Edwards Darin K, Jasny Edith, Yoon Heesik, Horscroft Nigel, Schanen Brian, Geter Tanya, Fotin-Mleczek Mariola, Petsch Benjamin, Wittman Vaughan
Sanofi Pasteur, VaxDesign Campus, 2501 Discovery Drive Suite 300, Orlando, FL, USA.
CureVac AG, Paul-Ehrlich-Str. 15, 72076, Tübingen, Germany.
J Transl Med. 2017 Jan 3;15(1):1. doi: 10.1186/s12967-016-1111-6.
Prophylactic and therapeutic vaccines often depend upon a strong activation of the innate immune system to drive a potent adaptive immune response, often mediated by a strong adjuvant. For a number of adjuvants immunological readouts may not be consistent across species.
In this study, we evaluated the innate immunostimulatory potential of mRNA vaccines in both humans and mice, using a novel mRNA-based vaccine encoding influenza A hemagglutinin of the pandemic strain H1N1pdm09 as a model. This evaluation was performed using an in vitro model of human innate immunity and in vivo in mice after intradermal injection.
Results suggest that immunostimulation from the mRNA vaccine in humans is similar to that in mice and acts through cellular RNA sensors, with genes for RLRs [ddx58 (RIG-1) and ifih1 (MDA-5)], TLRs (tlr3, tlr7, and tlr8-human only), and CLRs (clec4gp1, clec2d, cledl1) all significantly up-regulated by the mRNA vaccine. The up-regulation of TLR8 and TLR7 points to the involvement of both mDCs and pDCs in the response to the mRNA vaccine in humans. In both humans and mice activation of these pathways drove maturation and activation of immune cells as well as production of cytokines and chemokines known to attract and activate key players of the innate and adaptive immune system.
This translational approach not only allowed for identification of the basic mechanisms of self-adjuvantation from the mRNA vaccine but also for comparison of the response across species, a response that appears relatively conserved or at least convergent between the in vitro human and in vivo mouse models.
预防性和治疗性疫苗通常依赖于先天免疫系统的强烈激活来驱动有效的适应性免疫反应，这一过程通常由强大的佐剂介导。对于许多佐剂而言，免疫读数在不同物种间可能不一致。
在本研究中，我们以一种编码大流行株H1N1pdm09甲型流感血凝素的新型基于mRNA的疫苗为模型，评估了mRNA疫苗在人和小鼠中的先天免疫刺激潜力。该评估通过人类先天免疫的体外模型以及皮内注射后在小鼠体内进行。
结果表明，mRNA疫苗在人类中的免疫刺激作用与在小鼠中相似，且通过细胞RNA传感器发挥作用，其中RLRs基因[ddx58（RIG-1）和ifih1（MDA-5）]、TLRs基因（tlr3、tlr7以及仅在人类中的tlr8）和CLRs基因（clec4gp1、clec2d、cledl1）均被mRNA疫苗显著上调。TLR8和TLR7的上调表明，mDCs和pDCs均参与了人类对mRNA疫苗的反应。在人和小鼠中，这些通路的激活均驱动了免疫细胞的成熟和激活，以及已知可吸引和激活先天及适应性免疫系统关键细胞的细胞因子和趋化因子的产生。
这种转化方法不仅有助于确定mRNA疫苗自我佐剂化的基本机制，还能比较不同物种间的反应，这种反应在体外人类模型和体内小鼠模型之间似乎相对保守或至少趋同。
