆细胞。

一种能引起强而持久的茎特异性抗体反应的通用流感疫苗是有利的。我们利用核苷修饰的脂质纳米颗粒mRNA （mRNA- lnp）和未经修饰的修饰的树突状纳米颗粒mRNA (sam-MDNP)，表达嵌合血凝素（cHA）抗原，诱导具有流感病毒免疫的非人灵长类动物的茎特异性体液免疫。mRNA-LNP免疫诱导强大的茎特异性结合抗体，能够保护小鼠免受致命的异源流感病毒和骨髓浆细胞（BMPCs）的攻击，这种攻击持续长达8个月。sam-MDNP疫苗诱导较低的体液免疫，尽管表现出很强的先天激活。转录组学和细胞因子分析显示，mRNA-LNP组更持久地诱导干扰素反应、白细胞介素(IL)-1β信号传导和IL-6的产生，与血清抗体反应和BMPCs的诱导相关。这些结果确定了mRNA接种后与诱导BMPCs相关的转录特征，并强调了基于cha的mRNA- lnp疫苗在诱导持续的茎定向保护性抗体反应方面的实用性。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.