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加入5-甲基丁减轻了RIG-I介导的先天性免疫反应,以自我放大RNA疫苗

Wataru Akahata¹, Mai Komori¹, Amber L Morey¹

¹VLP Therapeutics, Inc., Gaithersburg, MD 20878, USA.

Science translational medicine

|November 12, 2025

概括

用5甲基cytidine (5mC) 修改的自我放大RNA (saRNA) 疫苗通过减弱血细胞树突细胞中的干扰素反应来降低反应性,同时保持强大的抗原表达和针对SARS-CoV-2的免疫反应.

科学领域:

疫苗学疫苗学疫苗学
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

自放大RNA (saRNA) 疫苗为传染病预防提供了一个有希望的平台.
之前开发了一种表达SARS-CoV-2尖端受体结合域 (S-RBD-TM) 的saRNA疫苗,显示出有效性.
临床试验表明,含有5-甲基 (5mC) 的saRNA疫苗可以降低反应性,同时保持免疫性.

研究的目的:

阐明5mC修饰的saRNA疫苗降低反应性和维持免疫性背后的机制.
研究5mC结合对抗原表达和先天免疫反应的影响.
为了确定参与不同免疫细胞saRNA识别的宿主感知途径.

主要方法:

在未修改的saRNA和5mC修改的saRNA (saRNA-5mC) 之间的抗原表达和免疫反应在体外和体内进行比较.
对I型干扰素诱导在血细胞树突细胞 (pDCs) 和其他抗原呈现细胞的分析.
研究RIG-I传感器在pDCs的saRNA检测中的作用.

主要成果:

在pDC中,saRNA-5mC显示抗原表达延长和I型干扰素诱导减弱,这是疫苗反应性的一个关键因素.
在体内,saRNA-5mC有效地减轻了过度的先天性免疫反应,而不影响B细胞和T细胞对SARS-CoV-2 RBD的反应.
通过RIG-I在pDC中检测未经修改的saRNA被5mC整合取消,而saRNA-5mC在巨细胞中诱导了RIG-I独立的先天激活.

结论:

将5mC纳入saRNA疫苗可以选择性地抑制pDCs的先天免疫感应,从而降低反应性.
saRNA-5mC平台通过通过替代途径吸引专业的抗原呈现细胞来保持强大的免疫性.
这些发现支持5mC修饰的saRNA疫苗技术在改善安全性和疗效方面的临床潜力.

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