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Cited by 504SARS-CoV-2 and COVID-19 ResearchRNA Interference and Gene DeliveryImmunotherapy and Immune Responses

The dawn of mRNA vaccines: the COVID-19 case

Open access
Verbeke, Rein, Lentacker, Ine, De Smedt, Stefaan C., Dewitte, Heleen·2021·Journal of Controlled Release
DOI 10.1016/j.jconrel.2021.03.043PMC PMC8008785
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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.

AI snapshot

Written from the paper’s full text.

TL;DR

This review explains how decades of mRNA, innate-immunity, and lipid-nanoparticle research enabled the rapid COVID-19 mRNA vaccines, and compares BNT162b2, mRNA-1273, and CVnCoV. It concludes that mRNA vaccines are highly efficacious and generally safe, but important unknowns remain about innate immune effects, durability, and which vaccine components drive differences in immunogenicity and reactogenicity.

Key findings

  • All three most advanced vaccines encode full-length SARS-CoV-2 Spike with K986P/V987P proline substitutions; BNT162b2 uses 30 μg mRNA two doses 21 days apart, mRNA-1273 uses 100 μg two doses 28 days apart, and CVnCoV uses 12 μg two doses 28 days apart. BNT162b2 and mRNA-1273 use N1-methylpseudouridine-modified mRNA plus dsRNA removal, whereas CVnCoV uses unmodified, sequence-engineered mRNA.
  • Efficacy was high: BNT162b2 showed up to 95% efficacy in phase 3, mRNA-1273 conferred 94.1% protection against symptomatic COVID-19, and real-world Israeli data for BNT162b2 estimated 97% effectiveness against symptomatic/severe disease and 94% against asymptomatic infection.
  • CVnCoV at 12 μg induced neutralizing antibody titers in all participants comparable to convalescent individuals, while BNT162b2 and mRNA-1273 generally surpassed convalescent titers, even in elderly trial groups. BNT162b2 elicited S-specific CD8+ T cell responses in 91.9% of participants, compared with low or undetectable levels for mRNA-1273.
  • Reactogenicity differed: fever after second mRNA-1273 dose occurred in 40% at 100 μg and 57% at 250 μg, but none at 25 μg; BNT162b2 fever after second 30 μg dose was 8% in ages 18–55 and 17% in ages 65–85; CVnCoV fever was reported by 57% after the first dose. Rare anaphylaxis after mRNA-1273 or BNT162b2 was estimated at approximately 1 in 100,000.

Methods

  • Narrative review synthesizing three decades of mRNA vaccine research, innate immune sensing of RNA, lipid nanoparticle delivery, coronavirus Spike antigen design, and (pre)clinical data for BNT162b2, mRNA-1273, and CVnCoV.
  • Compares vaccine composition in Table 1 and discusses design features, immunogenicity, reactogenicity, efficacy, and safety using published preclinical studies, phase 1/2/3 trials, real-world data, and preprints.
  • No new primary data, systematic search strategy, or meta-analysis is described.

Limitations

  • The paper states remaining unknowns: how innate immune responses to mRNA-LNPs affect translation, immunogenicity, and reactogenicity; how long immunity lasts; whether mRNA or the LNP vehicle drives the innate immune signature; and whether further optimization is possible.
  • The paper notes that direct comparisons between vaccine candidates require caution because of differences in test populations, study designs, vaccination approaches, and potential efficacy differences; it also states that no public data exist on the Acuitas LNPs used in CVnCoV and BNT162b2, and that it cannot pinpoint which components cause differential CD8+ T cell responses.
  • Evident from the text: the review relies heavily on early clinical reports, preprints, and manufacturer disclosures, and some LNP ratios and structural elements are described as not yet confirmed for the COVID-19 vaccines.

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

Integrity signals

Registry

Crossref · 10.1016/j.jconrel.2021.03.043

Cites

84 of 84 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 134 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Incorporating naturally occurring modified nucleotides into in vitro transcribed mRNA drastically reduces its innate immune activity.

    “by incorporating naturally occurring modified nucleotides into the IVT mRNA, its innate immune activity could be drastically reduced [6,7]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Andries O. Mc Cafferty S. De Smedt S.C. Weiss R. Sanders N.N. Kitada T. N-1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice J. Control. Release 217 2015 337 344 26342664 source

      Not checked in the free run.

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      Not checked in the free run.

  • Premisecitation

    Identification of Toll-like receptors by Jules Hoffman and Bruce Beutler elucidated how the mammalian immune system recognizes conserved patterns associated with pathogens or damage.

    “the identification of Toll-like receptors (TLRs) by Jules Hoffman and Bruce Beutler elucidated how the mammalian immune system could recognize highly conserved patterns associated with the presence of pathogens or damage [3]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] O’Neill L.A.J. Golenbock D. Bowie A.G. The history of toll-like receptors - redefining innate immunity Nat. Rev. Immunol. 13 2013 453 460 23681101 source

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  • Premisecitation

    Removing double-stranded RNA contaminants further ablates in vitro transcribed RNA's immunostimulatory activity.

    “Additional efforts to remove double-stranded (ds)RNA contaminants even further ablated IVT RNA's immunostimulatory activity [8,9]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Baiersdorfer M. Boros G. Muramatsu H. Mahiny A. Vlatkovic I. Sahin U. Kariko K. A facile method for the removal of dsRNA contaminant from in vitro-transcribed mRNA Mol. Ther. Nulceic Acids 15 2019 26 35 PMC6444222 30933724 source

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    • cites [9] Kariko K. Muramatsu H. Ludwig J. Weissman D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA Nucleic Acids Res. 39 2011 e142 PMC3241667 21890902 source

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  • Premisecitation

    Many modifications observed in natural mRNA are a way to avoid immune recognition, allowing the immune system to distinguish self from non-self RNA.

    “the many modifications observed in natural mRNA are in fact a way to avoid immune recognition, allowing the immune system to distinguish self from non-self RNA [5]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Kariko K. Buckstein M. Ni H.P. Weissman D. Suppression of RNA recognition by toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA Immunity 23 2005 165 175 16111635 source

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  • Premisecitation

    Precedent work by Moderna and the NIH NIAID demonstrated that membrane-bound MERS-CoV 2P S mRNA elicited more potent neutralizing antibody responses than secreted MERS-CoV 2P S or wild-type S mRNA.

    “Precedent work by Moderna and the NIH National Institute for Allergy and Infectious Diseases (NIAID) demonstrated that the membrane-bound MERS-CoV 2P S mRNA elicited more potent neutralizing antibody responses as compared to secreted MERS-CoV 2P S, or wild-type S mRNA”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Corbett K.S. Edwards D.K. Leist S.R. Abiona O.M. Boyoglu-Barnum S. Gillespie R.A. Himansu S. Schäfer A. Ziwawo C.T. DiPiazza A.T. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness Nature 586 2020 567 571 32756549 PMC7581537

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims. 38
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    Not only viral RNA, but also endogenous mRNA associated with apoptotic cells and in vitro transcribed mRNA can bind and activate TLR3, TLR7 and TLR8.

    “not only viral RNA, but also endogenous mRNA associated with apoptotic cells as well as in vitro transcribed (IVT) mRNA could bind and activate TLR3, TLR7 and TLR8 [4,5]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Kariko K. Ni H.P. Capodici J. Lamphier M. Weissman D. mRNA is an endogenous ligand for toll-like receptor 3 J. Biol. Chem. 279 2004 12542 12550 14729660 source

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    • cites [5] Kariko K. Buckstein M. Ni H.P. Weissman D. Suppression of RNA recognition by toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA Immunity 23 2005 165 175 16111635 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two mRNA-based COVID-19 vaccines, BNT162b2 and mRNA-1273, were granted the first historic authorization for emergency use, while CVnCoV progressed to phase 3 clinical testing.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] European Medicines Agency EMA Recommends First COVID-19 Vaccine for Authorisation in the EU https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu 2020

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [24] EMA Recommends COVID-19 Vaccine Moderna for Authorisation in the EU https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu 2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25] FDA Briefing Document - BNT162b2 https://www.fda.gov/media/144245/download 2020

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    COVID-19 mRNA vaccines consist of synthetic mRNA strands encoding the SARS-CoV-2 Spike glycoprotein, packaged in lipid nanoparticles to deliver mRNA to cells.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [48] Vogel A.B. Kanevsky I. Che Y. Swanson K.A. Muik A. Vormehr M. Kranz L.M. Walzer K.C. Hein S. Güler A. Immunogenic BNT162b vaccines protect rhesus macaques from SARS-CoV-2 Nature 2021 33524990 source

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    • cites [50] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans medRxiv 2020 (Preprint)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Scientific breakthroughs of the last decades laid the foundations for the rapid rise of mRNA vaccines during the COVID-19 pandemic.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Research into the use of mRNA as a source of protein has been around for three decades.

    “research into the use of mRNA as a source of protein has been around for three decades [1]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Verbeke R. Lentacker I. De Smedt S.C. Dewitte H. Three decades of messenger RNA vaccine development Nano Today 28 2019 100766 source

      Not checked in the free run.

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

    Premisecitation

    Use of mRNA as a source of antigen in vaccination approaches is by far the most popular application.

    “although it has been employed for various therapeutic targets, its use as a source of antigen in vaccination approaches is by far the most popular [2]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Pardi N. Hogan M.J. Porter F.W. Weissman D. mRNA vaccines - a new era in vaccinology Nat. Rev. Drug Discov. 17 2018 261 279 29326426 PMC5906799 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Modified and purified in vitro transcribed mRNA enables much higher protein expression and has a more favorable safety profile, drastically reducing production of pro-inflammatory type I interferons.

    “modified and purified IVT mRNA enables much higher protein expression and has a more favorable safety profile, as it drastically reduces the production of pro-inflammatory type I IFNs [6]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Andries O. Mc Cafferty S. De Smedt S.C. Weiss R. Sanders N.N. Kitada T. N-1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice J. Control. Release 217 2015 337 344 26342664 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In their final COVID-19 vaccines, both BioNTech and Moderna used highly-purified and N1-methyl-pseudouridine modified mRNA, whereas CureVac applied unmodified mRNA technology.

    “In their final COVID-19 vaccines, both BioNTech and Moderna have made use of a highly-purified and N1-methyl-pseudouridine (1mΨ) modified mRNA. In contrast, CureVac has applied its “unmodified” mRNA vaccine technology”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Thess A. Grund S. Mui B.L. Hope M.J. Baumhof P. Fotin-Mleczek M. Schlake T. Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals Mol. Ther. 23 2015 1456 1464 26050989 PMC4817881 source

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    • cites [11] Lutz J. Lazzaro S. Habbeddine M. Schmidt K.E. Baumhof P. Mui B.L. Tam Y.K. Madden T.D. Hope M.J. Heidenreich R. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines npj Vaccines 2 2017 PMC5648897 29263884 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1mΨ nucleotide modifications provide additional base pair stability, giving rise to a high degree of secondary structure that significantly improves mRNA translation.

    “1mΨ nucleotide-modifications were shown to provide additional base pair stability, giving rise to a high degree of secondary structure which significantly improves the mRNA translation [35]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Mauger D.M. Cabral B.J. Presnyak V. Su S.V. Reid D.W. Goodman B. Link K. Khatwani N. Reynders J. Moore M.J. mRNA structure regulates protein expression through changes in functional half-life Proc. Natl. Acad. Sci. U. S. A. 116 2019 24075 31712433 PMC6883848 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Isolation of neutralizing antibodies from COVID-19 patient serum confirmed strong immunogenicity of the Spike protein but showed equal immunogenicity of the receptor-binding domain and the N-terminal domain.

    “isolation of neutralizing antibodies from the serum of COVID-19 patients confirmed the strong immunogenicity of the S protein, but showed an equal immunogenicity of the RBD and the N-terminal domain (NTD)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Liu L. Wang P. Nair M.S. Yu J. Rapp M. Wang Q. Luo Y. Chan J.F.W. Sahi V. Figueroa A. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike Nature 584 2020 450 456 32698192 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When SARS-CoV-2 was identified, detailed investigations revealed large homology between the SARS-CoV-2 and SARS-CoV-1 Spike proteins, allowing vaccine developers to immediately turn to the Spike protein as vaccine target.

    “When the new SARS-CoV-2 virus was identified, detailed investigations into the structure and dynamics of the SARS-CoV-2 S protein revealed large homology to the SARS-CoV-1 S protein, which allowed the major players in vaccine development to immediately turn to the S protein as vaccine target [20,21]”
    Quote in the paperSubstantial claim0 of 2 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Spike protein mediates viral entry by binding to its cellular receptor, ACE2 for SARS-CoV-1 or DPP4/CD26 for MERS-CoV, and then undergoes structural changes resulting in fusion of viral and host cell membranes.

    “This protein mediates viral entry by first binding to its cellular receptor (i.e. angiotensin-converting enzyme 2, ACE2 for SARS-CoV-1 or dipeptidyl peptidase 4, DPP4/CD26 for MERS-CoV). Upon interaction, the S protein undergoes structural changes resulting in the fusion of viral and host cell membranes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All three mRNA vaccines target the same SARS-CoV-2 antigen and incorporate mRNA encoding the full-length, transmembrane anchored Spike protein with two proline substitutions K986P and V987P to stabilize the prefusion conformation.

    “All mRNA vaccines target the same SARS-CoV-2 antigen and incorporate mRNA encoding the full-length, transmembrane anchored S protein. The genetic sequence is slightly altered to stabilize the prefusion conformation of the glycoprotein using two proline (2P) substitutions (K986P and V987P mutations) (Fig. 2a) [21]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Wrapp D. Wang N.S. Corbett K.S. Goldsmith J.A. Hsieh C.L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science 367 2020 1260 1263 32075877 PMC7164637

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Vaccinating against the entire Spike protein, rather than only one of its structural components, is expected to result in an improved response that is less affected when the virus undergoes genetic drift.

    “This implies that vaccinating against the entire S protein, rather than only one of its structural components, is expected to result in an improved response which will be less affected when the virus undergoes genetic drift [28]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Liu L. Wang P. Nair M.S. Yu J. Rapp M. Wang Q. Luo Y. Chan J.F.W. Sahi V. Figueroa A. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike Nature 584 2020 450 456 32698192 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The promising COVID-19 vaccines rapidly received Fast Track designation by the FDA and EMA, resulting in their approval by both regulatory agencies before the end of 2020 for emergency use.

    “The promising COVID-19 vaccines rapidly received Fast Track designation by the FDA and EMA, resulting in their approval by both regulatory agencies before the end of 2020 for emergency use [[23], [24], [25], [26]]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] European Medicines Agency EMA Recommends First COVID-19 Vaccine for Authorisation in the EU https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu 2020

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [24] EMA Recommends COVID-19 Vaccine Moderna for Authorisation in the EU https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu 2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25] FDA Briefing Document - BNT162b2 https://www.fda.gov/media/144245/download 2020

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    During LNP formulation, low pH protonates the ionizable lipid's amine, enabling electrostatic complexation of positively charged lipids and negatively charged mRNA; dialysis or ultrafiltration then neutralizes pH, resulting in uncharged solid-core LNPs that densely package mRNA.

    “During the mixing step, the pH of the formulation is kept low to protonate the ionizable lipid's amine function, enabling electrostatic complexation of the now positively charged lipids and the negatively charged mRNA. A dialysis or ultrafiltration is then performed to neutralize the pH, resulting in uncharged, solid-core LNPs that densely package the mRNA [14]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

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

    Premisecitation

    Moderna claimed that with modified nucleotide and dsRNA removal, both local and systemic innate immune effects upon mRNA vaccine administration can be limited to a bare minimum in mice.

    “Moderna claimed that with such an approach, both local and systemic innate immune effects upon mRNA (vaccine) administration can be limited to a bare minimum in mice [37]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Nelson J. Sorensen E.W. Mintri S. Rabideau A.E. Zheng W. Besin G. Khatwani N. Su S.V. Miracco E.J. Issa W.J. Impact of mRNA chemistry and manufacturing process on innate immune activation Sci. Adv. 6 2020 (eaaz6893) PMC7314518 32637598 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous experience with SARS-CoV-1 showed that CD8+ and CD4+ memory T cells were detectable as late as 17 years post-infection, while neutralizing antibody titers had waned substantially by 1 year after infection.

    “previous experience with the closely related SARS-CoV-1, showed that CD8+ and CD4+ memory T cells were detectable as late as 17 years post-infection, while neutralizing antibody titers had waned substantially by 1 year after infection [69,70]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Sariol A. Perlman S. Lessons for COVID-19 immunity from other coronavirus infections Immunity 53 2020 248 263 32717182 PMC7359787 source

      Not checked in the free run.

    • cites [70] Le Bert N. Tan A.T. Kunasegaran K. Tham C.Y.L. Hafezi M. Chia A. Chng M.H.Y. Lin M. Tan N. Linster M. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls Nature 584 2020 457 462 32668444 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The CVnCoV vaccine candidate contains an unmodified mRNA, which employs sequence engineering, selected UTRs, and a stringent purification protocol to remove dsRNA fragments.

    “the CVnCoV vaccine candidate contains an “unmodified” mRNA, which employs sequence engineering (e.g., reduction in uridine content), selected UTRs, and a stringent purification protocol to remove dsRNA fragments [11]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Lutz J. Lazzaro S. Habbeddine M. Schmidt K.E. Baumhof P. Mui B.L. Tam Y.K. Madden T.D. Hope M.J. Heidenreich R. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines npj Vaccines 2 2017 PMC5648897 29263884 source

      Not checked in the free run.

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

    Interpretationnone given

    The local induction of type I IFNs and other inflammatory cytokines plays, in all likelihood, an important role in the reactogenicity of mRNA vaccines.

    “the (local) induction of type IFNs and other inflammatory cytokines plays - in all likelihood - an important role in the reactogenicity of mRNA vaccines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In COVID-19 patients, a coordinated adaptive immunity of CD4+ T cells, CD8+ T cells, and antibody responses was correlated to milder disease, whereas an uncoordinated response frequently failed to control disease.

    “In COVID-19 patients, a coordinated adaptive immunity of CD4+ T cells, CD8+ T cells, and antibody responses was correlated to milder disease, whereas an uncoordinated response frequently failed to control disease [68]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Rydyznski Moderbacher C. Ramirez S.I. Dan J.M. Grifoni A. Hastie K.M. Weiskopf D. Belanger S. Abbott R.K. Kim C. Choi J. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity Cell 183 2020 996 1012 33010815 PMC7494270 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Similar to classical vaccine approaches, COVID-19 mRNA vaccines are injected in the muscle, where they trigger localized and transient inflammation that recruits different immune cells to the injection site.

    “Similar to the more classical vaccine approaches, the COVID-19 mRNA vaccines are injected in the muscle, where they trigger localized and transient inflammation that recruits different immune cells to the injection site (Fig. 3 ) [11,41]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Lutz J. Lazzaro S. Habbeddine M. Schmidt K.E. Baumhof P. Mui B.L. Tam Y.K. Madden T.D. Hope M.J. Heidenreich R. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines npj Vaccines 2 2017 PMC5648897 29263884 source

      Not checked in the free run.

    • cites [41] Liang F. Lindgren G. Lin A. Thompson E.A. Ols S. Röhss J. John S. Hassett K. Yuzhakov O. Bahl K. Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques Mol. Ther. 25 2017 2635 2647 28958578 PMC5768558 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    According to mechanistic studies on the fate of mRNA LNPs in rhesus monkeys, primarily monocytes and dendritic cell subsets translate the mRNA, likely involving ApoE-dependent endocytosis.

    “According to mechanistic studies on the fate of mRNA LNPs in rhesus monkeys, primarily monocytes and DC subsets translate the mRNA, likely involving ApoE dependent endocytosis [41]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Liang F. Lindgren G. Lin A. Thompson E.A. Ols S. Röhss J. John S. Hassett K. Yuzhakov O. Bahl K. Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques Mol. Ther. 25 2017 2635 2647 28958578 PMC5768558 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The type I IFN activity of mRNA vaccines can prematurely stop mRNA translation, thereby reducing antigen availability and diminishing the vaccine's efficacy to obtain adaptive immune responses.

    “the type I IFN activity of mRNA vaccines can prematurely stop mRNA-translation, thereby reducing antigen availability and diminishing the vaccine's efficacy to obtain adaptive immune responses [63,64]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [63] Pepini T. Pulichino A.M. Carsillo T. Carlson A.L. Sari-Sarraf F. Ramsauer K. Debasitis J.C. Maruggi G. Otten G.R. Geall A.J. Induction of an IFN-mediated antiviral response by a self-amplifying RNA vaccine: implications for vaccine design J. Immunol. 198 2017 4012 4024 28416600 PMC5421303 source

      Not checked in the free run.

    • cites [64] Van Hoecke L. Roose K. Ballegeer M. Zhong Z. Sanders N.N. De Koker S. Saelens X. Van Lint S. The opposing effect of type I IFN on the T cell response by non-modified mRNA-lipoplex vaccines is determined by the route of administration Mol. Ther. Nucleic Acids 22 2020 373 381 33230442 PMC7533292 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The COVID-19 mRNA vaccines are primarily focused on triggering B cells to promote induction of neutralizing antibodies, but there are also good reasons to believe that CD8+ T cell and CD4+ T cell responses may contribute to protection against SARS-CoV-2.

    “The COVID-19 mRNA vaccines are primarily focused on triggering B cells to promote the induction of neutralizing antibodies, but there are also good reasons to believe that CD8+ T cell and CD4+ T cell responses may contribute to the protection against SARS-CoV-2 [66]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Karlsson A.C. Humbert M. Buggert M. The known unknowns of T cell immunity to COVID-19 Sci. Immunol. 5 2020 (eabe8063) 33208380 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because type I IFN activity can be better controlled with 1mΨ-modified mRNA, resulting in higher maximal tolerable doses, 1mΨ-modified mRNA vaccines might achieve more durable protein expression and prolonged antigen availability.

    “Since the type I IFN activity can be better controlled with 1mΨ-modified mRNA, resulting in higher maximal tolerable doses of the 1mΨ-modified mRNA vaccines, they might achieve a more durable protein expression and thus prolonged antigen availability.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    In germinal centers, B cells undergo affinity maturation and isotype switching; after clonal expansion, this gives rise to high affinity B cells and their differentiation into plasma cells and memory B cells, which determines the quality and durability of the antibody response.

    “In GCs, B cells undergo affinity maturation and isotype switching. After rounds of clonal expansion, this gives rise to high affinity B cells and their differentiation into plasma cells and memory B cells, which eventually determines the quality and durability of the antibody response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    mRNA-1273 vaccine efficacy is in line with BNT162b2, conferring 94.1% protection against symptomatic COVID-19 disease.

    “The vaccine efficacy of mRNA-1273 is in line with the outcome of BNT162b2, conferring 94.1% protection against symptomatic COVID-19 disease [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Baden L.R. El Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. Diemert D. Spector S.A. Rouphael N. Creech C.B. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine N. Engl. J. Med. 384 2021 403 416 33378609 PMC7787219 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both local and systemic AEs occurred dose-dependently, were mostly mild to moderate, and were more common after boost vaccination.

    “Both local and systemic AE occurred dose-dependently, were mostly mild to moderate and more common after boost vaccination.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Mulligan M.J. Lyke K.E. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Raabe V. Bailey R. Swanson K.A. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults Nature 586 2020 589 593 32785213 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In different prime-boost regimens of CoronaVac, no more than 37% of participants reported any localized or systemic AE after the second dose, with fever reported by a maximum of 5% of participants.

    “no more than 37% of the participants reported any (localized or systemic) AE after the second dose, with fever only reported by max. 5% of the participants (depending on the dosing and prime-boost schedule) [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Zhang Y. Zeng G. Pan H. Li C. Hu Y. Chu K. Han W. Chen Z. Tang R. Yin W. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial Lancet Infect. Dis. 21 2 2021 181 192 33217362 PMC7832443 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AEs occurred more frequently when NVX-CoV2373 was combined with the adjuvant, and slightly more AEs were reported after the boost dose.

    “AEs occurred more frequent when NVX-CoV2373 was combined with the adjuvant, and slightly more AEs were reported after the boost dose.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Keech C. Albert A. Cho I. Robertson A. Reed P. Neal S. Plested J.S. Zhu M. Cloney-Clark S. Zhou H. Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine N. Engl. J. Med. 383 2020 2320 2332 32877576 PMC7494251 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fever was reported by 57% of participants after the first dose of CVnCoV, but the incidence did not further increase after the boost vaccine.

    “fever was reported by 57% of the participants after the first dose, but the incidence of this AE did not further increase after the boost vaccine [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Kremsner P. Mann P. Bosch J. Fendel R. Gabor J.J. Kreidenweiss A. Kroidl A. Leroux-Roels I. Leroux-Roels G. Schindler C. Phase 1 assessment of the safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers medRxiv 2020 (Preprint) PMC8354521 34378087 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mRNA dose selected for phase 2b/3 clinical testing of CureVac's CVnCoV vaccine candidate was 12 μg, substantially lower than what is used in the nucleoside-modified mRNA vaccines.

    “The mRNA dose selected for phase 2b/3 clinical testing of CureVac's CVnCoV vaccine candidate was 12 μg, substantially lower than what is used in the nucleoside-modified mRNA vaccines.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Kremsner P. Mann P. Bosch J. Fendel R. Gabor J.J. Kreidenweiss A. Kroidl A. Leroux-Roels I. Leroux-Roels G. Schindler C. Phase 1 assessment of the safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers medRxiv 2020 (Preprint) PMC8354521 34378087 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    BNT162b2 was selected as lead candidate for further advancement because of its improved safety profile and its ability to induce immunity against epitopes in S1 and S2 regions of the S antigen, while BNT162b1 is restricted to epitopes inside the RBD region.

    “Because of its improved safety profile, together with the benefit of BNT162b2 to induce immunity against epitopes in S1 and S2 regions of the S antigen, while BNT162b1 is only restricted to epitopes inside the RBD region, made that BNT162b2 was selected as lead candidate for further advancement.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Walsh E.E. Frenck R.W. Falsey A.R. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Mulligan M.J. Bailey R. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates N. Engl. J. Med. 383 2020 2439 2450 33053279 PMC7583697

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Local reactogenicity was less prominent for BNT162b2, and particularly in the older cohort, fewer severe systemic AEs were reported.

    “Also local reactogenicity was less prominent for BNT162b2 and particularly in the older cohort, fewer severe systemic AEs were reported for this vaccine candidate.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Walsh E.E. Frenck R.W. Falsey A.R. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Mulligan M.J. Bailey R. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates N. Engl. J. Med. 383 2020 2439 2450 33053279 PMC7583697

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Adverse events peaked at day 2 after dosing and were resolved by day 7.

    “events also peaked at day 2 after dosing and were resolved by day 7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Mulligan M.J. Lyke K.E. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Raabe V. Bailey R. Swanson K.A. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults Nature 586 2020 589 593 32785213 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Typical other systemic AEs (fatigue, chills, myalgia, headache) occurred in more than half of dosed participants and were increasingly reported for higher dosages, particularly after the boost vaccine.

    “Typical other systemic AEs that occurred in more than half of the dosed participants were fatigue, chills, myalgia and headache, which were all increasingly reported for higher dosages, particularly after the boost vaccine [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Despite the high incidence of systemic AEs after a single dosage of CVnCoV, no major toxicities were reported and all AEs resolved within 2 days after dosing.

    “Despite the high incidence of systemic AEs after a single dosage, no major toxicities were reported and all AEs resolved within 2 days after dosing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Kremsner P. Mann P. Bosch J. Fendel R. Gabor J.J. Kreidenweiss A. Kroidl A. Leroux-Roels I. Leroux-Roels G. Schindler C. Phase 1 assessment of the safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers medRxiv 2020 (Preprint) PMC8354521 34378087 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The exceptionally rapid development and production of mRNA vaccines, as well as their high efficiency in preventing SARS-CoV-2 infection, demonstrate that mRNA-based therapeutics are ready for their place in the sun.

    “Their exceptionally rapid development and production as well as high efficiency to prevent SARS-CoV-2 infection, demonstrate that mRNA-based therapeutics are ready for their place in the sun.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The rapid pace at which COVID-19 mRNA vaccines reached market authorization was possible due to substantial pre-existing knowledge.

    “Although this rapid pace was possible due to substantial pre-existing knowledge”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Two mRNA vaccines were granted authorization for emergency use in less than one year.

  • May combine two claims.

    Interpretationreasoning

    Two mRNA vaccines were demonstrated to be generally safe and very efficacious in preventing symptomatic COVID-19 disease.

    “as they were demonstrated to be generally safe and very efficacious to prevent against symptomatic COVID-19 disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The prime ChAdOx1 nCoV-19 vaccine commonly caused fatigue and headache, but the incidence of these AEs could be significantly reduced by prophylactic paracetamol.

    “The prime vaccine commonly caused fatigue and headache, but the incidence of these AEs could be significantly reduced by prophylactic paracetamol.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Folegatti P.M. Ewer K.J. Aley P.K. Angus B. Becker S. Belij-Rammerstorfer S. Bellamy D. Bibi S. Bittaye M. Clutterbuck E.A. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial Lancet 396 2020 467 478 32702298 PMC7445431 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    All of the described vaccines are generally safe, commonly trigger local reactogenicity, and all AEs resolved within 2 days after dosing.

    “it is clear that all of the described vaccines are generally safe, commonly trigger local reactogenicity and that all AEs resolved within 2 days after dosing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the limited subset of 10 participants who received a prime-boost ChAdOx1 vaccine, fever was exclusively reported after the prime dose in 40% of subjects, but resolved after 2 days.

    “In the limited subset of 10 participants who received a prime-boost vaccine, fever was exclusively reported after the prime dose in 40% of the subjects, but once again resolved after 2 days.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Folegatti P.M. Ewer K.J. Aley P.K. Angus B. Becker S. Belij-Rammerstorfer S. Bellamy D. Bibi S. Bittaye M. Clutterbuck E.A. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial Lancet 396 2020 467 478 32702298 PMC7445431 source

      Not checked in the free run.

44 of 44

  • The paper relies on this without support.

    Two mRNA vaccines were granted authorization for emergency use in less than one year.

    “In less than one year, two mRNA vaccines were granted authorization for emergency use”

  • The paper relies on this without support.

    Neutralizing antibody levels above a certain threshold are protective against SARS-CoV-2.

    “but remained above levels that are expected to be protective”
2 of 2

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 is created via a cell-free enzymatic transcription reaction that enables rapid and scalable production.

    “mRNA is created via a cell-free enzymatic transcription reaction that enables rapid and scalable production, as illustrated by the current pandemic's rapid pursuit of RNA vaccines (Verbeke et al. 2021).”

    From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Verbeke et al. 2021

    In “COVID-19 creates momentum for mRNA vaccines” (page unavailable), the paper discusses in vitro-transcribed (IVT) mRNA, and “Conclusions and perspectives” describes exceptionally rapid development and production of COVID-19 mRNA vaccines. It does not explicitly describe a cell-free enzymatic transcription reaction; the scalable production system it identifies is microfluidic mixing to formulate mRNA-loaded nanoparticles, not transcription itself. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Tfh cells further help activate CD8+ cytotoxic T cells that may specifically recognize and eliminate virus-infected cells.

    “Tfh cells further help activate CD8+ cytotoxic T cells that may specifically recognize and eliminate virus-infected cells (Figure 1).6,55, 56, 57”

    From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [55]

  • Tfh cells recognize antigens on the APC surface and help to activate B cells, which in turn produce high-affinity virus-neutralizing antibodies.

    “Tfh cells recognize antigens on the APC surface and help to activate B cells, which in turn produce high-affinity virus-neutralizing antibodies.6,55, 56, 57”

    From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [55]

  • The COVID-19 vaccine candidates demonstrate the structurally modified mRNA approach allows for higher tolerated doses and may be more suitable for producing a fast antibody response.

    “The COVID-19 vaccine candidates demonstrate the structurally modified mRNA approach allows for higher tolerated doses and may be more suitable for producing a fast antibody response (Verbeke et al. 2021).”

    From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Verbeke et al. 2021

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.

  • Claim of EMA approval before 2021 conflicts with cited Moderna authorization date

    Minor

    The paper says the COVID-19 vaccines were approved by both the FDA and EMA before the end of 2020, but its cited EMA authorization recommendation for Moderna is dated 2021.

  • Humoral-immunity comparison reverses the stated result

    Minor

    The text says the modified mRNA vaccines generally surpassed convalescent antibody titers, whereas CVnCoV produced comparable titers. It then describes this as suggesting stronger humoral immunity from CVnCoV, reversing the comparison it just made.

2 of 2

Cites

Flagged first, then by citations

6 of the 90 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Sahin, 2020, BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans, medRxiv

Cited by

Sorted by citations

Related

Authors
Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H.
Affiliations
Ghent University (BE)
ORCID
Venue
Journal of Controlled Release
Publisher
Elsevier BV
Published
2021-05
Volume
333
Pages
511-520
ISSN
0168-3659 (ISSN-L)
DOI
10.1016/j.jconrel.2021.03.043
PMC
PMC8008785
OpenAlex
W3143214431
Semantic Scholar
625ba194b83ffb3092b932815a598844f28b3009
Cited by
504
References
90
Citations by year
2026: 72 · 2025: 72 · 2024: 88 · 2023: 118 · 2022: 94 · 2021: 60
FWCI
28.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Controlled Release (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
Funders
  • Universiteit Gent (F2020/IOF-StarTT/039, FAF-C/2018/1213)
  • Horizon 2020 European Innovation Council Fast Track to Innovation (810685)
  • Horizon 2020
  • FWO (G040319N, G016221N)
  • Kom op tegen kanker
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
mRNA vaccines, COVID-19 pandemic, SARS-CoV-2 spike protein, lipid nanoparticles, BNT162b2, mRNA-1273, vaccine design, immunogenicity, reactogenicity, emergency use authorization
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, BNT162 Vaccine, Humans, RNA, Messenger, Vaccines, Pandemics

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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