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Co-administration of GM-CSF expressing RNA is a powerful tool to enhance potency of SAM-based vaccines

机译：GM-CSF表达RNA的共同施用是一种强大的工具，可以提高基于SAM的疫苗效力

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Self-amplifying mRNAs (SAM)-based vaccines have been shown to induce a robust immune response in various animal species against both viral and bacterial pathogens. Due to their synthetic nature and to the versatility of the manufacturing process, SAM technology may represent an attractive solution for rapidly producing novel vaccines, which is particularly critical in case of pandemic infections or diseases mediated by newly emerging pathogens. Recent published data support the hypothesis that Antigen Presenting Cells (APCs) are responsible for CD8+ T-cell priming after SAM vaccination, suggesting cross-priming as the key mechanism for antigen presentation by SAM vaccines. In our study we investigated the possibility to enhance the immune response induced in mice by a single immunization with SAM by increasing the recruitment of APCs at the site of injection. To enhance SAM immunogenicity, we selected murine granulocyte-macrophage colony-stimulating factor (GM-CSF) as a model chemoat-tractant for APCs, and developed a SAM-GM-CSF vector. We evaluated whether the use of SAM-GM-CSF in combination with a SAM construct encoding the Influenza A virus nucleoprotein (NP) would lead to an increase of APC recruitment and NP-specific immune response. We indeed observed that the administration of SAM-GM-CSF enhances the recruitment of APCs at the injection site. Consistently with our hypothesis, co-administration of SAM-GM-CSF with SAM-NP significantly improved the magnitude of NP-specific CD8+ T-cell response both in terms of frequency of cytotoxic antigen-specific CD8+ T-cells and their functional activity in vivo. Furthermore, co-immunization with SAM-GM-CSF and SAM-NP provided an increase in protection against a lethal challenge with influenza virus. In conclusion, we demonstrated that increased recruitment of APCs at the site of injection is associated with an enhanced effectiveness of SAM vaccination and might be a powerful tool to potentiate the efficacy of RNA vaccination. (C) 2019 Elsevier Ltd. All rights reserved.
机译：已显示自我扩增的MRNA（SAM）的疫苗，以诱导各种动物物种对病毒和细菌病原体的鲁棒免疫应答。由于它们的合成性质和制造过程的多功能性，SAM技术可以代表一种迅速产生新型疫苗的有吸引力的解决方案，这在新出现的病原体介导的大流行感染或疾病的情况下尤其重要。最近的已发表的数据支持假设抗原呈递细胞（APC）对SAM疫苗接种后的CD8 + T细胞灌注负责，表明SAM疫苗作为抗原呈现的关键机制。在我们的研究中，我们通过增加在注射部位的募集方面，通过用SAM进行单一免疫，调查了提高小鼠中诱导的免疫应答的可能性。为了增强SAM免疫原性，我们选择鼠粒细胞 - 巨噬细胞群刺激因子（GM-CSF）作为APC的型号化学织物 - 递送剂，并开发了SAM-GM-CSF载体。我们评估了SAM-GM-CSF与编码流感病毒核蛋白（NP）的SAM构建体组合使用的是否会导致APC招生和NP特异性免疫应答的增加。我们确实观察到，SAM-GM-CSF的给药增强了注射部位的APC的募集。与我们的假设一致，在细胞毒性抗原特异性CD8 + T细胞的频率和其功能活性方面，SAM-GM-CSF的共同施用SAM-GM-CSF与SAM-NP的频率显着改善了NP特异性CD8 + T细胞反应的响应及其功能活性体内。此外，与SAM-GM-CSF和SAM-NP的共免疫提供了与流感病毒致死攻击的保护。总之，我们证明，增加注射部位的APC的募集与SAM疫苗接种的增强效能相关，并且可能是一种强大的工具，可以提高RNA疫苗接种的功效。 （c）2019 Elsevier Ltd.保留所有权利。

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