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文献精选 > 近年高分"mRNA疫苗"研究（IF≥30，近5年）

A Thermostable mRNA Vaccine against COVID-19. ​

文献信息 ​

DOI10.1016/j.cell.2020.07.024
PMID32795413
期刊Cell
影响因子42.5
JCR 分区Q1
发表年份2020
被引次数368
关键词新冠病毒, SARS-CoV-2, 脂质纳米粒子, mRNA疫苗, 适应小鼠的株
文献类型Journal Article, Research Support, Non-U.S. Gov't
ISSN0092-8674
页码1271-1283.e16
期号182(5)
作者Na-Na Zhang, Xiao-Feng Li, Yong-Qiang Deng, Hui Zhao, Yi-Jiao Huang, Guan Yang, Wei-Jin Huang, Peng Gao, Chao Zhou, Rong-Rong Zhang, Yan Guo, Shi-Hui Sun, Hang Fan, Shu-Long Zu, Qi Chen, Qi He, Tian-Shu Cao, Xing-Yao Huang, Hong-Ying Qiu, Jian-Hui Nie, Yuhang Jiang, Hua-Yuan Yan, Qing Ye, Xia Zhong, Xia-Lin Xue, Zhen-Yu Zha, Dongsheng Zhou, Xiao Yang, You-Chun Wang, Bo Ying, Cheng-Feng Qin

一句话小结 ​

本研究开发了一种基于脂质纳米颗粒的信使RNA疫苗ARCoV，能够有效诱导针对SARS-CoV-2的强效中和抗体和细胞免疫反应，并在小鼠模型中提供完全保护。ARCoV的液体制剂可在室温下保存至少一周，显示出其作为快速响应COVID-19疫情的疫苗候选者的重要性，目前已进入第一阶段临床试验。

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新冠病毒 · SARS-CoV-2 · 脂质纳米粒子 · mRNA疫苗 · 适应小鼠的株

摘要 ​

由于新冠病毒病2019（COVID-19）持续传播，迫切需要针对冠状病毒的疫苗。在所有方法中，基于信使RNA（mRNA）的疫苗作为一种快速而多功能的平台，迅速应对这一挑战。在此，我们开发了一种脂质纳米颗粒包裹的mRNA（mRNA-LNP），其编码了SARS-CoV-2的受体结合域（RBD），作为疫苗候选者（称为ARCoV）。对小鼠和非人灵长类动物进行ARCoV mRNA-LNP的肌肉免疫接种，诱导了针对SARS-CoV-2的强效中和抗体以及Th1偏向的细胞反应。在小鼠中，两剂ARCoV免疫接种提供了对SARS-CoV-2小鼠适应性毒株挑战的完全保护。此外，ARCoV以液体制剂形式生产，并且可以在室温下保存至少一周。目前，ARCoV正在进行第一阶段临床试验评估。

英文摘要 ​

There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.

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主要研究问题 ​

  1. ARCoV疫苗在不同人群中的免疫效果是否有显著差异？
  2. 除了SARS-CoV-2，ARCoV疫苗是否可以用于其他冠状病毒的预防？
  3. 在存储和运输方面，ARCoV疫苗的热稳定性如何影响其全球分发？
  4. ARCoV疫苗的研发过程中遇到了哪些主要技术挑战？
  5. 未来mRNA疫苗技术在应对新兴传染病方面的潜力如何？

核心洞察 ​

研究背景和目的 ​

新冠病毒（SARS-CoV-2）引发的COVID-19疫情全球蔓延，迫切需要有效的疫苗。信使RNA（mRNA）疫苗作为快速应对这一挑战的可行平台，展现出广泛的潜力。本研究旨在开发一种基于脂质纳米颗粒（LNP）包裹的mRNA疫苗（ARCoV），针对SARS-CoV-2的受体结合域（RBD），并评估其免疫原性和保护效果。

主要方法/材料/实验设计 ​

本研究采用LNP包裹的mRNA作为疫苗平台，主要步骤如下：

Mermaid diagram
  1. mRNA合成：通过T7 RNA聚合酶合成编码SARS-CoV-2 RBD的mRNA。
  2. LNP制备：将mRNA与脂质混合，通过T混合器自组装形成LNP。
  3. 小鼠免疫：将ARCoV mRNA-LNP通过肌肉注射给小鼠进行免疫。
  4. 免疫原性评估：检测小鼠血清中针对SARS-CoV-2 RBD的特异性IgG和中和抗体。
  5. 保护效果评估：使用小鼠适应的SARS-CoV-2毒株进行挑战实验。
  6. 非人灵长类动物实验：在猕猴中评估疫苗的免疫原性和安全性。

关键结果和发现 ​

  • 免疫原性：ARCoV疫苗在小鼠和非人灵长类动物中均能诱导强烈的特异性IgG和中和抗体反应。
  • 保护效果：在小鼠中，接受两剂ARCoV免疫后，完全阻止了SARS-CoV-2的肺部病毒复制。
  • 存储稳定性：ARCoV可以在室温下保存至少一周，显示出良好的热稳定性。
  • T细胞免疫反应：ARCoV疫苗能够诱导Th1偏向的细胞免疫反应，增强CD4+和CD8+ T细胞的产生。

主要结论/意义/创新性 ​

ARCoV是一种新型的mRNA疫苗，显示出在小鼠和非人灵长类动物中强大的免疫原性和保护效果。其热稳定性使其在COVID-19疫苗的全球分发中具有显著优势。此外，本研究首次提供了mRNA疫苗对SARS-CoV-2的保护相关性数据，为后续临床试验提供了重要依据。

研究局限性和未来方向 ​

  • 局限性：本研究主要基于小鼠适应性毒株，未来需要在转基因小鼠和野生型SARS-CoV-2毒株中进一步验证保护效果。
  • 未来方向：需要评估ARCoV在长期免疫反应中的有效性，并进行临床试验以验证其在人类中的安全性和有效性。同时，继续进行长期稳定性评估，以确保疫苗在不同环境条件下的有效性。

参考文献 ​

  1. mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases. - Giulietta Maruggi;Cuiling Zhang;Junwei Li;Jeffrey B Ulmer;Dong Yu - Molecular therapy : the journal of the American Society of Gene Therapy (2019)
  2. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. - Neeltje van Doremalen;Teresa Lambe;Alexandra Spencer;Sandra Belij-Rammerstorfer;Jyothi N Purushotham;Julia R Port;Victoria A Avanzato;Trenton Bushmaker;Amy Flaxman;Marta Ulaszewska;Friederike Feldmann;Elizabeth R Allen;Hannah Sharpe;Jonathan Schulz;Myndi Holbrook;Atsushi Okumura;Kimberly Meade-White;Lizzette Pérez-Pérez;Nick J Edwards;Daniel Wright;Cameron Bissett;Ciaran Gilbride;Brandi N Williamson;Rebecca Rosenke;Dan Long;Alka Ishwarbhai;Reshma Kailath;Louisa Rose;Susan Morris;Claire Powers;Jamie Lovaglio;Patrick W Hanley;Dana Scott;Greg Saturday;Emmie de Wit;Sarah C Gilbert;Vincent J Munster - Nature (2020)
  3. Immunological analysis of phase II glioblastoma dendritic cell vaccine (Audencel) trial: immune system characteristics influence outcome and Audencel up-regulates Th1-related immunovariables. - Friedrich Erhart;Johanna Buchroithner;René Reitermaier;Katrin Fischhuber;Simone Klingenbrunner;Ido Sloma;Dror Hibsh;Renana Kozol;Sol Efroni;Gerda Ricken;Adelheid Wöhrer;Christine Haberler;Johannes Hainfellner;Günther Krumpl;Thomas Felzmann;Alexander M Dohnal;Christine Marosi;Carmen Visus - Acta neuropathologica communications (2018)
  4. A thermostable messenger RNA based vaccine against rabies. - Lothar Stitz;Annette Vogel;Margit Schnee;Daniel Voss;Susanne Rauch;Thorsten Mutzke;Thomas Ketterer;Thomas Kramps;Benjamin Petsch - PLoS neglected tropical diseases (2017)
  5. Messenger RNA-Based Vaccines Against Infectious Diseases. - Mohamad-Gabriel Alameh;Drew Weissman;Norbert Pardi - Current topics in microbiology and immunology (2022)
  6. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. - Wanbo Tai;Lei He;Xiujuan Zhang;Jing Pu;Denis Voronin;Shibo Jiang;Yusen Zhou;Lanying Du - Cellular & molecular immunology (2020)
  7. Lipid-based nanoparticle formulations for small molecules and RNA drugs. - Ludger M Ickenstein;Patrick Garidel - Expert opinion on drug delivery (2019)
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  9. Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells. - Marco Maugeri;Muhammad Nawaz;Alexandros Papadimitriou;Annelie Angerfors;Alessandro Camponeschi;Manli Na;Mikko Hölttä;Pia Skantze;Svante Johansson;Martina Sundqvist;Johnny Lindquist;Tomas Kjellman;Inga-Lill Mårtensson;Tao Jin;Per Sunnerhagen;Sofia Östman;Lennart Lindfors;Hadi Valadi - Nature communications (2019)
  10. Immunological Lessons from Respiratory Syncytial Virus Vaccine Development. - Tracy J Ruckwardt;Kaitlyn M Morabito;Barney S Graham - Immunity (2019)

引用本文的文献 ​

  1. Theoretical basis for stabilizing messenger RNA through secondary structure design. - Hannah K Wayment-Steele;Do Soon Kim;Christian A Choe;John J Nicol;Roger Wellington-Oguri;Andrew M Watkins;R Andres Parra Sperberg;Po-Ssu Huang;Eterna Participants;Rhiju Das - bioRxiv : the preprint server for biology (2021)
  2. Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection. - Yun Tan;Feng Liu;Xiaoguang Xu;Yun Ling;Weijin Huang;Zhaoqin Zhu;Mingquan Guo;Yixiao Lin;Ziyu Fu;Dongguo Liang;Tengfei Zhang;Jian Fan;Miao Xu;Hongzhou Lu;Saijuan Chen - Frontiers of medicine (2020)
  3. A systematic review of SARS-CoV-2 vaccine candidates. - Yetian Dong;Tong Dai;Yujun Wei;Long Zhang;Min Zheng;Fangfang Zhou - Signal transduction and targeted therapy (2020)
  4. Learning from the past: development of safe and effective COVID-19 vaccines. - Shan Su;Lanying Du;Shibo Jiang - Nature reviews. Microbiology (2021)
  5. A materials-science perspective on tackling COVID-19. - Zhongmin Tang;Na Kong;Xingcai Zhang;Yuan Liu;Ping Hu;Shan Mou;Peter Liljeström;Jianlin Shi;Weihong Tan;Jong Seung Kim;Yihai Cao;Robert Langer;Kam W Leong;Omid C Farokhzad;Wei Tao - Nature reviews. Materials (2020)
  6. Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment. - Sameer Kumar Malladi;Randhir Singh;Suman Pandey;Savitha Gayathri;Kawkab Kanjo;Shahbaz Ahmed;Mohammad Suhail Khan;Parismita Kalita;Nidhi Girish;Aditya Upadhyaya;Poorvi Reddy;Ishika Pramanick;Munmun Bhasin;Shailendra Mani;Sankar Bhattacharyya;Jeswin Joseph;Karthika Thankamani;V Stalin Raj;Somnath Dutta;Ramandeep Singh;Gautham Nadig;Raghavan Varadarajan - The Journal of biological chemistry (2021)
  7. Spike Glycoprotein-Mediated Entry of SARS Coronaviruses. - Lin Wang;Ye Xiang - Viruses (2020)
  8. Therapeutic modalities and novel approaches in regenerative medicine for COVID-19. - Roya Ramezankhani;Roya Solhi;Arash Memarnejadian;Fatemeharefeh Nami;Seyed Mohammad Reza Hashemian;Tine Tricot;Massoud Vosough;Catherine Verfaillie - International journal of antimicrobial agents (2020)
  9. RBD-Fc-based COVID-19 vaccine candidate induces highly potent SARS-CoV-2 neutralizing antibody response. - Zezhong Liu;Wei Xu;Shuai Xia;Chenjian Gu;Xinling Wang;Qian Wang;Jie Zhou;Yanling Wu;Xia Cai;Di Qu;Tianlei Ying;Youhua Xie;Lu Lu;Zhenghong Yuan;Shibo Jiang - Signal transduction and targeted therapy (2020)
  10. Identifying and repurposing antiviral drugs against severe acute respiratory syndrome coronavirus 2 with in silico and in vitro approaches. - Koichi Watashi - Biochemical and biophysical research communications (2021)

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