Synergistic effect of nucleoside modification and ionizable lipid composition on translation and immune responses to mRNA vaccines.

IF 6.5 1区医学 Q1 IMMUNOLOGY

NPJ Vaccines Pub Date : 2025-09-29 DOI:10.1038/s41541-025-01263-1

Hillary Danz, Allison Dauner, Shraddha Sharma, Mihaela Babiceanu, Nicholas Clark, Robert Jordan Ontiveros, Robert Amezquita, Alisa Zhilin-Roth, Eric Reyes, Catherine Khoo, Kara Gilbert, Janhavi Nadkarni, Omkar Chaudhary, Christina Lee, Ana Kume, Azadeh Bahadoran, Mona Motwani, Bin Lu, Wei Zong, Andrew Kettring, Alex Shumate, Shrirang Karve, Anusha Dias, Monica Wu, Xiaobo Gu, Yanhua Yan, Daniel G Anderson, Brian Schanen, Sudha Chivukula, Frank DeRosa

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Abstract

Lipid nanoparticle (LNP) components can impact the safety and immunogenicity of mRNA vaccines. Here we examine the mechanisms contributing to the performance of mRNA-LNP vaccines by exploring the impact of nucleoside modifications and LNP components on translational efficiency, innate immune activation, and immunogenicity. Our data reveals several molecular and immunological parameters affected by nucleoside modification including a synergistic effect of the mRNA and ionizable lipid composition on the immune activation triggered by the mRNA-LNP formulation. Our results indicate changes in the LNP composition, independent from whether the mRNA is modified or unmodified, caused differential expression of genes associated with innate and antiviral immunity. We believe these findings offer valuable insights into mRNA vaccine function and offer strategies for enhancing vaccine efficacy and reducing the reactogenicity of next generation mRNA vaccines.

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核苷修饰和可电离脂质组成对mRNA疫苗翻译和免疫应答的协同作用。

脂质纳米颗粒（LNP）成分可影响mRNA疫苗的安全性和免疫原性。在这里，我们通过探索核苷修饰和LNP成分对翻译效率、先天免疫激活和免疫原性的影响，来研究mRNA-LNP疫苗性能的影响机制。我们的数据揭示了一些受核苷修饰影响的分子和免疫学参数，包括mRNA和可电离脂质组成对mRNA- lnp配方触发的免疫激活的协同效应。我们的研究结果表明，LNP组成的变化（与mRNA是否被修饰或未修饰无关）导致了与先天免疫和抗病毒免疫相关基因的差异表达。我们相信这些发现为mRNA疫苗的功能提供了有价值的见解，并为提高疫苗效力和降低下一代mRNA疫苗的反应原性提供了策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Vaccines Immunology and Microbiology-Immunology

CiteScore

11.90

自引率

4.30%

发文量

146

审稿时长

11 weeks

期刊介绍： Online-only and open access, npj Vaccines is dedicated to highlighting the most important scientific advances in vaccine research and development.