Literature Information

DOI10.1016/j.jconrel.2021.03.043
PMID33798667
JournalJournal of controlled release : official journal of the Controlled Release Society
Impact Factor11.5
JCR QuartileQ1
Publication Year2021
Times Cited221
KeywordsmRNA vaccines, COVID-19, SARS-CoV-2, immunogenicity, clinical trials
Literature TypeJournal Article, Research Support, Non-U.S. Gov’t, Review
ISSN0168-3659
Pages511-520
Issue333()
AuthorsRein Verbeke, Ine Lentacker, Stefaan C De Smedt, Heleen Dewitte

TL;DR

This review examines the rapid development and authorization of mRNA vaccines, specifically BNT162b2, mRNA-1273, and CVnCoV, during the COVID-19 pandemic, highlighting the scientific breakthroughs that enabled their creation and the impact of structural design on their immunogenicity and reactogenicity. The findings underscore the potential of mRNA technology in vaccine development while identifying areas for further research to enhance future mRNA vaccines.

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mRNA vaccines · COVID-19 · SARS-CoV-2 · immunogenicity · clinical trials

Abstract

In less than one year since the outbreak of the COVID-19 pandemic, two mRNA-based vaccines, BNT162b2 and mRNA-1273, were granted the first historic authorization for emergency use, while another mRNA vaccine, CVnCoV, progressed to phase 3 clinical testing. The COVID-19 mRNA vaccines represent a new class of vaccine products, which consist of synthetic mRNA strands encoding the SARS-CoV-2 Spike glycoprotein, packaged in lipid nanoparticles to deliver mRNA to cells. This review digs deeper into the scientific breakthroughs of the last decades that laid the foundations for the rapid rise of mRNA vaccines during the COVID-19 pandemic. As well as providing momentum for mRNA vaccines, SARS-CoV-2 represents an ideal case study allowing to compare design-activity differences between the different mRNA vaccine candidates. Therefore, a detailed overview of the composition and (pre)clinical performance of the three most advanced mRNA vaccines is provided and the influence of choices in their structural design on to their immunogenicity and reactogenicity profile is discussed in depth. In addition to the new fundamental insights in the mRNA vaccines’ mode of action highlighted here, we also point out which unknowns remain that require further investigation and possibly, optimization in future mRNA vaccine development.

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Primary Questions Addressed

  1. What are the key scientific breakthroughs that enabled the rapid development of mRNA vaccines during the COVID-19 pandemic?
  2. How do the structural designs of different mRNA vaccines influence their immunogenicity and reactogenicity profiles?
  3. What are the potential implications of the findings from the COVID-19 mRNA vaccine case study for future vaccine development?
  4. What challenges remain in understanding the mode of action of mRNA vaccines, and how might these be addressed in future research?
  5. In what ways can the comparison of different mRNA vaccine candidates enhance our understanding of vaccine design and efficacy?

Key Findings

Research Topic and Scope

This review focuses on the rapid development and approval of mRNA vaccines for COVID-19, specifically the vaccines BNT162b2 (BioNTech/Pfizer), mRNA-1273 (Moderna), and CVnCoV (CureVac). It explores the scientific advancements that facilitated this new class of vaccines, their mechanisms of action, and the differences and similarities among the leading candidates.

Major Findings and Perspectives

  • mRNA Vaccine Breakthroughs: The COVID-19 pandemic catalyzed the introduction of mRNA vaccines, which represent a novel approach in vaccinology, diverging from traditional methods that utilize weakened or inactivated pathogens. This review discusses how the mRNA vaccines utilize synthetic mRNA strands encoding the SARS-CoV-2 Spike glycoprotein, delivered via lipid nanoparticles (LNPs).

  • Immunogenicity and Reactogenicity: The review highlights the structural design of the mRNA vaccines, particularly how modifications in the mRNA sequence (such as the use of N1-methyl-pseudouridine) and the design of LNPs influence their immunogenicity and reactogenicity. The review provides a comparative analysis of the three vaccines regarding their antigen targets, mRNA design, and delivery systems.

Research Progress

  • Historical Context: The review outlines the historical context of vaccine development, emphasizing the role of prior research on coronaviruses (SARS and MERS) that laid the groundwork for the rapid advancement of COVID-19 vaccines.

  • Technical Innovations: Key innovations in mRNA vaccine technology include the use of modified nucleotides to enhance stability and reduce innate immune activation, and the development of advanced lipid nanoparticles for efficient delivery of mRNA into cells.

Controversies and Gaps

  • Innate Immune Response: The review discusses ongoing debates regarding the role of innate immune responses in the effectiveness of mRNA vaccines, particularly the balance between eliciting a robust immune response and minimizing reactogenicity. It notes that while type I interferons (IFNs) can enhance immune responses, they may also limit mRNA translation and vaccine efficacy.

  • Safety and Reactogenicity: Although the review confirms the overall safety of mRNA vaccines, it acknowledges the higher incidence of systemic adverse events, such as fever, compared to traditional vaccines. The review highlights the need for further research to understand the mechanisms behind these reactions.

Future Research Directions

  • Long-Term Immunity: Future studies are encouraged to investigate the durability of immune responses elicited by mRNA vaccines, particularly the longevity of memory B and T cells.

  • Broader Applications: The review suggests that the success of mRNA vaccines against COVID-19 may accelerate the development of mRNA-based therapeutics for other infectious diseases and in oncology, highlighting the versatility of this technology.

Summary of Key Differences Among mRNA Vaccines

FeatureBNT162b2 (BioNTech/Pfizer)mRNA-1273 (Moderna)CVnCoV (CureVac)
mRNA ModificationsN1-methyl-pseudouridineN1-methyl-pseudouridineUnmodified nucleotides
Antigen TargetFull-length Spike proteinFull-length Spike proteinFull-length Spike protein
Dosage30 μg per dose100 μg per dose12 μg per dose
Delivery SystemIonizable cationic lipidsIonizable cationic lipidsIonizable cationic lipids
Approval StatusEmergency use authorizedEmergency use authorizedPhase 2b/3 initiated

Conclusion and Implications

The swift approval of mRNA vaccines for COVID-19 marks a significant milestone in vaccine development, showcasing the potential of mRNA technology. While challenges remain regarding the understanding of immune responses and the optimization of vaccine formulations, the success of these vaccines may pave the way for future innovations in mRNA-based therapeutics across various medical fields.

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Literatures Citing This Work

  1. mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. - Linde Schoenmaker;Dominik Witzigmann;Jayesh A Kulkarni;Rein Verbeke;Gideon Kersten;Wim Jiskoot;Daan J A Crommelin - International journal of pharmaceutics (2021)
  2. Lack of Informations about COVID-19 Vaccine: From Implications to Intervention for Supporting Public Health Communications in COVID-19 Pandemic. - Silva Guljaš;Zvonimir Bosnić;Tamer Salha;Monika Berecki;Zdravka Krivdić Dupan;Stjepan Rudan;Ljiljana Majnarić Trtica - International journal of environmental research and public health (2021)
  3. Intracellular Routing and Recognition of Lipid-Based mRNA Nanoparticles. - Christophe Delehedde;Luc Even;Patrick Midoux;Chantal Pichon;Federico Perche - Pharmaceutics (2021)
  4. Metal-Organic Frameworks-Based Nanomaterials for Drug Delivery. - Mohammad Reza Saeb;Navid Rabiee;Masoud Mozafari;Ebrahim Mostafavi - Materials (Basel, Switzerland) (2021)
  5. The dynamics of quantitative SARS-CoV-2 antispike IgG response to BNT162b2 vaccination. - Shun Kaneko;Masayuki Kurosaki;Toru Sugiyama;Yuka Takahashi;Yoshimi Yamaguchi;Masayuki Nagasawa;Namiki Izumi - Journal of medical virology (2021)
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… (211 more literatures)

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