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Curated Papers > Highly Cited Authoritative Literature on "mRNA Vaccines"

Developing mRNA-vaccine technologies. ​

Literature Information ​

DOI10.4161/rna.22269
PMID23064118
JournalRNA biology
Impact Factor3.4
JCR QuartileQ2
Publication Year2012
Times Cited299
Keywordsadjuvant, formulation, mRNA, mRNA design, mRNA production
Literature TypeJournal Article, Review
ISSN1547-6286
Pages1319-30
Issue9(11)
AuthorsThomas Schlake, Andreas Thess, Mariola Fotin-Mleczek, Karl-Josef Kallen

TL;DR ​

mRNA vaccines represent a novel and flexible vaccine platform that combines safety with the ability to elicit a strong immune response without MHC haplotype restrictions, making them suitable for diverse applications. This research highlights the advantages of mRNA technology in vaccine development, emphasizing its potential to revolutionize immunization strategies.

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adjuvant · formulation · mRNA · mRNA design · mRNA production

Abstract ​

mRNA vaccines combine desirable immunological properties with an outstanding safety profile and the unmet flexibility of genetic vaccines. Based on in situ protein expression, mRNA vaccines are capable of inducing a balanced immune response comprising both cellular and humoral immunity while not subject to MHC haplotype restriction. In addition, mRNA is an intrinsically safe vector as it is a minimal and only transient carrier of information that does not interact with the genome. Because any protein can be expressed from mRNA without the need to adjust the production process, mRNA vaccines also offer maximum flexibility with respect to development. Taken together, mRNA presents a promising vector that may well become the basis of a game-changing vaccine technology platform. Here, we outline the current knowledge regarding different aspects that should be considered when developing an mRNA-based vaccine technology.

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Primary Questions Addressed ​

  1. What are the key challenges faced in the large-scale production of mRNA vaccines?
  2. How does the immune response induced by mRNA vaccines compare to traditional vaccine platforms?
  3. What advancements in mRNA delivery systems could enhance vaccine efficacy?
  4. How can mRNA vaccine technology be adapted for use against emerging infectious diseases?
  5. What regulatory considerations must be addressed when developing new mRNA vaccine candidates?

Key Findings ​

Research Background and Objectives ​

The article discusses the development of mRNA vaccine technologies, highlighting their potential as a flexible and safe platform for inducing immune responses against various diseases, including infections and cancer. The authors aim to outline the critical aspects of mRNA vaccine technology, including production, design, uptake, formulation, and immunological properties.

Main Methods/Materials/Experimental Design ​

The study emphasizes several key areas in the development of mRNA vaccines, which can be summarized in the following flowchart:

Mermaid diagram

  1. mRNA Production:

    • Involves in vitro transcription of a cDNA template using bacteriophage RNA polymerase.
    • Purification of mRNA to remove contaminants that could inhibit protein expression.

  2. mRNA Design:

    • Focuses on key elements such as capping, poly(A) tail length, untranslated regions (UTRs), and open reading frame (ORF) design to enhance translation and stability.

  3. mRNA Uptake:

    • Investigates mechanisms of mRNA entry into cells, emphasizing the importance of caveolae/lipid rafts and macropinocytosis.

  4. Formulation:

    • Explores the use of complexing agents to protect mRNA from degradation and enhance cellular uptake.

  5. Protein Expression:

    • Discusses the relationship between mRNA design and the resulting protein expression levels, which are crucial for effective immunogenicity.

Key Results and Findings ​

  • mRNA vaccines can induce both cellular and humoral immune responses without MHC haplotype restriction, providing a significant safety advantage over DNA vaccines.
  • Proper purification of mRNA enhances its efficacy by improving protein expression in vivo.
  • Capping strategies using anti-reverse cap analogs (ARCAs) and optimal poly(A) tail lengths can significantly boost translation efficiency.
  • mRNA uptake mechanisms are influenced by temperature, dose, and the presence of specific receptors, which can be targeted to enhance vaccine delivery.
  • Formulation with lipids or polymers is critical for protecting mRNA and facilitating its entry into target cells.

Main Conclusions/Significance/Innovation ​

The authors conclude that mRNA vaccines represent a promising new platform for vaccine development due to their safety, flexibility, and ability to elicit strong immune responses. They highlight the importance of optimizing various aspects of mRNA design and formulation to enhance the efficacy of these vaccines. The article emphasizes the potential of mRNA technology to revolutionize both therapeutic and prophylactic vaccination strategies against a range of diseases.

Research Limitations and Future Directions ​

  • The study acknowledges that while mRNA vaccines show great promise, challenges remain in terms of large-scale production, stability, and delivery mechanisms.
  • Future research should focus on improving mRNA stability, exploring novel delivery systems, and optimizing formulations to maximize immunogenicity.
  • The authors suggest that combining mRNA vaccines with other therapeutic modalities could enhance their effectiveness, particularly in cancer treatment. Further clinical trials are necessary to evaluate the efficacy of these vaccines in diverse populations and disease settings.

References ​

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  2. Systematic discovery of structural elements governing stability of mammalian messenger RNAs. - Hani Goodarzi;Hamed S Najafabadi;Panos Oikonomou;Todd M Greco;Lisa Fish;Reza Salavati;Ileana M Cristea;Saeed Tavazoie - Nature (2012)
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  5. Interferon-inducible antiviral effectors. - Anthony J Sadler;Bryan R G Williams - Nature reviews. Immunology (2008)
  6. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. - Katalin Karikó;Michael Buckstein;Houping Ni;Drew Weissman - Immunity (2005)
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  8. Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. - Katalin Karikó;Hiromi Muramatsu;Jason M Keller;Drew Weissman - Molecular therapy : the journal of the American Society of Gene Therapy (2012)
  9. In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. - I Hoerr;R Obst;H G Rammensee;G Jung - European journal of immunology (2000)
  10. Recombinant vector vaccines in vaccinology. - M R Hilleman - Developments in biological standardization (1994)

Literatures Citing This Work ​

  1. A novel, disruptive vaccination technology: self-adjuvanted RNActive(®) vaccines. - Karl-Josef Kallen;Regina Heidenreich;Margit Schnee;Benjamin Petsch;Thomas Schlake;Andreas Thess;Patrick Baumhof;Birgit Scheel;Sven D Koch;Mariola Fotin-Mleczek - Human vaccines & immunotherapeutics (2013)
  2. A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs. - Karl-Josef Kallen;Andreas Theß - Therapeutic advances in vaccines (2014)
  3. Translation of genomics-guided RNA-based personalised cancer vaccines: towards the bedside. - V Boisguérin;J C Castle;M Loewer;J Diekmann;F Mueller;C M Britten;S Kreiter;Ö Türeci;U Sahin - British journal of cancer (2014)
  4. Three-Dimensional Mapping of mRNA Export through the Nuclear Pore Complex. - Steven J Schnell;Jiong Ma;Weidong Yang - Genes (2014)
  5. mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer. - Steffen Rausch;Christian Schwentner;Arnulf Stenzl;Jens Bedke - Human vaccines & immunotherapeutics (2014)
  6. Bridging infectious disease vaccines with cancer immunotherapy: a role for targeted RNA based immunotherapeutics. - Elias J Sayour;Luis Sanchez-Perez;Catherine Flores;Duane A Mitchell - Journal for immunotherapy of cancer (2015)
  7. An Enterovirus-Like RNA Construct for Colon Cancer Suicide Gene Therapy. - Mahsa Rasekhian;Ladan Teimoori-Toolabi;Safieh Amini;Kayhan Azadmanesh - Iranian biomedical journal (2015)
  8. Sequence-engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals. - Andreas Thess;Stefanie Grund;Barbara L Mui;Michael J Hope;Patrick Baumhof;Mariola Fotin-Mleczek;Thomas Schlake - Molecular therapy : the journal of the American Society of Gene Therapy (2015)
  9. Efficient expression of stabilized mRNA PEG-peptide polyplexes in liver. - S T Crowley;J A Poliskey;N J Baumhover;K G Rice - Gene therapy (2015)
  10. RNA-Based Vaccines in Cancer Immunotherapy. - Megan A McNamara;Smita K Nair;Eda K Holl - Journal of immunology research (2015)

... (289 more literatures)

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