mRNA vaccines: A matter of delivery.
mRNA vaccines: A matter of delivery.
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DOI：
10.1016/j.eclinm.2021.100746
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发表时间：
2021-03
影响因子：
15.1
通讯作者：
Gao GF
中科院分区：
文献类型：
--
作者：
Cao Y;Gao GF
随着美国食品药品监督管理局（fda）批准辉瑞公司和Moderna公司的信使RNA （mRNA）疫苗紧急使用，以信使RNA （mRNA）为基础的疫苗受到了全世界的关注。这是基于mrna的疫苗首次被批准用于健康人群，标志着科学和公共卫生成就的一个重要里程碑。mRNA疫苗是一种新形式的疫苗，通过将编码病毒抗原的合成mRNA转染到人细胞中引发免疫反应。一旦mRNA分子进入细胞质，被转染的细胞将遗传信息翻译成特定的病毒抗原。这些抗原随后呈现在细胞表面，在那里它们可以被免疫细胞识别。与通常含有灭活（或减毒活）致病生物体、蛋白肽或抗原产生的DNA片段的常规疫苗相比，mRNA疫苗具有若干优势。首先，基于mrna的疫苗可以快速开发。基于目标病毒的测序信息，它们可以在几天或几个月内开发出来，而传统疫苗往往需要数年时间，并且需要对目标病毒有深入的了解，才能使疫苗有效和安全。其次，这些新型疫苗可以快速生产。由于体外转录反应的高产量，mRNA的生产可以快速，廉价和可扩展。第三，疫苗风险低。mRNA不包含可能导致感染和插入突变的感染性病毒成分。mRNA疫苗的开发源于1990年美国威斯康辛大学的研究人员首次在小鼠体内用合成mRNA生产蛋白质的演示。他们随后的工作表明，在大鼠大脑中使用编码mRNA的抗利尿激素可以引起生理反应。虽然最初的报告很有希望，但它并没有引起制药行业的太多关注，主要是因为担心引发不必要的先天免疫反应，以及mRNA产物的不稳定性。经过15年的努力，2005年，dr。Kariko和Weissman发现了一种通过修饰mRNA核苷[4]来逃避先天免疫反应的有效方法。这一重大突破彻底改变了mRNA治疗的药物潜力，并导致相关研究的大量投资，导致mRNA修饰和纯化的重要发现，以减少先天免疫反应并提高mRNA的稳定性。mRNA疫苗有效应用的挑战在于微观和宏观层面的递送。裸mRNA可被胞外rna酶迅速降解，具有免疫原性，且不能单独穿透细胞膜在细胞质中转录。因此，细胞内递送对于促进mRNA的细胞摄取和保护mRNA免受rna酶降解至关重要。迄今为止，已经开发了许多递送方法，包括树突状细胞的体外负载，物理递送方法，阳离子肽鱼精蛋白和阳离子脂质纳米颗粒（LNPs）递送，其中LNPs似乎是最吸引人且最常用的工具[2]。LNPs通常由四个组成部分组成：(1)阳离子或可电离脂质，智能大分子，可被功能化以改善mRNA的包裹，提高细胞摄取效率，促进内体逃逸；(2)脂锚聚乙二醇（PEG），用于减小颗粒尺寸，防止…
Vaccines based on messenger RNA (mRNA) are attracting worldwide attention as the Pfizer and Moderna vaccines have been authorized for emergency use by the US Food and Drug Administration and similar authorities around the world. This is the first time that mRNA-based vaccines have ever been approved for use on healthy population [1], and marks a critical milestone for achievement in both science and public health. mRNA vaccines are a new form of vaccines that trigger immune responses by transfecting synthetic mRNA encoding viral antigens into human cells. Once the mRNA molecules are in the cytosol, the transfected cells translate the genetic information to the specific viral antigens. These antigens are then presented on the cell surface where they can be recognized by the immune cells [2]. mRNA vaccines have several advantages in comparison with conventional vaccines usually containing inactivated (or live attenuated) disease-causing organisms, protein peptides or DNA fragments made by antigens. Firstly, mRNA-based vaccines can be rapidly developed. They can be developed within days or months based on sequencing information from a target virus, while conventional vaccines often take years and require a deep understanding of the target virus to make the vaccine effective and safe. Secondly, these novel vaccines can be rapidly produced. Due to high yields from in vitro transcription reactions, mRNA production can be rapid, inexpensive and scalable. Thirdly, vaccine risks are low. mRNA does not contain infectious viral elements that pose risks for infection and insertional mutagenesis. The development of mRNA vaccines has its roots in the 1990 demonstration of protein production from synthetic mRNA administrated in mice for the first time by researchers at the University of Wisconsin, USA [3]. Their subsequent work showed that the administration of vasopressin encoding mRNA in rat brains could elicit a physiological response. While the initial report was promising, it did not attract much attention from the pharmaceutical industry, largely because of concerns associated with the triggering of unwanted innate immune response, and the instability of the mRNA product. After 15 more years of effort, in 2005, Drs. Kariko and Weissman found an effective way to evade the innate immune response by modifying the mRNA’s nucleosides [4]. This major breakthrough completely altered the pharmaceutical potential of mRNA therapies and resulted in substantial investment in associated research, leading to important discoveries in mRNA modification and purification to reduce the innate immune response and improve mRNA stability. The challenge for effective application of mRNA vaccines lies in the delivery at both the micro and macro levels. Naked mRNA is rapidly degraded by extracellular RNases, it can be immunogenic, and alone, it cannot penetrate cell membranes to be transcribed in the cytosol. Thus, intracellular delivery is essential to facilitate cellular uptake of mRNA and to protect it from RNase degradation. To date, numerous delivery methods have been developed, including ex vivo loading of dendritic cells, physical delivery methods, cationic peptide protamine, and cationic lipid nanoparticles (LNPs) delivery, among which LNPs seems to be the most appealing and commonly used tool [2]. LNPs often consists of four components:(1) cationic or ionizable lipids, smart macromolecules that can be functionalized to improve the entrapment of mRNA, to increase cellular uptake efficiency, and promote endosomal escape;(2) lipid-anchored polyethylene glycol (PEG), which is used for reducing particle sizes, preventing …
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DOI：
10.1038/nrd.2017.243
发表时间：
2018-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Pardi N;Hogan MJ;Porter FW;Weissman D
通讯作者：
Weissman D
BNT162B2 mRNA COVID-19疫苗的安全性和功效。
DOI：
10.1056/nejmoa2034577
发表时间：
2020-12-31
期刊：
The New England journal of medicine
影响因子：
--
作者：
Polack FP;Thomas SJ;Kitchin N;Absalon J;Gurtman A;Lockhart S;Perez JL;Pérez Marc G;Moreira ED;Zerbini C;Bailey R;Swanson KA;Roychoudhury S;Koury K;Li P;Kalina WV;Cooper D;Frenck RW Jr;Hammitt LL;Türeci Ö;Nell H;Schaefer A;Ünal S;Tresnan DB;Mather S;Dormitzer PR;Şahin U;Jansen KU;Gruber WC;C4591001 Clinical Trial Group
通讯作者：
C4591001 Clinical Trial Group
影响因子：
56.9
作者：
WOLFF, JA;MALONE, RW;FELGNER, PL
通讯作者：
FELGNER, PL
影响因子：
32.4
作者：
Karikó, K;Buckstein, M;Weissman, D
通讯作者：
Weissman, D