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Cited by 1,555RNA Interference and Gene DeliverySARS-CoV-2 and COVID-19 ResearchImmunotherapy and Immune Responses

mRNA vaccines for infectious diseases: principles, delivery and clinical translation

Open access
Chaudhary, Namit, Weissman, Drew, Whitehead, Kathryn A.·2021·Nature Reviews Drug Discovery
DOI 10.1038/s41573-021-00283-5PMC PMC8386155
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Abstract

Over the past several decades, messenger RNA (mRNA) vaccines have progressed from a scepticism-inducing idea to clinical reality. In 2020, the COVID-19 pandemic catalysed the most rapid vaccine development in history, with mRNA vaccines at the forefront of those efforts. Although it is now clear that mRNA vaccines can rapidly and safely protect patients from infectious disease, additional research is required to optimize mRNA design, intracellular delivery and applications beyond SARS-CoV-2 prophylaxis. In this Review, we describe the technologies that underlie mRNA vaccines, with an emphasis on lipid nanoparticles and other non-viral delivery vehicles. We also overview the pipeline of mRNA vaccines against various infectious disease pathogens and discuss key questions for the future application of this breakthrough vaccine platform. The COVID-19 pandemic has established mRNA vaccines as a rapid, effective and safe approach for the protection of individuals from infectious disease. Here, Whitehead and colleagues review the principles of mRNA vaccine design, synthesis and delivery, assessing recent progress and key issues in the development of mRNA vaccines for a range of infectious diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

This review describes the principles of mRNA vaccine design, lipid nanoparticle and other delivery systems, and clinical translation for infectious diseases, with emphasis on the rapid COVID-19 vaccine effort. It concludes that mRNA vaccines are a versatile and validated platform but still require optimization in delivery, durability, safety, variant coverage, and global access.

Key findings

  • mRNA vaccines moved from a scepticism-inducing idea to clinical reality, and COVID-19 catalysed the fastest vaccine development in history; as of 18 June 2021, 185 COVID-19 vaccine candidates were preclinical and 102 were in clinical trials, including 19 mRNA vaccines.
  • BNT162b2 showed 95% overall efficacy in phase III trials involving 43,548 participants, with 90–100% efficacy across subgroups; mRNA-1273 showed 94.1% efficacy in phase III trials involving 30,420 volunteers, and two doses of mRNA-1273 or BNT162b2 were 90% effective in real-world conditions among 3,950 healthcare personnel, first responders, and other frontline workers.
  • CureVac’s CVnCoV demonstrated only 47% efficacy in phase IIb/III trials involving 40,000 participants across ten countries; interim analysis attributed the modest efficacy to emerging SARS-CoV-2 variants, with 57% of sequenced cases caused by variants of concern.
  • Lipid nanoparticles are the most clinically advanced mRNA delivery vehicles and typically contain an ionizable lipid, cholesterol, a helper phospholipid, and a PEGylated lipid; modified nucleosides such as N1-methylpseudouridine are used in BNT162b2 and mRNA-1273 to avoid innate immune recognition and improve translation.

Methods

  • Narrative review, not a primary experimental study; it synthesizes published preclinical and clinical literature on mRNA vaccine design, delivery vehicles, and infectious disease applications.
  • Data include clinical trial tables for mRNA vaccines against infectious diseases beyond COVID-19 and against SARS-CoV-2, with a stated snapshot as of 18 June 2021.
  • Main analysis is qualitative synthesis of mRNA structure and synthesis, lipid/polymer/peptide/emulsion delivery systems, disease-specific vaccine progress, and key issues; no systematic search, meta-analysis, or primary data collection is described.

Limitations

  • The paper states that the duration of antibody response is complex, varies by antigen, and will require longer-term data for comprehensive understanding.
  • The paper states that mechanisms remain unclear for several issues, including vaccine-associated enhanced disease in RSV, the thermostability of CVnCoV and ARCoV, endosomal escape for some delivery systems, and allergic reactions potentially linked to PEGylated lipids.
  • Evident from the text: as a narrative review with a June 2021 data cutoff, it does not systematically assess study quality and its clinical landscape is rapidly evolving beyond the variants and vaccines discussed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41573-021-00283-5

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Conventional vaccines do not effectively tackle pathogens such as the malaria parasite Plasmodium falciparum, hepatitis C and human immunodeficiency virus (HIV), which evade immune surveillance.

    “Despite their evident success, however, conventional vaccines do not effectively tackle pathogens such as the malaria parasite Plasmodium falciparum, hepatitis C and human immunodeficiency virus (HIV), which evade immune surveillance2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Kennedy, R. B., Ovsyannikova, I. G., Palese, P. & Poland, G. A. Current challenges in vaccinology. Front. Immunol. 11, 1181 (2020). source

      Not checked in the free run.

  • Premisecitation

    A single mRNA vaccine can enable the targeting of multiple microbes or viral variants with a single formulation.

    “and enabling the targeting of multiple microbes or viral variants with a single formulation8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Wu, K. et al. Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice. bioRxiv https://www.biorxiv.org/content/10.1101/2021.04.13.439482v1 (2021). source

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  • Interpretationnone given

    mRNA vaccines can rapidly and safely protect patients from infectious disease.

    “Although it is now clear that mRNA vaccines can rapidly and safely protect patients from infectious disease, additional research is required to optimize mRNA design, intracellular delivery and applications beyond SARS-CoV-2 prophylaxis.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    A 5 litre bioreactor can produce almost a million mRNA vaccine doses in a single reaction.

    “For example, a 5 litre bioreactor can produce almost a million mRNA vaccine doses in a single reaction6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Kis, Z., Kontoravdi, C., Dey, A. K., Shattock, R. & Shah, N. Rapid development and deployment of high-volume vaccines for pandemic response. J. Adv. Manuf. Process. 2, e10060 (2020). source

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  • Premisenone given

    mRNA vaccines can be manufactured in a cell-free manner, allowing rapid, scalable and cost-effective production.

    “mRNA vaccines can be manufactured in a cell-free manner, allowing rapid, scalable and cost-effective production.”
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  • Classified as probably not a substantial claim. 26
  • May combine two claims. 72
  • The quote only partly states this claim. 2

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    Interpretationnone given

    In 2020, the COVID-19 pandemic catalysed the most rapid vaccine development in history, with mRNA vaccines at the forefront of those efforts.

    “In 2020, the COVID-19 pandemic catalysed the most rapid vaccine development in history, with mRNA vaccines at the forefront of those efforts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    mRNA does not integrate into the genome, obviating concerns about insertional mutagenesis.

    “Unlike some viral vaccines, mRNA does not integrate into the genome, obviating concerns about insertional mutagenesis5.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source

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  • May combine two claims.

    Premisecitation

    A single mRNA vaccine can encode multiple antigens, strengthening the immune response against resilient pathogens.

    “Moreover, a single mRNA vaccine can encode multiple antigens, strengthening the immune response against resilient pathogens7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Freyn, A. W. et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Mol. Ther. 28, 1569–1584 (2020). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Successful vaccination campaigns eradicated life-threatening diseases such as smallpox and nearly eradicated polio.

    “Successful vaccination campaigns eradicated life-threatening diseases such as smallpox and nearly eradicated polio1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Pollard, A. J. & Bijker, E. M. A guide to vaccinology: from basic principles to new developments. Nat. Rev. Immunol. 21, 83–100 (2021). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Conventional vaccines require regular modification to address rapidly mutating pathogens, such as the influenza virus.

    “Furthermore, they require regular modification to address rapidly mutating pathogens, such as the influenza virus.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Research on MERS-CoV and SARS-CoV suggested that the antigen should be the spike protein and that its amino acid sequence should be slightly modified to lock the protein in its prefusion conformation, maximizing its immunogenicity.

    “For example, research on MERS-CoV and SARS-CoV suggested that the antigen should be the spike protein and that its amino acid sequence should be slightly modified to lock the protein in its prefusion conformation, maximizing its immunogenicity127.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). This study reports the development process of mRNA-1273. source

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    Premisecitation

    Human mRNA codons rarely have A or U at the third position, and replacing A or U at the third position in the open reading frame with G or C is a patented optimization strategy.

    “For instance, the biopharmaceutical company CureVac AG discovered that human mRNA codons rarely have A or U at the third position and patented a strategy that replaces A or U at the third position in the open reading frame with G or C21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] von der Mülbe, F., Hoerr, I. & Pascolo, S. Pharmaceutical composition containing a stabilised mRNA optimised for translation in its coding regions. US 2015/0104476 A1 (2015).

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    Premisenone given

    The Moderna and Pfizer-BioNTech vaccines were approved 11 months after initiation, 8 months of which were spent in clinical trials.

    “The Moderna and Pfizer–BioNTech vaccines, in contrast, were approved 11 months after initiation, 8 months of which were spent in clinical trials.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    2′-O-methylation of the first or second nucleotide from the 5′ end prevents recognition by cytosolic sensors of viral RNA and hence prevents unintended immune responses.

    “As in mammals, the first or second nucleotide from the 5′ end is methylated on the 2′ hydroxyl of the ribose (2′-O-methylation), which prevents recognition by cytosolic sensors of viral RNA10, and hence prevents unintended immune responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C. & Thakur, A. Opportunities and challenges in the delivery of mRNA-based vaccines. Pharmaceutics 12, 102 (2020). source

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    Premisecitation

    UTR performance can vary by cell type, so alternative UTR sequences optimized for the desired application and intended cell target may be used.

    “However, because UTR performance can vary by cell type, alternative UTR sequences may be used that have been optimized for the desired application and intended cell target16–18.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Sample, P. J. et al. Human 5′ UTR design and variant effect prediction from a massively parallel translation assay. Nat. Biotechnol. 37, 803–809 (2019). This study designs novel UTR sequences and predicts ribosome loading using deep learning. source

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    • cites [17] Orlandini von Niessen, A. G. et al. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening. Mol. Ther. 27, 824–836 (2019). source

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    • cites [18] Zeng, C. et al. Leveraging mRNA sequences and nanoparticles to deliver SARS-CoV-2 antigens in vivo. Adv. Mater. 32, 2004452 (2020). source

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    During the SARS-CoV-2 pandemic, mRNA-based vaccines were shown to be highly effective against SARS-CoV-2.

    “During the SARS-CoV-2 pandemic, mRNA-based vaccines were shown to be highly effective against SARS-CoV-2 and were developed and administered at unprecedented speed to millions of people globally to combat COVID-19 (Box 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Pfizer-BioNTech and Moderna received $1.95 billion and $2.48 billion, respectively, from the US government through its Operation Warp Speed initiative.

    “A colossal investment was also required for each vaccine candidate, with Pfizer–BioNTech and Moderna receiving $1.95 billion and $2.48 billion, respectively, from the US government through its Operation Warp Speed initiative (see Related links).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The Pfizer-BioNTech and Moderna SARS-CoV-2 vaccines have validated the mRNA platform and stimulated substantial interest in the application of mRNA for both prophylactic and therapeutic indications.

    “These vaccines, initially developed by Pfizer–BioNTech and Moderna, have validated the platform and stimulated substantial interest in the application of mRNA for both prophylactic and therapeutic indications.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These studies enabled Moderna to generate the mRNA-1273 sequence in 2 days and start phase I trials in 66 days.

    “These studies enabled Moderna to generate the mRNA-1273 sequence in 2 days and start phase I trials in 66 days127.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). This study reports the development process of mRNA-1273. source

      Not checked in the free run.

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    Premisecitation

    The 5′ cap protects mRNA sterically from degradation by exonucleases and works synergistically with the poly(A) tail, poly(A) binding proteins and translation initiation factor proteins to circularize mRNA and recruit ribosomes for initiating translation.

    “Further, the 5′ cap protects the mRNA sterically from degradation by exonucleases, and it works synergistically with the poly(A) tail at the 3′ end, poly(A) binding proteins and translation initiation factor proteins to circularize mRNA and recruit ribosomes for initiating translation10,11.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C. & Thakur, A. Opportunities and challenges in the delivery of mRNA-based vaccines. Pharmaceutics 12, 102 (2020). source

      Not checked in the free run.

    • cites [11] Linares-Fernández, S., Lacroix, C., Exposito, J. Y. & Verrier, B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol. Med. 26, 311–323 (2020). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    mRNA-based SARS-CoV-2 vaccines were developed and administered at unprecedented speed to millions of people globally.

    “During the SARS-CoV-2 pandemic, mRNA-based vaccines were shown to be highly effective against SARS-CoV-2 and were developed and administered at unprecedented speed to millions of people globally to combat COVID-19 (Box 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MERS-CoV and SARS-CoV vaccines required about 2 years of development before entering phase I trials and have yet to be approved.

    “For example, MERS-CoV and SARS-CoV vaccines required about 2 years of development before entering phase I trials259 and have yet to be approved.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Kim, Y. C., Dema, B. & Reyes-Sandoval, A. COVID-19 vaccines: breaking record times to first-in-human trials. NPJ Vaccines 5, 34 (2020). source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    As of 18 June 2021, 185 COVID-19 vaccine candidates were in preclinical development and an additional 102 had entered clinical trials.

    “As of 18 June 2021, 185 COVID-19 vaccine candidates were in preclinical development and an additional 102 had entered clinical trials (see Related links).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Poly(A) tails of >100 bp are optimal for therapeutic mRNAs; however, the DNA sequences that encode these long poly(A) stretches can destabilize the DNA plasmids used for transcription.

    “Poly(A) tails of >100 bp are optimal for therapeutic mRNAs; however, the DNA sequences that encode these long poly(A) stretches can destabilize the DNA plasmids used for transcription.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Together, these innovations have overcome significant manufacturing bottlenecks and facilitated the development of a simple, cost-effective and scalable one-step mRNA synthesis process.

    “Together, these innovations have overcome significant manufacturing bottlenecks and facilitated the development of a simple, cost-effective and scalable one-step mRNA synthesis process.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Incorporating the poly(A) tail in the DNA plasmid eliminates reaction steps and reduces overall production time and material loss.

    “The poly(A) tail is encoded in the DNA template, which eliminates reaction steps and reduces overall production time and material loss29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Pardi, N., Hogan, M. J. & Weissman, D. Recent advances in mRNA vaccine technology. Curr. Opin. Immunol. 65, 14–20 (2020). source

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    Premisecitation

    mRNA-1273 has 90% efficacy in real-world conditions in the USA.

    “90% efficacy in real-world conditions in USA132”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Thompson, M. G. et al. Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers — eight U.S. locations, December 2020–March 2021. Morb. Mortal. Wkly Rep. 70, 495–500 (2021). source

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    Premisecitation

    Each pathogen poses a unique set of challenges, including high lethality, rapid mutations, immune evasion, new strains and variants.

    “Each pathogen poses a unique set of challenges, including high lethality, rapid mutations, immune evasion, new strains and variants252–258.”
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    • cites [252] Harvey, W. T. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 19, 409–424 (2021). source

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    • cites [254] Jusu, M. O. et al. Rapid establishment of a cold chain capacity of −60 °C or colder for the STRIVE Ebola vaccine trial during the Ebola outbreak in Sierra Leone. J. Infect. Dis. 217, S48–S55 (2018). source

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    • cites [255] Panchaud, A., Stojanov, M., Ammerdorffer, A., Vouga, M. & Baud, D. Emerging role of Zika virus in adverse fetal and neonatal outcomes. Clin. Microbiol. Rev. 29, 659–694 (2016). source

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    • cites [256] Cuevas, J. M., Geller, R., Garijo, R., López-Aldeguer, J. & Sanjuán, R. Extremely high mutation rate of HIV-1 in vivo. PLoS Biol. 13, e1002251 (2015). source

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    Premisecitation

    The attached SARS-CoV-2 spike protein is cut by transmembrane serine protease 2, inducing a conformational change that exposes the fusion peptide and facilitates fusion with the cell or endosomal membrane.

    “The attached spike protein is then cut open by the cell’s transmembrane serine protease 2, which induces a conformational change that exposes the spike protein’s fusion peptide and facilitates fusion with the cell or endosomal membrane118.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Shang, J. et al. Cell entry mechanisms of SARS-CoV-2. Proc. Natl Acad. Sci. USA 117, 11727–11734 (2020). This study describes the cell-entry mechanism of SARS-CoV-2. source

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    Premisenone given

    Inside the body, mRNA is engulfed by cells of the innate immune system and degraded by nucleases.

    “Moreover, inside the body, it is engulfed by cells of the innate immune system and degraded by nucleases.”
    Quote in the paperSubstantial claim

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    Premisecitation

    CVnCoV induced anti-spike IgG, anti-RBD IgG and serum-neutralization titres comparable to convalescent serum.

    “anti-spike IgG, anti-RBD IgG and serum-neutralization titres comparable to convalescent serum133”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Kremsner, P. et al. Phase 1 assessment of the safety and immunogenicity of an mRNA- lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers. medRxiv https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). source

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    Premisecitation

    In rhesus macaques, two 100 μg doses of BNT162b2 delivered 21 days apart elicited neutralizing antibody titres 10.2-18.0 times higher than convalescent patient serum and strong CD4+ and CD8+ T cell responses.

    “In preclinical studies in rhesus macaques, two 100 μg doses of BNT162b2 delivered 21 days apart elicited neutralizing antibody titres 10.2–18.0 times higher than convalescent patient serum as well as strong CD4+ and CD8+ T cell responses122.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Vogel, A. B. et al. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature 592, 283–289 (2021). source

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    Premisenone given

    TAK-919 has the same formulation as mRNA-1273.

    “same formulation as mRNA-1273”
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    Premisecitation

    Both BNT162b1 and BNT162b2 were well tolerated and efficacious, but only BNT162b2 advanced to phase II/III trials owing to its milder systemic and local adverse reactions.

    “Both candidates were well tolerated and efficacious, but only the BNT162b2 vaccine advanced to phase II/III trials owing to its milder systemic and local adverse reactions124.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Walsh, E. E. et al. Safety and immunogenicity of two RNA-based covid-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020). source

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    Premisecitation

    mRNA-1273 uses the ionizable lipid SM-102 to formulate lipid nanoparticles that encapsulate an N1-methylpseudouridine-modified mRNA encoding the SARS-CoV-2 spike protein with two proline substitutions that confer the prefusion conformation.

    “The vaccine uses the ionizable lipid SM-102 to formulate LNPs that encapsulate an N1-methylpseudouridine-modified mRNA. The sequence encodes the SARS-CoV-2 spike protein with two proline substitutions that confer the prefusion conformation127.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). This study reports the development process of mRNA-1273. source

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    Premisecitation

    In a mass vaccination campaign involving 3,159,136 participants in Israel, two doses of BNT162b2 were 94% effective at preventing symptomatic COVID-19, 87% effective at preventing hospitalizations and 92% effective at preventing the onset of severe COVID-19.

    “In a mass vaccination campaign involving 3,159,136 participants in Israel, two doses of BNT162b2 were 94% effective at preventing symptomatic COVID-19, 87% effective at preventing hospitalizations and 92% effective at preventing the onset of severe COVID-19 (ref.126).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Dagan, N. et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N. Engl. J. Med. 384, 1412–1423 (2021). source

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    Premisecitation

    Compared with serum from patients recovering from COVID-19, vaccinated macaque serum contained 15-fold higher titres of neutralizing antibodies, 348-fold more potent inhibitory activity for spike binding to angiotensin-converting enzyme 2 and 12-fold higher virus-neutralizing activity.

    “In comparison with serum from patients recovering from COVID-19, vaccinated macaque serum contained 15-fold higher titres of neutralizing antibodies, 348-fold more potent inhibitory activity for spike binding to the angiotensin-converting enzyme 2 and 12-fold higher virus-neutralizing activity128.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Corbett, K. S. et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med. 383, 1544–1555 (2020). source

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    Premisecitation

    A 50 ng dose of nucleoside-modified mRNA encoding three conserved influenza proteins (neuraminidase, nucleoprotein and matrix-2 ion channel protein) in addition to the haemagglutinin stalk generated broadly protective antibodies and protected mice from a 500× LD50 viral challenge.

    “Another study used LNPs to deliver a 50 ng dose of nucleoside-modified mRNA encoding three conserved influenza proteins: neuraminidase, nucleoprotein and matrix-2 ion channel protein (Fig. 4) in addition to the haemagglutinin stalk7. Incredibly, this minuscule mRNA dose generated broadly protective antibodies and protected mice from an extraordinarily large viral challenge (500× LD50).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Freyn, A. W. et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Mol. Ther. 28, 1569–1584 (2020). source

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    Premisecitation

    In preclinical studies, CV2CoV showed 1.8-fold higher protein expression than CVnCoV in vitro, and elicited high titres of cross-neutralizing antibodies against the B.1.1.7, B.1.1.298 and B.1.351 variants in rats.

    “In preclinical studies, CV2CoV showed 1.8-fold higher protein expression than CVnCoV in vitro, and elicited high titres of cross-neutralizing antibodies against the B.1.1.7, B.1.1.298 and B.1.351 variants in rats134.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Roth, N. et al. CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats. bioRxiv, https://www.biorxiv.org/content/10.1101/2021.05.13.443734v1.full (2021).

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    Premisecitation

    In transgenic mice expressing human angiotensin-converting enzyme 2, doses of 2 μg and 10 μg of ARCT-021 produced strong T cell responses, high IgG titres and protected mice from SARS-CoV-2 infection.

    “In transgenic mice expressing human angiotensin-converting enzyme 2, doses of 2 µg and 10 µg produced strong T cell responses, high IgG titres and protected mice from SARS-CoV-2 infection137.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] de Alwis, R. et al. A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice. Mol. Ther. 29, 1970–1983 (2021). source

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    Premisecitation

    Adverse effects of the Moderna influenza candidates were limited to pain at the injection site, redness, muscle pain, joint pain, headache, fatigue and chills/common-cold-like symptoms, indicating that the vaccine is safe and well tolerated.

    “Adverse effects were limited to pain at the injection site, redness, muscle pain, joint pain, headache, fatigue and chills/common-cold-like symptoms, indicating that the vaccine is safe and well tolerated150.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). source

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    Premisecitation

    In the first demonstration of an effective mRNA vaccine against influenza in 2012, three intradermal injections of 80 μg RNActive-mRNA encoding haemagglutinin from the PR8 H1N1 strain induced homologous and heterologous immunity against H1N1 and H5N1 strains, respectively, and protected the mice against a lethal viral dose (10× LD50).

    “In the first demonstration of an effective mRNA vaccine against influenza in 2012, three intradermal injections of 80 µg RNActive-mRNA encoding haemagglutinin from the PR8 H1N1 strain induced homologous and heterologous immunity against H1N1 and H5N1 strains, respectively, and protected the mice against a lethal viral dose (10× LD50)141.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Petsch, B. et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat. Biotechnol. 30, 1210–1216 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CVnCoV uses lipid nanoparticles formulated using an ionizable lipid from Acuitas Therapeutics (potentially ALC-0315) and an unmodified mRNA sequence encoding a full-length spike protein with the two proline substitutions.

    “CVnCoV uses LNPs formulated using an ionizable lipid from Acuitas Therapeutics (potentially ALC-0315) and an unmodified mRNA sequence encoding a full-length spike protein with the two proline substitutions133.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Kremsner, P. et al. Phase 1 assessment of the safety and immunogenicity of an mRNA- lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers. medRxiv https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In phase I clinical trials, primer and booster injections of a 12 μg dose of CVnCoV administered 28 days apart generated neutralizing antibodies similar to those in plasma from patients convalescing from COVID-19 and was well tolerated.

    “In phase I clinical trials, primer and booster injections of a 12 μg dose of CVnCoV administered 28 days apart generated neutralizing antibodies similar to those in plasma from patients who were convalescing from COVID-19 and was well tolerated133.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Kremsner, P. et al. Phase 1 assessment of the safety and immunogenicity of an mRNA- lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers. medRxiv https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Interpretationnone given

    Although the ARCT-021 dose is higher than the LNP-nCoVsaRNA dose, no booster is required, ensuring that recipients are fully vaccinated after a single injection.

    “Although the ARCT-021 dose is higher than the LNP-nCoVsaRNA dose, no booster is required, ensuring that recipients are fully vaccinated after a single injection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The broadly protective antibodies conferred homologous immunity against Cal09 H1N1, heterologous immunity against PR8 H1N1 and heterosubtypic immunity against H5N1 in mice and protected them against a lethal viral challenge.

    “The broadly protective antibodies conferred homologous immunity against Cal09 H1N1, heterologous immunity against PR8 H1N1 and heterosubtypic immunity against H5N1 in mice and protected them against a lethal viral challenge149.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Pardi, N. et al. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat. Commun. 9, 3361 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The neutralizing antibody titres generated by the mRNA vaccine were 50-100 times higher than those induced by purified inactivated virus and DNA vaccines in mice, and 50 times higher than a 1 mg DNA vaccine in macaques.

    “Of note, the neutralizing antibody titres generated by the mRNA vaccine were 50–100 times higher than those induced by purified inactivated virus and DNA vaccines in mice, and 50 times higher than a 1 mg DNA vaccine in macaques153.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Pardi, N. et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543, 248–251 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In two separate phase I trials in 2016, Moderna evaluated two influenza candidates dosed via two intramuscular injections of lipid nanoparticles encapsulating nucleoside-modified mRNA expressing full-length haemagglutinin from H10N8 and H7N9.

    “In two separate phase I trials in 2016, Moderna evaluated two influenza candidates. These vaccines were dosed via two intramuscular injections of LNPs encapsulating nucleoside-modified mRNA expressing full-length haemagglutinin from H10N8 and H7N9 (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mrna vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CureVac's candidate vaccine CVnCoV is stable for 3 months at 5 °C and 24 h at room temperature.

    “CureVac’s candidate vaccine CVnCoV is stable for 3 months at 5 °C and 24 h at room temperature (see Related links).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Related links

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several preclinical studies have delivered mRNA vaccines encoding HIV proteins using multiple delivery vehicles, but they have had varied success.

    “Several preclinical studies have delivered mRNA vaccines encoding HIV proteins using multiple delivery vehicles, including cationic nanoemulsions109,161, DOTAP/DOPE liposomes162, polymers84,163,164 and ionizable LNPs165,166, but they have had varied success.”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [109] Brito, L. A. et al. A cationic nanoemulsion for the delivery of next-generation RNA vaccines. Mol. Ther. 22, 2118–2129 (2014). source

      Not checked in the free run.

    • cites [161] Bogers, W. M. et al. Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion. J. Infect. Dis. 211, 947–955 (2015). source

      Not checked in the free run.

    • cites [162] Pollard, C. et al. Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol. Ther. 21, 251–259 (2013). source

      Not checked in the free run.

    • cites [84] Li, M. et al. Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. J. Control. Rel. 228, 9–19 (2016). source

      Not checked in the free run.

    • cites [163] Moyo, N. et al. Efficient induction of T cells against conserved HIV-1 regions by mosaic vaccines delivered as self-amplifying mRNA. Mol. Ther. Methods Clin. Dev. 12, 32–46 (2019). source

      Not checked in the free run.

    • cites [164] Zhao, M., Li, M., Zhang, Z., Gong, T. & Sun, X. Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA. Drug Deliv. 23, 2596–2607 (2016). source

      Not checked in the free run.

    • cites [165] Blakney, A. K., McKay, P. F., Yus, B. I., Aldon, Y. & Shattock, R. J. Inside out: optimization of lipid nanoparticle formulations for exterior complexation and in vivo delivery of saRNA. Gene Ther. 26, 363–372 (2019). source

      Not checked in the free run.

    • cites [166] Pardi, N. et al. Characterization of HIV-1 nucleoside-modified mRNA vaccines in rabbits and rhesus macaques. Mol. Ther. Nucleic Acids 15, 36–47 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Moderna delivered mRNA encoding the monoclonal antibody CHKV-24 4 h after chikungunya virus inoculation and protected mice from chikungunya virus-induced arthritis.

    “Using a similar approach, Moderna successfully delivered mRNA encoding the mAb CHKV-24, 4 h after chikungunya virus inoculation and protected mice from chikungunya virus-induced arthritis158.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Kose, N. et al. A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against Chikungunya infection. Sci. Immunol. 4, 6647 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The broadly neutralizing monoclonal antibodies VRC01 neutralize 98% of HIV strains and prevent transmission of antibody-sensitive strains with 75.4% efficacy.

    “Notably, the broadly neutralizing mAbs, VRC01, have recently gained attention thanks to their ability to neutralize 98% of HIV strains167 and prevent transmission of antibody-sensitive strains with 75.4% efficacy168.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167] Singh, A. Eliciting B cell immunity against infectious diseases using nanovaccines. Nat. Nanotechnol. 16, 16–24 (2021). source

      Not checked in the free run.

    • cites [168] Corey, L. et al. Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. N. Engl. J. Med. 384, 1003–1014 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interim results suggest that mRNA-1893 induces 94-100% seroconversion in 10 μg and 30 μg dose groups and is well tolerated.

    “These encouraging preclinical results prompted a phase I trial, and interim results suggest that the vaccine — mRNA-1893 (Table 1) — induces 94–100% seroconversion in 10 μg and 30 μg dose groups and is well tolerated (see Related links).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Related links

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two 10 μg doses of the lipid nanoparticle-encapsulated modified prM-E mRNA delivered 21 days apart protected mice from a Zika challenge and diminished the production of dengue-enhancing antibodies.

    “Two 10 µg doses of the LNP-encapsulated modified mRNA delivered 21 days apart protected mice from a Zika challenge and diminished the production of dengue-enhancing antibodies156.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Richner, J. M. et al. Modified mRNA vaccines protect against Zika virus infection. Cell 168, 1114–1125.e10 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although the delivery route did not affect the immune response, the delivery device did, with only the intradermal injector producing a short-lived humoral response.

    “Interestingly, although the delivery route did not affect the immune response, the delivery device did, with only the intradermal injector producing a short-lived humoral response188.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Alberer, M. et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet 390, 1511–1520 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 1968, a formalin-inactivated RSV vaccine candidate caused vaccine-associated enhanced disease in children, triggering excessive eosinophil and neutrophil infiltration in the lungs, resulting in severe bronchiolitis or pneumonia in 80% of the vaccinated children and two fatalities.

    “In 1968, for example, a formalin-inactivated RSV vaccine candidate caused vaccine-associated enhanced disease (VAED) in children. This response triggered excessive eosinophil and neutrophil infiltration in the lungs, resulting in severe bronchiolitis or pneumonia in 80% of the vaccinated children and two fatalities172.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Kim, H. W. et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J. Epidemiol. 89, 422–434 (1969). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In phase I clinical trials, mRNA-1777 elicited a robust humoral response with RSV neutralizing antibodies, a CD4+ T cell response to RSV F peptides and no serious adverse events.

    “In phase I clinical trials, mRNA-1777 elicited a robust humoral response with RSV neutralizing antibodies, a CD4+ T cell response to RSV F peptides and no serious adverse events181.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Aliprantis, A. O. et al. A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults. Hum. Vaccines Immunother. 17, 1248–1261 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 2019, the FDA approved a recombinant vesicular stomatitis virus (VSV)-based Ebola vaccine (rVSV-EBOV).

    “In 2019, the FDA approved a recombinant vesicular stomatitis virus (VSV)-based Ebola vaccine (rVSV-EBOV).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Related links

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In non-human primates, two 100 μg doses of CV7202 spaced 28 days apart were well tolerated and provoked 20-fold higher antibody titres than a commercially licensed rabies vaccine.

    “In non-human primates, two 100 µg doses spaced 28 days apart were well tolerated and provoked 20-fold higher antibody titres than a commercially licensed rabies vaccine189.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Lutz, J. et al. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. NPJ Vaccines 2, 29 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phase I results suggest that two 1 μg doses of CV7202 yield high neutralizing titres, strong adaptive immune responses, and were well tolerated.

    “Phase I results suggest that two 1 µg doses yield high neutralizing titres, strong adaptive immune responses, and were well tolerated190.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Aldrich, C. et al. Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: a phase 1 trial. Vaccine 39, 1310–1318 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The vaccine elicited glycoprotein-specific IgG antibodies and robust expression of IFNγ and IL-2 by CD8+ and CD4+ T cells, and two dosing regimens (two 4 μg doses or one 40 μg dose) protected mice from a lethal challenge.

    “The vaccine elicited glycoprotein-specific IgG antibodies and robust expression of IFNγ and IL-2 by CD8+ and CD4+ T cells, and two dosing regimens (two 4 μg doses or one 40 μg dose) protected mice from a lethal challenge184.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Chahal, J. S. et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc. Natl Acad. Sci. USA 113, E5250 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two 15 μg primer-booster doses of a squalene-based cationic nanoemulsion loaded with self-amplifying mRNA encoding PMIF improved helper T cell development and elicited anti-Plasmodium IgG antibodies and memory T cell responses.

    “Two 15 µg primer–booster doses improved helper T cell development and elicited anti-Plasmodium IgG antibodies and memory T cell responses192.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Baeza Garcia, A. et al. Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection. Nat. Commun. 9, 2714 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another study vaccinated guinea pigs with two 20 μg doses of a lipid nanoparticle-encapsulated, nucleoside-modified mRNA encoding the EBOV glycoprotein, inducing high antibody titres and protecting the animals from a lethal viral challenge.

    “Another study vaccinated guinea pigs with two 20 μg doses of a LNP-encapsulated, nucleoside-modified mRNA encoding the EBOV glycoprotein, inducing high antibody titres and protecting the animals from a lethal viral challenge185.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] Meyer, M. et al. Modified mRNA-based vaccines elicit robust immune responses and protect guinea pigs from Ebola virus disease. J. Infect. Dis. 217, 451–455 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a preclinical study, two 80 μg CV7201 vaccine doses delivered 21 days apart induced high neutralizing antibody titres and elicited antigen-specific CD4+ and CD8+ T cell responses in mice and pigs.

    “In a preclinical study, two 80 µg vaccine doses delivered 21 days apart induced high neutralizing antibody titres and elicited antigen-specific CD4+ and CD8+ T cell responses in mice and pigs187.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Schnee, M. et al. An mRNA vaccine encoding rabies virus glycoprotein induces protection against lethal infection in mice and correlates of protection in adult and newborn pigs. PLoS Negl. Trop. Dis. 10, e0004746 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In clinical trials, two doses of mRNA-1273 elicited durable antibody responses over a period of 6 months; although antibody titres declined slightly, high neutralizing ability was retained across all age groups.

    “In clinical trials, two doses of mRNA-1273 also elicited durable antibody responses over a period of 6 months. Although antibody titres declined slightly over the duration of the study, high neutralizing ability was retained across all age groups205.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Doria-Rose, N. et al. Antibody persistence through 6 months after the second dose of mRNA-1273 vaccine for covid-19. N. Engl. J. Med. 384, 2259–2261 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One study in mice showed that lipid nanoparticles encapsulating nucleoside-modified mRNA circulated for longer and induced stronger TFH cell and germinal centre B cell responses than lipid nanoparticles carrying unmodified mRNA.

    “One study in mice showed that LNPs encapsulating nucleoside-modified mRNA circulated for longer and induced stronger TFH cell and germinal centre B cell responses than LNPs carrying unmodified mRNA200.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Novel strategies against HIV and influenza involve delivering mRNA vaccines that target conserved regions such as the haemagglutinin stalk on influenza, or encoding broadly neutralizing antibodies such as VRC01 that bind to conserved regions of the CD4 binding site on the HIV gp120 protein.

    “Novel strategies against these viruses involve delivering mRNA vaccines that target conserved regions such as the haemagglutinin stalk on influenza149, or encodeing broadly neutralizing antibodies such as VRC01 that bind to conserved regions of the CD4 binding site on the HIV gp120 protein206.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [149] Pardi, N. et al. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat. Commun. 9, 3361 (2018). source

      Not checked in the free run.

    • cites [206] Li, Y. et al. Mechanism of neutralization by the broadly neutralizing HIV-1 monoclonal antibody VRC01. J. Virol. 85, 8954–8967 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The duration of antibody response is a complex phenomenon that will vary from antigen to antigen and will require longer-term data for a comprehensive understanding.

    “These results are promising; however, the duration of antibody response is a complex phenomenon that will vary from antigen to antigen and will require longer-term data for a comprehensive understanding.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Moderna is evaluating the original mRNA-1273 vaccine and updated versions mRNA-1273.351 and mRNA-1273.211 as third dose boosters.

    “At the time of this writing, Moderna is evaluating the original mRNA-1273 vaccine and updated versions of the vaccine as a third dose booster — mRNA-1273.351, which encodes the spike protein from the B.1.351 variant, and mRNA-1273.211, a multivariant vaccine that is a 1:1 mix of mRNA-1273 and mRNA-1273.351 (ref.8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Wu, K. et al. Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice. bioRxiv https://www.biorxiv.org/content/10.1101/2021.04.13.439482v1 (2021). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Three 50 μg doses of an mRNA vaccine comprising lipid nanoparticles encapsulating nucleoside-modified mRNA encoding PfGARP antigen were able to reduce parasitaemia in Aotus monkeys after a P. falciparum challenge.

    “Three 50 μg doses were able to reduce parasitaemia in Aotus monkeys after a P. falciparum challenge193.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] Raj, D. K. et al. Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria. Nature 582, 104–108 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PfGARP is expressed on the surface of infected erythrocytes and is recognized by antibodies from children who are relatively resistant to P. falciparum.

    “PfGARP is expressed on the surface of infected erythrocytes and is recognized by antibodies from children who are relatively resistant to P. falciparum193.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] Raj, D. K. et al. Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria. Nature 582, 104–108 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Anti-PEG antibodies might heighten the risk of allergic reactions in certain individuals and impede vaccine efficacy.

    “Anti-PEG antibodies have been reported in 40% of the population, which might heighten the risk of allergic reactions in certain individuals and impede vaccine efficacy218.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [218] Kozma, G. T., Shimizu, T., Ishida, T. & Szebeni, J. Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals. Adv. Drug Deliv. Rev. 154–155, 163–175 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rare in utero transmission of SARS-CoV-2 has been reported.

    “Rare in utero transmission of SARS-CoV-2 has also been reported222,223; its implications on maternal, fetal and neonatal health are under active investigation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [222] Barrero-Castillero, A. et al. COVID-19: neonatal-perinatal perspectives. J. Perinatol. 41, 940–951 (2021). source

      Not checked in the free run.

    • cites [223] Fenizia, C. et al. Analysis of SARS-CoV-2 vertical transmission during pregnancy. Nat. Commun. 11, 5128 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cytomegalovirus infection causes complications in up to 1% of pregnancies.

    “Cytomegalovirus infection, for example, causes complications in up to 1% of pregnancies and can lead to congenital disabilities and neurological impairment in infants220.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [220] Bialas, K. M., Swamy, G. K. & Permar, S. R. Perinatal cytomegalovirus and varicella zoster virus infections: epidemiology, prevention, and treatment. Clin. Perinatol. 42, 61–75 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Zika virus can infect cortical neurons and glial cells in the fetus, resulting in cell death, neuroinflammation and severe congenital malformations.

    “Zika virus can infect cortical neurons and glial cells in the fetus, resulting in cell death, neuroinflammation and severe congenital malformations221.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [221] Yockey, L. J., Lucas, C. & Iwasaki, A. Contributions of maternal and fetal antiviral immunity in congenital disease. Science 368, 608–612 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Overall, mRNA vaccines have promising safety profiles, with only mild or moderate adverse events occurring in clinical trials.

    “Overall, mRNA vaccines have promising safety profiles, with only mild or moderate adverse events occurring in clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cytomegalovirus infection can lead to congenital disabilities and neurological impairment in infants.

    “Cytomegalovirus infection, for example, causes complications in up to 1% of pregnancies and can lead to congenital disabilities and neurological impairment in infants220.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [220] Bialas, K. M., Swamy, G. K. & Permar, S. R. Perinatal cytomegalovirus and varicella zoster virus infections: epidemiology, prevention, and treatment. Clin. Perinatol. 42, 61–75 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Maternal IgG antibodies readily cross the placenta by binding to the neonatal Fc receptor, enter the fetal circulation and protect the fetus from pathogens.

    “Maternal IgG antibodies readily cross the placenta by binding to the neonatal crystallizable fragment (Fc) receptor, enter the fetal circulation and protect the fetus from pathogens224.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [224] Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715–725 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a preclinical study, CureVac's RNActive delivery platform activated TLR7 and generated durable immune responses against a lethal influenza dose in 18-month-old mice.

    “In a preclinical study, CureVac’s RNActive delivery platform activated TLR7 and generated durable immune responses against a lethal influenza dose in 18-month-old mice105.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Kallen, K. J. et al. A novel, disruptive vaccination technology: self-adjuvanted RNActive® vaccines. Hum. Vaccines Immunother. 9, 2263–2276 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mRNA-1273 and BNT162b2 did not increase the incidence of neonatal death or congenital anomalies.

    “Preliminary data suggest that mRNA-1273 and BNT162b2 elicited similar adverse events in pregnant and non-pregnant people, and the vaccines did not increase the incidence of neonatal death or congenital anomalies231.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [231] Shimabukuro, T. T. et al. Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons. N. Engl. J. Med. 384, 2273–2282 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    By 2050, the proportion of the global population over 60 years old is expected to almost double from 12% to 22%.

    “By 2050, the proportion of the global population over 60 years old is expected to almost double from 12% to 22% (see Related links).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Related links

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    70-90% of influenza-related mortalities occur in people older than 65 years.

    “70–90% of influenza-related mortalities occur in people older than 65 years232”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Crooke, S. N., Ovsyannikova, I. G., Poland, G. A. & Kennedy, R. B. Immunosenescence and human vaccine immune responses. Immun. Ageing 16, 25 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Moderna vaccine candidate mRNA-1273 showed 86.4% efficacy in volunteers ≥65 years old, compared with 95.6% efficacy in 18-65-year-old volunteers.

    “The Moderna vaccine candidate mRNA-1273 was also highly effective, and showed 86.4% efficacy in volunteers ≥65 years old, in comparison with 95.6% efficacy in 18–65-year-old volunteers131.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced Toll-like receptor expression stalls cytokine and chemokine secretion by monocytes and macrophages and limits crosstalk with the adaptive immune system.

    “Reduced Toll-like receptor expression stalls cytokine and chemokine secretion by monocytes and macrophages and limits crosstalk with the adaptive immune system234.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [234] Van Den Biggelaar, A. H. J. et al. Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study. Exp. Gerontol. 39, 1407–1414 (2004). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    COVID-19 is reported to be 62 times more fatal in patients older than 65 than in younger patients.

    “COVID-19 is reported to be 62 times more fatal in patients older than 65 than it is in younger patients233.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Yanez, N. D., Weiss, N. S., Romand, J. A. & Treggiari, M. M. COVID-19 mortality risk for older men and women. BMC Public Health 20, 1742 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Vertically transferred maternal antibodies can prevent neonatal infection but can also impede the efficacy of vaccines administered to infants later in life.

    “Although vertically transferred maternal antibodies can prevent neonatal infection, they can also impede the efficacy of vaccines that are administered to infants later in life.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Enhanced efficacy will lower the acceptance rates required for herd immunity.

    “Enhanced efficacy will lower the acceptance rates required for herd immunity, and improved safety will stem media reports of adverse events and, thus, decrease fear of vaccination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Public mistrust fuelled by misinformation and anti-vaccination movements threatens the maintenance of herd immunity and puts vulnerable populations at risk.

    “public mistrust fuelled by misinformation and anti-vaccination movements threatens the maintenance of herd immunity and puts our most vulnerable populations at risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MF59 amplifies the immunogenicity of influenza vaccines and has been approved for use in elderly adults.

    “MF59 amplifies the immunogenicity of influenza vaccines and has been approved for use in elderly adults110.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Tsai, T. F. Fluad®-MF59®-adjuvanted influenza vaccine in older adults. Infect. Chemother. 45, 159–174 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Access to vaccines is the greatest challenge in achieving widespread protection against infectious diseases, especially in low-income countries.

    “Access to vaccines is the greatest challenge in achieving widespread protection against infectious diseases, especially in low-income countries.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The first two mRNA vaccines, developed at revolutionary speed to fight SARS-CoV-2, have exceeded expectations.

    “The first two mRNA vaccines, which were developed at revolutionary speed to fight SARS-CoV-2, have exceeded expectations and offer hope that the COVID-19 pandemic will end.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Vaccines have eradicated several infectious diseases in portions of the world and saved countless lives.

    “it is undeniable that vaccines have eradicated several infectious diseases in portions of the world and saved countless lives.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Decades of progress in mRNA design and nucleic acid delivery technology, together with the discovery of novel antigen targets, have made mRNA vaccines an extraordinary tool for combating emerging pandemics and existing infectious diseases.

    “Decades of progress in mRNA design and nucleic acid delivery technology, together with the discovery of novel antigen targets have made mRNA vaccines an extraordinary tool for combating emerging pandemics and existing infectious diseases.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Improved safety will stem media reports of adverse events and thus decrease fear of vaccination.

    “Enhanced efficacy will lower the acceptance rates required for herd immunity, and improved safety will stem media reports of adverse events and, thus, decrease fear of vaccination.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Measles was eradicated from the USA in 2000 and infected more than 1,200 people in 2019 owing to poor vaccine compliance in multiple communities.

    “measles, which was eradicated from the USA in 2000, infected more than 1,200 people in 2019 owing to poor vaccine compliance in multiple communities (see Related links).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Related links

      Not checked in the free run.

90 of 90

  • The paper relies on this without support.

    mRNA vaccines encoding conformation-specific proteins, conserved regions of antigens or monoclonal antibodies can be safely delivered to healthy adults, children, elderly people and pregnant people.

    “Depending on the challenges, mRNA vaccines encoding conformation-specific proteins, conserved regions of antigens or monoclonal antibodies can be safely delivered to healthy adults, children, elderly people and pregnant people.”

  • The paper relies on this without support.

    On 11 December 2020, BNT162b2 received emergency authorization from the FDA and became the first mRNA drug approved for use in humans.

    “On 11 December 2020, the Pfizer–BioNTech vaccine BNT162b2 received emergency authorization from the FDA and became the first mRNA drug approved for use in humans.”

  • The paper relies on this without support.

    One week later, mRNA-1273 was authorized for use in the USA.

    “One week later, the Moderna vaccine mRNA-1273 was also authorized for use in the USA.”

  • The paper relies on this without support.

    BNT162b2 and mRNA-1273 were the first SARS-CoV-2 vaccines to be authorized in the USA, the UK, Canada and several other countries.

    “Ultimately, they were the first SARS-CoV-2 vaccines to be authorized in the USA, the UK, Canada and several other countries.”

  • The paper relies on this without support.

    Usually, the antigen encoded by vaccine mRNA is either the full-length spike protein or the spike protein's receptor-binding domain.

    “Usually, the antigen encoded by the vaccine mRNA is either the full-length spike protein or the spike protein’s receptor-binding domain.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • mRNA vaccines are promising alternatives to conventional vaccines because of their high potency, low manufacturing cost, and short preparation period.

    “mRNA vaccines are promising alternatives to conventional vaccines because of their high potency, low manufacturing cost, and short preparation period (Bok et al., 2021; Chaudhary et al., 2021).”

    From A novel Toxoplasma gondii TGGT1_316290 mRNA-LNP vaccine elicits protective immune response against toxoplasmosis in mice (2023) · cites this paper as Chaudhary et al., 2021

  • ChulaCov19 is a wild-type non-stabilized spike-protein-encoded mRNA vaccine encapsulated with a different LNP that is thermostable at 2-8 °C for at least 3 months.

    “Unlike currently approved mRNA vaccines, such as Pfizer/BNT and Moderna 4 , ChulaCov19 is a wild-type non-stabilized spike-protein-encoded mRNA vaccine encapsulated with a different LNP that is thermostable at 2-8 °C for at least 3 months.”

    From Safety and immunogenicity of a prefusion non-stabilized spike protein mRNA COVID-19 vaccine: a phase I trial (2022) · cites this paper as [4]

  • Many nucleoside-modified mRNA COVID-19 vaccines, including BNT162b2, BNT162b1, BNT162b3, mRNA-1273, TAK919, mRNA-1273.211, mRNA-1273.351, mRNA-1283, ChulaCov19, and PTX-COVID19-B, have been approved for commercialization or entered clinical trials.

    “Many nucleoside-modified mRNA COVID-19 vaccines, including BNT162b2, BNT162b1, and BNT162b3 developed by BioNTech27,177; mRNA-1273, TAK919, mRNA-1273.211, mRNA-1273.351, mRNA-1283 developed by Moderna28,178; ChulaCov19 developed by Chulalongkorn University; and PTX-COVID19-B developed by Providence Therapeutics, have been approved for commercialization or entered clinical trials.104”

    From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [104]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • BNT162b1 is both excluded from and listed in phase II/III trials

    Minor

    The text says only BNT162b2 advanced to phase II/III trials, but Table 2 lists BNT162b1 in a phase II/III trial.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Roth, N. et al. CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats. bioRxiv, https://www.biorxiv.org/content/10.1101/2021.05.13.443734v1.full (2021). · DOI

Cited by

Sorted by citations

Related

Authors
Chaudhary, N., Weissman, D., & Whitehead, K. A.
Affiliations
  • Carnegie Mellon University (US)
  • University of Pennsylvania (US)
Corresponding author
Whitehead, Kathryn A.
ORCID
Venue
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Published
2021-08-25
Volume
20
Issue
11
Pages
817-838
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
DOI
10.1038/s41573-021-00283-5
PMC
PMC8386155
OpenAlex
W3193427089
Semantic Scholar
359f6d39ae42aac7ba1a1647d4ff9e1e4ee1bf85
Cited by
1,555
References
267
Citations by year
2026: 284 · 2025: 405 · 2024: 320 · 2023: 299 · 2022: 219 · 2021: 27
FWCI
22.68
Type
journal article
Language
en
Update notices
correction (2021-09-21)
Open access
Licence
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP2HD098860)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
mRNA vaccines, lipid nanoparticles, mRNA vaccine design, mRNA synthesis, COVID-19 vaccines, infectious disease vaccines, vaccine development pipeline, clinical translation
MeSH terms
Drug Development, COVID-19, SARS-CoV-2, mRNA Vaccines, Clinical Trials as Topic, Communicable Disease Control, Humans, RNA, Messenger, Vaccines, Synthetic, Drug Design

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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