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In Vitro Transcribed mRNA Vaccines with Programmable Stimulation of Innate Immunity
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-08-01 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00443 Kristin H. Loomis 1 , Kevin E. Lindsay 1 , Chiara Zurla 1 , Sushma M. Bhosle 1 , Daryll A. Vanover 1 , Emmeline L. Blanchard 1 , Jonathan L. Kirschman 1 , Ravi V. Bellamkonda 1 , Philip J. Santangelo 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-08-01 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00443 Kristin H. Loomis 1 , Kevin E. Lindsay 1 , Chiara Zurla 1 , Sushma M. Bhosle 1 , Daryll A. Vanover 1 , Emmeline L. Blanchard 1 , Jonathan L. Kirschman 1 , Ravi V. Bellamkonda 1 , Philip J. Santangelo 1
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In vitro transcribed (IVT) mRNA is an appealing platform for next generation vaccines, as it can be manufactured rapidly at large scale to meet emerging pathogens. However, its performance as a robust vaccine is strengthened by supplemental immune stimulation, which is typically provided by adjuvant formulations that facilitate delivery and stimulate immune responses. Here, we present a strategy for increasing translation of a model IVT mRNA vaccine while simultaneously modulating its immune-stimulatory properties in a programmable fashion, without relying on delivery vehicle formulations. Substitution of uridine with the modified base N1-methylpseudouridine reduces the intrinsic immune stimulation of the IVT mRNA and enhances antigen translation. Tethering adjuvants to naked IVT mRNA through antisense nucleotides boosts the immunostimulatory properties of adjuvants in vitro, without impairing transgene production or adjuvant activity. In vivo, intramuscular injection of tethered IVT mRNA-TLR7 agonists leads to enhanced local immune responses, and to antigen-specific cell-mediated and humoral responses. We believe this system represents a potential platform compatible with any adjuvant of interest to enable specific programmable stimulation of immune responses.
中文翻译：
可编程转录的先天免疫的体外转录的mRNA疫苗。
体外转录（IVT）mRNA是下一代疫苗的诱人平台，因为它可以大规模快速生产，以满足新出现的病原体。但是，补充免疫刺激可增强其作为强效疫苗的性能，补充免疫刺激通常由辅助制剂提供，可促进递送和刺激免疫反应。在这里，我们提出了一种策略，可增加IVT模型mRNA疫苗的翻译，同时以可编程方式调节其免疫刺激特性，而无需依赖运载工具的配方。用修饰的碱基N1-甲基伪尿苷取代尿苷可减少IVT mRNA的内在免疫刺激并增强抗原翻译。体外，而不会损害转基因的产生或佐剂活性。在体内，肌内注射拴系的IVT mRNA-TLR7激动剂可导致增强的局部免疫反应，以及抗原特异性细胞介导的和体液反应。我们相信，该系统代表了与任何感兴趣的佐剂兼容的潜在平台，以实现对免疫反应的特定可编程刺激。
更新日期：2018-08-01
中文翻译：
可编程转录的先天免疫的体外转录的mRNA疫苗。
体外转录（IVT）mRNA是下一代疫苗的诱人平台，因为它可以大规模快速生产，以满足新出现的病原体。但是，补充免疫刺激可增强其作为强效疫苗的性能，补充免疫刺激通常由辅助制剂提供，可促进递送和刺激免疫反应。在这里，我们提出了一种策略，可增加IVT模型mRNA疫苗的翻译，同时以可编程方式调节其免疫刺激特性，而无需依赖运载工具的配方。用修饰的碱基N1-甲基伪尿苷取代尿苷可减少IVT mRNA的内在免疫刺激并增强抗原翻译。体外，而不会损害转基因的产生或佐剂活性。在体内，肌内注射拴系的IVT mRNA-TLR7激动剂可导致增强的局部免疫反应，以及抗原特异性细胞介导的和体液反应。我们相信，该系统代表了与任何感兴趣的佐剂兼容的潜在平台，以实现对免疫反应的特定可编程刺激。
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