BioNTech AG, Mainz, Germany.
Wiley Interdiscip Rev RNA. 2013 Nov-Dec;4(6):737-49. doi: 10.1002/wrna.1189. Epub 2013 Jul 25.
Twenty years after the demonstration that messenger RNA (mRNA) was expressed and immunogenic upon direct injection in mice, the first successful proof-of-concept of specific protection against viral infection in small and large animals was reported. These data indicate wider applicability to infectious disease and should encourage continued translation of mRNA-based prophylactic vaccines into human clinical trials. At the conceptual level, mRNA-based vaccines-more than other genetic vectors-combine the simplicity, safety, and focused immunogenicity of subunit vaccines with favorable immunological properties of live viral vaccines: (1) mRNA vaccines are molecularly defined and carry no excess information. In the environment and upon physical contact, RNA is rapidly degraded by ubiquitous RNases and cannot persist. These characteristics also guarantee tight control over their immunogenic profile (including avoidance of vector-specific immune responses that could interfere with repeated administration), pharmacokinetics, and dosing. (2) mRNA vaccines are synthetically produced by an enzymatic process, just requiring information about the nucleic acid sequence of the desired antigen. This greatly reduces general complications associated with biological vaccine production, such as handling of infectious agents, genetic variability, environmental risks, or restrictions to vaccine distribution. (3) RNA can be tailored to provide potent adjuvant stimuli to the innate immune system by direct activation of RNA-specific receptors; this may reduce the need for additional adjuvants. The formation of native antigen in situ affords great versatility, including intracellular localization, membrane association, posttranslational modification, supra-molecular assembly, or targeted structural optimization of delivered antigen. Messenger RNA vaccines induce balanced immune responses including B cells, helper T cells, and cytotoxic T lymphocytes, rendering them an extremely adaptable platform. This article surveys the design, mode of action, and capabilities of state-of-the-art mRNA vaccines, focusing on the paradigm of influenza prophylaxis.
二十年前，人们已经证明信使 RNA（mRNA）在直接注射到小鼠中时会表达并具有免疫原性，此后，首次成功证明了在小动物和大动物中针对病毒感染的特定保护作用。这些数据表明其具有更广泛的适用性，可以用于传染病，并应鼓励继续将基于 mRNA 的预防性疫苗转化为人体临床试验。从概念上讲，与其他遗传载体相比，基于 mRNA 的疫苗更具优势，它将亚单位疫苗的简单性、安全性和针对性免疫原性与活病毒疫苗的有利免疫特性相结合：（1）mRNA 疫苗具有分子定义性，并且不携带多余的信息。在环境中和物理接触时，RNA 会被广泛存在的 RNA 酶迅速降解，无法持久存在。这些特性还能保证对其免疫原性特征（包括避免可能干扰重复给药的载体特异性免疫反应）、药代动力学和剂量进行严格控制。（2）mRNA 疫苗通过酶促过程进行合成，只需要有关所需抗原的核酸序列的信息。这大大降低了与生物疫苗生产相关的一般复杂性，例如处理传染性病原体、遗传变异性、环境风险或对疫苗分配的限制。（3）RNA 可以通过直接激活 RNA 特异性受体来为固有免疫系统提供有效的佐剂刺激；这可能减少对额外佐剂的需求。在原位形成天然抗原提供了很大的多功能性，包括细胞内定位、膜结合、翻译后修饰、超分子组装或递呈抗原的靶向结构优化。信使 RNA 疫苗可诱导平衡的免疫反应，包括 B 细胞、辅助性 T 细胞和细胞毒性 T 淋巴细胞，使其成为一种极其适应的平台。本文综述了最先进的 mRNA 疫苗的设计、作用模式和功能，重点介绍了流感预防的范例。
