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Curated Papers > Recent high-impact research on "mRNA vaccines" (IF ≥ 30, last 5 years)

A Thermostable mRNA Vaccine against COVID-19. ​

Literature Information ​

DOI10.1016/j.cell.2020.07.024
PMID32795413
JournalCell
Impact Factor42.5
JCR QuartileQ1
Publication Year2020
Times Cited368
KeywordsCOVID-19, SARS-CoV-2, lipid nanoparticle, mRNA vaccine, mouse-adapted strain
Literature TypeJournal Article, Research Support, Non-U.S. Gov't
ISSN0092-8674
Pages1271-1283.e16
Issue182(5)
AuthorsNa-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

TL;DR ​

This study presents ARCoV, a lipid nanoparticle-encapsulated mRNA vaccine encoding the receptor binding domain of SARS-CoV-2, which demonstrates strong neutralizing antibody responses and effective protection against the virus in animal models. The vaccine's ability to be stored at room temperature for a week highlights its potential for rapid deployment in response to the COVID-19 pandemic, with ARCoV currently undergoing phase 1 clinical trials.

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COVID-19 · SARS-CoV-2 · lipid nanoparticle · mRNA vaccine · mouse-adapted strain

Abstract ​

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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Primary Questions Addressed ​

  1. What are the potential advantages of using lipid nanoparticle-encapsulated mRNA technology in vaccine development compared to traditional vaccine platforms?
  2. How does the immune response elicited by the ARCoV vaccine compare to that of other COVID-19 vaccines currently in use?
  3. What specific challenges are associated with the storage and distribution of mRNA vaccines, and how does ARCoV address these issues?
  4. In what ways could the Th1-biased cellular response induced by ARCoV impact long-term immunity against SARS-CoV-2?
  5. What are the implications of the findings from the phase 1 clinical trials for the future development of mRNA vaccines for other infectious diseases?

Key Findings ​

Research Background and Purpose ​

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has created an urgent need for effective vaccines. Traditional vaccine development processes are often slow, which necessitates rapid and adaptable solutions. Messenger RNA (mRNA) vaccines have emerged as a promising platform due to their quick design and production capabilities. This study aims to develop and evaluate a thermostable mRNA vaccine candidate, named ARCoV, targeting the receptor binding domain (RBD) of SARS-CoV-2.

Main Methods/Materials/Experimental Design ​

The study employed a lipid nanoparticle (LNP) formulation to encapsulate the mRNA encoding the RBD of SARS-CoV-2. The vaccine was tested in mice and non-human primates (NHPs) to assess its immunogenicity and protective efficacy.

Experimental Design Overview ​

Mermaid diagram
  • mRNA Synthesis: The mRNA was produced using T7 RNA polymerase from a linearized DNA template.
  • LNP Formulation: Lipids were mixed with mRNA in an aqueous solution, followed by tangential flow filtration for purification.
  • In Vitro Testing: The expression of the RBD protein was confirmed in various cell lines (HeLa, HEK293T, etc.).
  • In Vivo Testing: Mice were immunized intramuscularly with ARCoV, followed by serum collection for antibody response analysis.
  • Immunogenicity Assessment: Both humoral (antibody) and cellular (T cell) responses were measured.
  • Challenge Studies: Mice were challenged with a mouse-adapted strain of SARS-CoV-2 to evaluate vaccine efficacy.

Key Results and Findings ​

  • Immunogenicity: ARCoV induced robust neutralizing antibody responses and T cell immunity in both mice and NHPs.
  • Efficacy: Mice vaccinated with two doses of ARCoV were fully protected against SARS-CoV-2 infection, with no detectable viral RNA in the lungs post-challenge.
  • Thermostability: ARCoV can be stored at room temperature for at least one week without significant loss of efficacy, making it suitable for deployment in areas lacking cold chain logistics.
ParameterResults
Neutralizing Antibody Titer (NT50)Mice: ~1/2,540 (2 mg), ~1/7,079 (10 mg)
Protective EfficacyFull protection against SARS-CoV-2 in mice
Storage StabilityStable at 4°C and 25°C for 7 days

Main Conclusions/Significance/Innovation ​

The study demonstrates that ARCoV is a promising mRNA vaccine candidate against COVID-19, capable of eliciting strong immune responses and providing full protection in animal models. Its thermostability enhances its potential for widespread use, particularly in resource-limited settings. The findings support the ongoing development of ARCoV for clinical trials and highlight the efficacy of mRNA vaccines in responding to pandemic threats.

Research Limitations and Future Directions ​

  • Limitations: The study utilized a mouse-adapted strain of SARS-CoV-2, which may not fully represent the virus's behavior in humans. Long-term durability of the immune response remains to be assessed.
  • Future Directions: Further studies should include evaluations with wild-type SARS-CoV-2 strains and extended follow-up on the duration of immunity in animal models and eventual human trials.

In summary, ARCoV represents a significant advancement in mRNA vaccine technology, providing a framework for rapid response to emerging infectious diseases.

References ​

  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)
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  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)
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Literatures Citing This Work ​

  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)

... (358 more literatures)

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