Elsevier

Current Opinion in Immunology

Volume 65, August 2020, Pages 14-20
Current Opinion in Immunology

Recent advances in mRNA vaccine technology

https://doi.org/10.1016/j.coi.2020.01.008Get rights and content

Highlights

  • mRNA vaccines address many of the weaknesses of conventional vaccine types.

  • Innovations in recent years revolutionized the applicability of mRNA vaccines.

  • mRNA vaccines have demonstrated a high level of efficacy in preclinical studies.

  • Human clinical trials of mRNA vaccines are being heavily pursued.

Messenger RNA (mRNA) vaccines represent a relatively new vaccine class showing great promise for the future. This optimism is built on recently published studies demonstrating the efficacy of mRNA vaccines in combatting several types of cancer and infectious pathogens where conventional vaccine platforms may fail to induce protective immune responses. These results would not have been possible without critical recent innovations in the field, such as the development of safe and efficient materials for in vivo mRNA delivery and advanced protocols for the production of high quality mRNA. This review summarizes the most important developments in mRNA vaccines from the past few years and discusses the challenges and future directions for the field.

Section snippets

Introduction: overcoming early challenges for RNA vaccines

The concept of genetic (DNA and RNA) vaccines was raised decades ago with the hope that a flexible, easy-to-produce, safe and effective vaccine class could be generated. Until the late 2000s, the emphasis was on the development of DNA-based approaches [1] due to the hurdles stemming from RNA’s instability, inefficient in vivo delivery, and its stimulation of excessive inflammatory responses. Producing in vitro-transcribed (IVT) messenger RNA (mRNA) is a fairly straightforward process [2,3], but

Recent innovations

The most important innovations in mRNA vaccine technology in recent years have been in the areas of: 1) engineering of mRNA sequences, 2) development of methods that enable simple, rapid and large-scale cGMP production of mRNA; and 3) development of highly efficient and safe mRNA vaccine delivery materials.

Future directions and outstanding questions regarding mRNA vaccines

While the past several years have witnessed a rapid pace of innovation in mRNA manufacturing, in vivo delivery, and immunogenicity, there remains much room for improvement and investigation. Here, we briefly highlight three interrelated topics that, if better understood, could propel the field further: (1) differences in mRNA preparation, (2) differences between animal models and humans, and (3) mechanisms of immunogenicity of mRNA vaccines.

Conclusions

The past several years yielded critically important advancements in the field of mRNA vaccines and provided evidence for the viability of this novel vaccine modality. New manufacturing methods and delivery materials will facilitate the rapid, inexpensive mass production of next-generation mRNA vaccines. Data from human trials for both cancer and infectious disease mRNA vaccines are encouraging, but further improvements of the delivery materials and a more complete understanding of the

Conflict of interest statement

In accordance with the University of Pennsylvania policies and procedures and our ethical obligations as researchers, we report that Drew Weissman is named on patents that describe the use of nucleoside-modified mRNA as a platform to deliver therapeutic proteins. Drew Weissman and Norbert Pardi are also named on a patent describing the use of modified mRNA in lipid nanoparticles as a vaccine platform. We have disclosed those interests fully to the University of Pennsylvania, and we have in

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

N.P. was supported by the National Institute of Allergy and Infectious Diseases (1R01AI146101). D.W. was supported by the National Institute of Allergy and Infectious Diseases (R01-AI050484, R01-AI124429 and R01-AI084860). M.J.H. is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute. The authors apologize to all colleagues whose great studies could not be cited here owing to space limitations.

References (59)

  • S. John et al.

    Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity

    Vaccine

    (2018)
  • M. Meyer et al.

    Modified mRNA-based vaccines elicit robust immune responses and protect guinea pigs from Ebola virus disease

    J Infect Dis

    (2018)
  • N. Veiga et al.

    Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes

    Nat Commun

    (2018)
  • L. Heesen et al.

    A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for potent melanoma immunotherapy

    Ann Oncol

    (2017)
  • S.L. Linderman et al.

    Antibodies with ‘Original Antigenic Sin’ properties are valuable components of secondary immune responses to influenza viruses

    PLoS Pathog

    (2016)
  • J.J. Suschak et al.

    Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity

    Hum Vaccine Immunother

    (2017)
  • N. Pardi et al.

    In vitro transcription of long RNA containing modified nucleosides

    Methods Mol Biol

    (2013)
  • D. Weissman et al.

    HPLC purification of in vitro transcribed long RNA

    Methods Mol Biol

    (2013)
  • K. Kariko et al.

    Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA

    Nucleic Acids Res

    (2011)
  • U. Sahin et al.

    mRNA-based therapeutics — developing a new class of drugs

    Nat Rev Drug Discov

    (2014)
  • N. Pardi et al.

    mRNA vaccines - a new era in vaccinology

    Nat Rev Drug Discov

    (2018)
  • K.H. Asrani et al.

    Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA

    RNA Biol

    (2018)
  • P.J. Sample et al.

    Human 5’ UTR design and variant effect prediction from a massively parallel translation assay

    Nat Biotechnol

    (2019)
  • Z. Trepotec et al.

    Maximizing the translational yield of mRNA therapeutics by minimizing 5’-UTRs

    Tissue Eng Part A

    (2019)
  • A.K. Blakney et al.

    Structural components for amplification of positive and negative strand VEEV splitzicons

    Front Mol Biosci

    (2018)
  • S.C. Devarkar et al.

    Structural basis for m7G recognition and 2’-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I

    Proc Natl Acad Sci U S A

    (2016)
  • C. Schuberth-Wagner et al.

    A conserved histidine in the RNA sensor RIG-I controls immune tolerance to N1-2’O-methylated self RNA

    Immunity

    (2015)
  • O.A.W. Haabeth et al.

    mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice

    Proc Natl Acad Sci U S A

    (2018)
  • C.J. McKinlay et al.

    Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters

    Proc Natl Acad Sci U S A

    (2018)
  • Cited by (267)

    • Advances and prospects of mRNA vaccines in cancer immunotherapy

      2024, Biochimica et Biophysica Acta - Reviews on Cancer
    View all citing articles on Scopus
    View full text