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Cited by 308SARS-CoV-2 and COVID-19 ResearchRNA Interference and Gene DeliveryImmunotherapy and Immune Responses

COVID-19 mRNA vaccines: Platforms and current developments

Open access
Szabó, Gábor Tamás, Mahiny, Azita Josefine, Vlatkovic, Irena·2022·Molecular Therapy
DOI 10.1016/j.ymthe.2022.02.016PMC PMC8856755
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Abstract

Since the first successful application of messenger ribonucleic acid (mRNA) as a vaccine agent in a preclinical study nearly 30 years ago, numerous advances have been made in the field of mRNA therapeutic technologies. This research uncovered the unique favorable characteristics of mRNA vaccines, including their ability to give rise to non-toxic, potent immune responses and the potential to design and upscale them rapidly, making them excellent vaccine candidates during the coronavirus disease 2019 (COVID-19) pandemic. Indeed, the first two vaccines against COVID-19 to receive accelerated regulatory authorization were nucleoside-modified mRNA vaccines, which showed more than 90% protective efficacy against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alongside tolerable safety profiles in the pivotal phase III clinical trials. Real-world evidence following the deployment of global vaccination campaigns utilizing mRNA vaccines has bolstered clinical trial evidence and further illustrated that this technology can be used safely and effectively to combat COVID-19. This unprecedented success also emphasized the broader potential of this new drug class, not only for other infectious diseases, but also for other indications, such as cancer and inherited diseases. This review presents a brief history and the current status of development of four mRNA vaccine platforms, nucleoside-modified and unmodified mRNA, circular RNA, and self-amplifying RNA, as well as an overview of the recent progress and status of COVID-19 mRNA vaccines. We also discuss the current and anticipated challenges of these technologies, which may be important for future research endeavors and clinical applications.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes the history, mechanisms, and clinical status of four COVID-19 mRNA vaccine platforms—nucleoside-modified, unmodified, circRNA, and self-amplifying RNA—as of January 31, 2022. Nucleoside-modified LNP-mRNA vaccines were the first authorized and showed >90% efficacy in pivotal trials, while unmodified and saRNA candidates had not reached approval and circRNA remained preclinical.

Key findings

  • As of January 14, 2022, the WHO vaccine tracker listed 333 vaccine candidates in development, 139 in clinical phase; 23 (17%) were mRNA-based. The first two vaccines to receive CMA/EUA were nucleoside-modified mRNA vaccines from BioNTech/Pfizer and Moderna, showing >90% protective efficacy against symptomatic SARS-CoV-2 in phase III trials.
  • BNT162b2 showed 95% protection against symptomatic COVID-19 in participants ≥16 years, 100% efficacy in 12- to 15-year-olds, and 90.7% efficacy in 5- to 11-year-olds at a 10 μg dose. mRNA-1273 showed 94.1% efficacy in ≥18 years and 95% efficacy in 12- to 17-year-olds. Booster doses increased neutralizing antibody titers against variants including omicron (B.1.1.529).
  • Four mRNA platforms are reviewed: nucleoside-modified and unmodified mRNA, circRNA, and saRNA. Nucleoside-modified LNP-mRNA was the most successful; unmodified CVnCoV showed only 48% efficacy and was withdrawn from regulatory approval; saRNA candidates were in clinical trials with lower doses but higher reactogenicity; one circRNA candidate remained preclinical as of January 31, 2022.
  • The LNP component has adjuvant activity dependent on its ionizable lipid and IL-6 induction, enhancing T follicular helper cell and humoral responses. Modified nucleosides improve mRNA stability and translational capacity while decreasing innate immune activation.

Methods

  • Narrative review summarizing preclinical and clinical data for COVID-19 vaccine candidates across four mRNA vaccine platforms, plus history, mechanism of immunization, manufacturing, and challenges.
  • Data sources: PubMed, medRxiv and bioRxiv preprints, company and health agency announcements/press releases, ClinicalTrials.gov, and the Chinese Clinical Trial Registry; references published as of January 31, 2022.
  • Main analysis: qualitative synthesis with tables of clinical trials, doses, regimens, antigen coding sequences, formulations, clinical outcomes, and regulatory dates; no systematic search or meta-analysis is described.

Limitations

  • Stated: details of existing mRNA vaccines and their manufacturing processes are proprietary and not disclosed, so they “can only be speculated”; many clinical outcomes in the tables are listed as “not published.”
  • Stated: murine models may poorly predict clinical outcomes of mRNA-LNP systemic inflammation because humans secrete pro-inflammatory IL-1β whereas mice upregulate the IL-1 receptor antagonist; lipid components themselves may activate differing immune responses depending on type and formulation.
  • Evident: data cutoff of January 31, 2022, in a fast-moving field; reliance on preprints, press releases, and company communications may introduce bias; no systematic review or meta-analysis was performed.

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Crossref · 10.1016/j.ymthe.2022.02.016

Cites

Statistics

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Claims the paper makes

0 of 186 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    No saRNA COVID-19 vaccine candidate has been developed using the previously successfully applied size reduction method.

    “However, there is no saRNA COVID-19 vaccine candidate that was developed using the previously successfully applied size reduction method.157,158”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [157] Blakney A.K. McKay P.F. Shattock R.J. Structural components for amplification of positive and negative strand VEEV splitzicons Front. Mol. Biosci. 5 2018 71 10.3389/fmolb.2018.00071 30094239 PMC6070733 source

      Not checked in the free run.

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      Not checked in the free run.

  • Premisecitation

    Of COVID-19 vaccines that entered clinical trials as of this writing, 23 (17%) are mRNA-based candidates.

    “Of the COVID-19 vaccines that have entered clinical trials as of this writing, 23 (17%) are mRNA-based candidates.2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] WHO Vaccine tracker: vaccines as of 14th January https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

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

  • Premisecitation

    First published in 1984, in vitro mRNA transcription (IVT) made transcription of a selected functional mRNA from a template in the desired quantity possible.

    “First published in 1984, IVT made the transcription of a selected functional mRNA from a template in the desired quantity possible.20,21”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Melton D.A. Krieg P.A. Rebagliati M.R. Maniatis T. Zinn K. Green M.R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter Nucleic Acids Res. 12 1984 7035 7056 10.1093/nar/12.18.7035 6091052 PMC320141 source

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      Not checked in the free run.

  • Premisecitation

    Development of protective lipid-based formulations made subsequent mRNA research pursuits less complex.

    “However, the development of protective lipid-based formulations, which were first successfully used in 1978 in a study where rabbit reticulocyte 9S mRNA was introduced into mouse lymphocytes, resulting in globin synthesis,17 made subsequent mRNA research pursuits less complex.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Dimitriadis G.J. Translation of rabbit globin mRNA introduced by liposomes into mouse lymphocytes Nature 274 1978 923 924 10.1038/274923a0 683336 source

      Not checked in the free run.

  • Premisecitation

    It was not until 1993 that mRNA was used as a vaccine for the first time to elicit a specific immune response against the encoded pathogenic antigen in a preclinical setting using lipid-based delivery.

    “It was not until 1993 that mRNA was used as a vaccine for the first time to elicit a specific immune response against the encoded pathogenic antigen in a preclinical setting using lipid-based delivery.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Martinon F. Krishnan S. Lenzen G. Magné R. Gomard E. Guillet J.G. Lévy J.P. Meulien P. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA Eur. J. Immunol. 23 1993 1719 1722 10.1002/eji.1830230749 8325342 source

      Not checked in the free run.

  • May combine two claims. 62
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingnone given

    Currently there are no marketed unmodified mRNA vaccines, but candidates are being investigated in clinical trials.

    “Currently, there are no marketed unmodified mRNA vaccines, but candidates are being investigated in clinical trials (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    There is only one circRNA COVID-19 vaccine candidate under development, produced using a group I ribozyme autocatalysis strategy, and as of January 31, 2022, it has not yet entered clinical trials.

    “Despite these potential benefits, there is only one circRNA COVID-19 vaccine candidate under development, which is produced using a group I ribozyme autocatalysis strategy49 but, as of January 31, 2022, has not yet entered clinical trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Wesselhoeft R.A. Kowalski P.S. Anderson D.G. Engineering circular RNA for potent and stable translation in eukaryotic cells Nat. Commun. 9 2018 2629 10.1038/s41467-018-05096-6 29980667 PMC6035260 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Real-world evidence following global mRNA vaccination campaigns has bolstered clinical trial evidence and illustrated that mRNA technology can be used safely and effectively to combat COVID-19.

    “Real-world evidence following the deployment of global vaccination campaigns utilizing mRNA vaccines has bolstered clinical trial evidence and further illustrated that this technology can be used safely and effectively to combat COVID-19.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ionizable lipid-containing LNPs are known to have significantly higher delivery efficiency in hepatocytes after intravenous injection or in muscle cells after intramuscular injection.

    “which are known to have significantly higher delivery efficiency in hepatocytes after intravenous (i.v.) injection31 or in muscle cells after intramuscular (i.m.) injection.32”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Akinc A. Maier M.A. Manoharan M. Fitzgerald K. Jayaraman M. Barros S. Ansell S. Du X. Hope M.J. Madden T.D. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs Nat. Nanotechnol. 14 2019 1084 1087 10.1038/s41565-019-0591-y 31802031 source

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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared with traditional vaccines, mRNA-based vaccines have features that allow them to be rapidly designed and upscaled while still being highly potent and low cost.

    “Compared with traditional vaccines, which are relatively slow and laborious to develop,1,11,12 mRNA-based vaccines have features that allow them to be rapidly designed and upscaled while still being highly potent and low cost.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Pardi N. Hogan M.J. Weissman D. Recent advances in mRNA vaccine technology Curr. Opin. Immunol. 65 2020 14 20 10.1016/j.coi.2020.01.008 32244193 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mRNA technologies came to the forefront of the COVID-19 vaccine race mainly because the technology requires a sequenced viral genome rather than live virus and takes merely a couple of days to design.

    “Rapid development and highly efficient immune responses brought messenger ribonucleic acid (mRNA) technologies to the forefront of the COVID-19 vaccine race, mainly due to the fact that the technology requires a sequenced viral genome rather than live virus and takes merely a couple of days to design.3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] 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 10.1038/s41586-020-2622-0 32756549 PMC7581537

      Not checked in the free run.

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

    Premisecitation

    circRNA was first identified in 1976 and later detected in human cells.

    “circRNA was first identified in 197646 and was later detected in human cells.47”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Sanger H.L. Klotz G. Riesner D. Gross H.J. Kleinschmidt A.K. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures Proc. Natl. Acad. Sci. U S A 73 1976 3852 3856 10.1073/pnas.73.11.3852 1069269 PMC431239 source

      Not checked in the free run.

    • cites [47] Hsu M.T. Coca-Prados M. Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells Nature 280 1979 339 340 10.1038/280339a0 460409 source

      Not checked in the free run.

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

    Interpretationnone given

    Without extensive research and technological advances over the past three decades, the achievement of COVID-19 mRNA vaccine development and approval would not have been possible.

    “Without the extensive research and technological advances over the past three decades, this achievement would not have been possible.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In 1978, protein expression was induced in human cells after liposomal mRNA transport.

    “In the same year, protein expression was also induced in human cells after liposomal mRNA transport.18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Ostro M.J. Giacomoni D. Lavelle D. Paxton W. Dray S. Evidence for translation of rabbit globin mRNA after liposome-mediated insertion into a human cell line Nature 274 1978 921 923 10.1038/274921a0 683335 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The first two COVID-19 vaccines to receive accelerated regulatory authorization were nucleoside-modified mRNA vaccines, and they showed more than 90% protective efficacy against symptomatic SARS-CoV-2 infection with tolerable safety profiles in pivotal phase III trials.

    “the first two vaccines to receive conditional marketing authorization (CMA) from the European Medicines Agency or emergency use authorization (EUA) from the US Food and Drug Administration (FDA) were nucleoside-modified mRNA vaccines from BioNTech/Pfizer and Moderna, respectively, and showed over 90% protective efficacy against symptomatic SARS-CoV-2 infection in their phase III clinical trials,8,”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. Perez J.L. Pérez Marc G. Moreira E.D. Zerbini C. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine N. Engl. J. Med. 383 2020 2603 2615 10.1056/NEJMoa2034577 33301246 PMC7745181 source

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    • cites [10] WHO WHO target product profiles for COVID-19 vaccines Updated April 9, 2020 https://www.who.int/publications/m/item/who-target-product-profiles-for-covid-19-vaccines

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

  • May combine two claims.

    Premisecitation

    Uridine-containing mRNA stimulates the innate immune response and has an established adjuvant function when used as a vaccine.

    “Uridine-containing mRNA stimulates the innate immune response and has an established adjuvant function when used as a vaccine.34,35”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In combination with LNPs, modified mRNA is now the basis for the separate mRNA vaccine platform that has been proven most successful based on an optimal immune response originating from the compromise between LNP adjuvant function and modified mRNA, allowing improved efficacy and safety.

    “In combination with LNPs, modified mRNA is now the basis for the separate mRNA vaccine platform41,44 that has been proven as the most successful based on its optimal immune response originating from the compromise between LNP adjuvant function33 and modified mRNA, allowing improved efficacy and safety.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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      Not checked in the free run.

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

    Premisecitation

    As of January 14, 2022, there were 333 vaccine candidates in development, of which 139 had entered the clinical phase according to the World Health Organization's vaccine tracker.

    “As of January 14, 2022, there were 333 vaccine candidates in development, of which 139 have entered the clinical phase according to the World Health Organization's vaccine tracker.2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] WHO Vaccine tracker: vaccines as of 14th January https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

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

  • May combine two claims.

    Premisecitation

    LNPs possess a potent adjuvant function, demonstrating beneficial effects in vaccine application.

    “Moreover, it was recently found that LNPs possess a potent adjuvant function, which further demonstrates their beneficial effects in vaccine application.33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Alameh M.-G. Tombácz I. Bettini E. Lederer K. Sittplangkoon C. Wilmore J.R. Gaudette B.T. Soliman O.Y. Pine M. Hicks P. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses Immunity 2021 10.1016/j.immuni.2021.11.001 PMC8566475 34852217 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Incorporation of modified nucleosides into mRNA can significantly improve biological stability and translational capacity while decreasing the innate immune response.

    “However, the incorporation of modified nucleosides into mRNA can significantly improve the biological stability and translational capacity of the mRNA while decreasing the innate immune response.36, 37, 38”
    Quote in the paperSubstantial claim0 of 3 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study comparing LNPs and lipoplexes, differences were found in cytokine induction, indicating that the ionizable lipid of the LNP formulation is likely responsible.

    “In an elegant study comparing LNPs and lipoplexes, differences were found in cytokine induction, which indicate that the ionizable lipid of the LNP formulation is likely responsible.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Humans secrete pro-inflammatory IL-1β, whereas mice upregulate induction of the IL-1 receptor antagonist to control inflammation.

    “It has been reported that humans secrete pro-inflammatory interleukin (IL)-1β, whereas mice upregulate the induction of the IL-1 receptor antagonist to control inflammation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Mellman I. Tahtinen S. Tong A.-J. Himmels P. Oh J. Paler-Martinez A. Kim L. Wichner S. Oei Y. McCarron M. IL-1β and IL-1ra are key regulators of the inflammatory response to RNA vaccines 2021 10.21203/rs.3.rs-378991/v1 35332327

      Not checked in the free run.

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

    Premisecitation

    Later, transfection efficacy was further enhanced with incorporation of a synthetic cationic lipid into liposomes for mRNA delivery.

    “Later, the efficacy of transfection was further enhanced with the incorporation of a synthetic cationic lipid into liposomes for mRNA delivery.19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upscaling of cell-free vaccine production is relatively straightforward, providing a cutting-edge tool for rapid response in epidemics and pandemics.

    “Furthermore, the upscaling of cell-free vaccine production is relatively straightforward, thereby providing a cutting-edge tool for rapid response in epidemics and pandemics.4, 5, 6, 7”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Alameh M.-G. Weissman D. Pardi N. Messenger RNA-based vaccines against infectious diseases Curr. Top. Microbiol. Immunol. 2020 10.1007/82_2020_202 32300916 source

      Not checked in the free run.

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      Not checked in the free run.

    • cites [6] Pardi N. Hogan M.J. Weissman D. Recent advances in mRNA vaccine technology Curr. Opin. Immunol. 65 2020 14 20 10.1016/j.coi.2020.01.008 32244193 source

      Not checked in the free run.

    • cites [7] Pardi N. Weissman D. Nucleoside modified mRNA vaccines for infectious diseases Methods Mol. Biol. 1499 2017 109 121 10.1007/978-1-4939-6481-9_6 27987145 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    mRNA vaccines have favorable characteristics including the ability to give rise to non-toxic, potent immune responses and the potential to be designed and upscaled rapidly, making them excellent vaccine candidates during the COVID-19 pandemic.

    “This research uncovered the unique favorable characteristics of mRNA vaccines, including their ability to give rise to non-toxic, potent immune responses and the potential to design and upscale them rapidly, making them excellent vaccine candidates during the coronavirus disease 2019 (COVID-19) pandemic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Lipid components themselves may activate immune responses that may differ depending on the type of component and formulation.

    “Another challenge in this area is the fact that the lipid components themselves may activate immune responses that may differ depending on the type of component and formulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both the full-length S protein and the RBD itself are immunogenic and induce a strong protective neutralizing antibody response after recognition by the immune system.

    “Both the full-length S protein and the RBD itself are immunogenic and induce a strong protective neutralizing antibody response after recognition by the immune system.62,63”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Amanat F. Stadlbauer D. Strohmeier S. Nguyen T.H.O. Chromikova V. McMahon M. Jiang K. Arunkumar G.A. Jurczyszak D. Polanco J. A serological assay to detect SARS-CoV-2 seroconversion in humans Nat. Med. 26 2020 1033 1036 10.1128/mBio.02281-16 32398876 PMC8183627 source

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    • cites [63] Kirchdoerfer R.N. Cottrell C.A. Wang N. Pallesen J. Yassine H.M. Turner H.L. Corbett K.S. Graham B.S. McLellan J.S. Ward A.B. Pre-fusion structure of a human coronavirus spike protein Nature 531 2016 118 121 10.1038/nature17200 26935699 PMC4860016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    saRNA can lead to high antigen production at a low dose along with intracellular RNA replication of the antigen of interest.

    “Along with the intracellular RNA replication of the antigen of interest, saRNA can lead to high antigen production at a low dose.52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Fleeton M.N. Chen M. Berglund P. Rhodes G. Parker S.E. Murphy M. Atkins G.J. Liljeström P. Self-replicative RNA vaccines elicit protection against influenza A virus, respiratory syncytial virus, and a tickborne encephalitis virus J. Infect. Dis. 183 2001 1395 1398 10.1086/319857 11294672 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nucleoside-modified LNP-mRNA vaccines were the first to enter clinical trials and receive EUAs, CMAs, and later full regulatory approvals.

    “Numerous vaccine candidates were being investigated in the early stages of the COVID-19 pandemic, including nucleoside-modified LNP-mRNA vaccines, which were the first to enter clinical trials74 and receive EUAs, CMAs, and later full regulatory approvals.75, 76, 77, 78, 79”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [74] Moderna Moderna announces first participant dosed in NIH-led phase 1 study of mRNA vaccine (mRNA-1273) against novel coronavirus: announcment of mRNA 1273 in phase 1 Updated March 16, 2020 https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participant-dosed-nih-led-phase-1-study

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

    • cites [75] EMA An overview of Comirnaty and why it is authorised in the EU Updated November 2021 https://www.ema.europa.eu/en/documents/overview/comirnaty-epar-medicine-overview_en.pdf

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

    • cites [76] EMA An overview of Spikevax and why it is authorised in the EU Updated December 2021 https://www.ema.europa.eu/en/documents/overview/spikevax-previously-covid-19-vaccine-moderna-epar-medicine-overview_en.pdf

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

    • cites [77] FDA BNT162b2 EUA review document https://www.fda.gov/media/144416/download

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

    • cites [78] FDA BNT162b2 FDA BLA document https://www.fda.gov/media/151710/download

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

    • cites [79] FDA Moderna COVID19 mRNA vaccine EUA review https://www.fda.gov/media/144673/download

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

  • May combine two claims.

    Premiseown data

    At present, there are eight nucleoside-modified LNP-mRNA vaccine candidates in clinical trials, all sharing the key feature of enabling replacement of all uridines in the mRNA with 1-methylpseudouridine (m1Ψ).

    “At present, there are a total of eight nucleoside-modified LNP-mRNA vaccine candidates in clinical trials, all of which share the key feature of enabling the replacement of all uridines in the mRNA with 1-methylpseudouridine (m1Ψ) (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immune responses are improved by introducing two consecutive proline residues (2P), which are known to retain the full-length S protein in the prefusion conformation.

    “Immune responses are improved by introducing two consecutive proline residues (2P), which are known to retain the full-length S protein in the prefusion conformation.64,65”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Pallesen J. Wang N. Corbett K.S. Wrapp D. Kirchdoerfer R.N. Turner H.L. Cottrell C.A. Becker M.M. Wang L. Shi W. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen Proc. Natl. Acad. Sci. U S A 114 2017 E7348 E7357 10.1073/pnas.1707304114 28807998 PMC5584442 source

      Not checked in the free run.

    • cites [65] Wrapp D. Wang N. 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 10.1126/science.abb2507 32075877 PMC7164637 source

      Not checked in the free run.

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

    Premisecitation

    Although circRNA was initially thought not to serve as a translational template, later reports contradicted this hypothesis.

    “Although it was initially thought not to serve as a translational template, later reports contradicted this hypothesis, triggering further research.48”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Chen C.Y. Sarnow P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs Science 268 1995 415 417 10.1126/science.7536344 7536344 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mRNA-1273 showed 94.1% efficacy at preventing COVID-19 illness, including severe disease, in participants 18 years or older and 95% efficacy in 12- to 17-year-olds.

    “94.1% efficacy at preventing COVID-19 illness, including severe disease in participants 18 years or older995% efficacy in 12- to 17-year olds84”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Ali K. Berman G. Zhou H. Deng W. Faughnan V. Coronado-Voges M. Ding B. Dooley J. Girard B. Hillebrand W. Evaluation of mRNA-1273 SARS-CoV-2 vaccine in adolescents N. Engl. J. Med. 385 2021 2241 2251 10.1056/NEJMoa2109522 34379915 PMC8385554 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    LNP-driven adjuvant activity leads to induction of strong Tfh cell responses and humoral immunity, thus enhancing the efficacy of mRNA-based vaccines.

    “This LNP-driven adjuvant activity leads to induction of strong Tfh cell responses and humoral immunity, thus enhancing the efficacy of mRNA-based vaccines.33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Alameh M.-G. Tombácz I. Bettini E. Lederer K. Sittplangkoon C. Wilmore J.R. Gaudette B.T. Soliman O.Y. Pine M. Hicks P. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses Immunity 2021 10.1016/j.immuni.2021.11.001 PMC8566475 34852217 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    circRNA has enhanced biostability compared with linear RNA due to the lack of terminals preventing degradation, and could be a promising research avenue.

    “Given its enhanced biostability compared with linear RNA due to the lack of terminals preventing degradation,49 circRNA could be a promising research avenue.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Wesselhoeft R.A. Kowalski P.S. Anderson D.G. Engineering circular RNA for potent and stable translation in eukaryotic cells Nat. Commun. 9 2018 2629 10.1038/s41467-018-05096-6 29980667 PMC6035260 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BNT162b2 showed 95% protection against symptomatic COVID-19 in participants 16 years or older and 100% efficacy in participants 12 to 15 years of age.

    “95% protection against symptomatic COVID-19 in participants 16 years or older8 and 100% efficacy in participants 12 to 15 years of age80”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. Perez J.L. Pérez Marc G. Moreira E.D. Zerbini C. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine N. Engl. J. Med. 383 2020 2603 2615 10.1056/NEJMoa2034577 33301246 PMC7745181 source

      Not checked in the free run.

    • cites [80] Frenck R.W. Klein N.P. Kitchin N. Gurtman A. Absalon J. Lockhart S. Perez J.L. Walter E.B. Senders S. Bailey R. Safety, immunogenicity, and efficacy of the BNT162b2 covid-19 vaccine in adolescents N. Engl. J. Med. 385 2021 239 250 10.1056/NEJMoa2107456 34043894 PMC8174030 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [6] Pardi N. Hogan M.J. Weissman D. Recent advances in mRNA vaccine technology Curr. Opin. Immunol. 65 2020 14 20 10.1016/j.coi.2020.01.008 32244193 source

      Not checked in the free run.

    • cites [55] Verbeke R. Lentacker I. Smedt S.C.D. Dewitte H. The dawn of mRNA vaccines: the COVID-19 case J. Control Release 333 2021 511 520 10.1016/j.jconrel.2021.03.043 33798667 PMC8008785 source

      Not checked in the free run.

    • cites [56] Kim J. Eygeris Y. Gupta M. Sahay G. Self-assembled mRNA vaccines Adv. Drug Deliv. Rev. 170 2021 83 112 10.1016/j.addr.2020.12.014 33400957 PMC7837307 source

      Not checked in the free run.

    • cites [57] Sahin U. Karikó K. Türeci Ö. mRNA-based therapeutics--developing a new class of drugs Nat. Rev. Drug Discov. 13 2014 759 780 10.1038/nrd4278 25233993 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    LNP-mRNA is endocytosed and released through endosomal escape to the cytoplasm, where the antigen of interest is produced and presented as a membrane-bound antigen by transfected cells, including muscle cells and APCs, resulting in activation of B cells, CD4+ helper T cells, and CD8+ cytotoxic T cell responses.

    “LNP-mRNA is endocytosed and released through the process of endosomal escape to the cytoplasm, where the antigen of interest is produced and presented as a membrane-bound antigen by transfected cells, including muscle cells and APCs, resulting in activation of B cells, CD4+ helper T cells, and CD8+ cytotoxic T cell responses (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In an interim analysis of a single booster dose following prime-boost vaccination, mRNA-1273 and multiple variant-modified versions had high safety and tolerability and increased neutralization titers against key SARS-CoV-2 variants of concern and interest, including beta, gamma, delta, and omicron.

    “In an interim analysis of a single booster dose following p-b vaccination, Moderna tested mRNA-1273 and multiple variant-modified versions and found high safety and tolerability, as well as increased neutralization titers against key variants of concern and variants of interest of SARS-CoV-2, including beta (B.1.351), gamma (P.1), delta (B.1.617.2), and omicron (B.1.1.529).86”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Choi A. Koch M. Wu K. Chu L. Ma L. Hill A. Nunna N. Huang W. Oestreicher J. Colpitts T. Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis Nat. Med. 2021 10.1038/s41591-021-01527-y PMC8604720 34526698 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the BNT162b2 phase II/III trial, with a total of 43,548 participants 16 years of age or older, two doses of BNT162b2 resulted in confirmation of the favorable safety profile and 95% vaccine efficacy.

    “In the BNT162b2 phase II/III trial, with a total of 43,548 participants 16 years of age or older, two doses of BNT162b2 resulted in confirmation of the favorable safety profile and 95% vaccine efficacy (prevention of COVID-19).8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. Perez J.L. Pérez Marc G. Moreira E.D. Zerbini C. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine N. Engl. J. Med. 383 2020 2603 2615 10.1056/NEJMoa2034577 33301246 PMC7745181 source

      Not checked in the free run.

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

    Premisecitation

    Owing to reduced efficacy of LNP-mRNA vaccines over time and the emergence of highly transmissible SARS-CoV-2 variants such as delta and omicron, the effects of booster vaccination are being examined.

    “Owing to the reduced efficacy of LNP-mRNA vaccines over time and the emergence of highly transmissible SARS-CoV-2 variants such as delta (B.1.617.2) and omicron (B.1.1.529),109,110 the effects of booster vaccination are being examined.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [109] Goldberg Y. Mandel M. Bar-On Y.M. Bodenheimer O. Freedman L. Haas E.J. Milo R. Alroy-Preis S. Ash N. Huppert A. Waning Immunity after the BNT162b2 Vaccine in Israel N Engl J Med. 385 2021 e85 34706170 PMC8609604 source

      Not checked in the free run.

    • cites [110] Garcia-Beltran W.F. St Denis K.J. Hoelzemer A. Lam E.C. Nitido A.D. Sheehan M.L. Berrios C. Ofoman O. Chang C.C. Hauser B.M. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant Cell 2022 10.1016/j.cell.2021.12.033 PMC8733787 34995482 source

      Not checked in the free run.

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

    Premisenone given

    BNT162b2 was granted EUA by the FDA on December 11, 2020, for a 30 μg dose for individuals 16 years or older for the prevention of COVID-19, and mRNA-1273 EUA was granted on December 18, 2020, for individuals 18 years and older at a dose of 100 μg.

    “BNT162b2 was granted EUA by the FDA on December 11, 2020, for a 30 μg dose for individuals 16 years or older for the prevention of COVID-19, and the EUA for mRNA-1273 was granted shortly after on December 18, 2020, for individuals 18 years of age and older at a dose of 100 μg.”
    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 design and preclinical testing of nucleoside-modified mRNA vaccines is based on years of research; thus, at the start of the COVID-19 pandemic they were well placed for rapid adjustments and application to SARS-CoV-2.

    “The design and preclinical testing of nucleoside-modified mRNA vaccines is based on years of research; thus, at the start of the COVID-19 pandemic they were well placed for rapid adjustments and application to SARS-CoV-2.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The details of the manufacturing processes are proprietary to the companies producing nucleoside-modified mRNA vaccines and not disclosed in literature.

    “The details of the manufacturing processes are proprietary to the companies producing nucleoside-modified mRNA vaccines and not disclosed in literature.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    All eight nucleoside-modified mRNAs are formulated using one of three types of LNP originating from Acuitas, Moderna, and Genevant, which consist of four components: ionizable lipids, structural lipids, stealth lipids, and cholesterol.

    “All eight nucleoside-modified mRNAs are formulated using one of three types of LNP originating from Acuitas, Moderna, and Genevant, which consist of four components: ionizable lipids, structural lipids, stealth lipids, and cholesterol.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The exact purification processes performed for BNT162b2 and mRNA-1273 used on a large manufacturing scale are undisclosed.

    “The exact purification processes performed for BNT162b2 and mRNA-1273 used on a large manufacturing scale are undisclosed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    mRNA-1273 demonstrated a favorable safety profile and 94.1% vaccine efficacy in preventing COVID-19 illness, including severe disease, in adults aged 18 years and older in a pivotal phase II/III trial.

    “a favorable safety profile and 94.1% vaccine efficacy (protection in preventing COVID-19 illness, including severe disease) for those ≥18 years of age was demonstrated in a pivotal clinical phase II/III trial.9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] 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 10.1056/NEJMoa2035389 33378609 PMC7787219 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BNT162b1 had an acceptable safety profile and high levels of humoral and T cell responses in younger (ages 18-55 years) and older adults (ages 65-85 years) in an Asian population.

    “acceptable safety profile and high levels of humoral and T cell responses in younger (ages 18–55 years) and older adults (ages 65–85 years) in an Asian population83”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Li J. Hui A. Zhang X. Yang Y. Tang R. Ye H. Ji R. Lin M. Zhu Z. Türeci Ö. Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: a randomized, placebo-controlled, double-blind phase 1 study Nat. Med. 27 2021 1062 1070 10.1016/S1473-3099(20)30773-8 33888900 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Capping of BNT162b2 was performed co-transcriptionally using a trinucleotide cap1 analog, while Moderna used enzymatic capping to obtain cap1 for their preclinical mRNA-1273.

    “Capping of BNT162b2 was performed co-transcriptionally using a trinucleotide cap1 analog ((m27,3′-O)Gppp(m2′-O)ApG) (TriLink),81,92 while Moderna used enzymatic capping to obtain cap1 for their preclinical mRNA-1273.3”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [81] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans Nature 595 2021 572 577 10.1038/s41586-021-03653-6 34044428

      Not checked in the free run.

    • cites [92] Sahin U. Muik A. Derhovanessian E. Vogler I. Kranz L.M. Vormehr M. Baum A. Pascal K. Quandt J. Maurus D. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses Nature 586 2020 594 599 10.1038/s41586-020-2814-7 32998157

      Not checked in the free run.

    • cites [3] 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 10.1038/s41586-020-2622-0 32756549 PMC7581537

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 12- to 17-year-olds, mRNA-1273 showed 95% vaccine efficacy and had an acceptable safety profile.

    “In 12- to 17-year-olds, mRNA-1273 showed 95% vaccine efficacy and had an acceptable safety profile.84”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Ali K. Berman G. Zhou H. Deng W. Faughnan V. Coronado-Voges M. Ding B. Dooley J. Girard B. Hillebrand W. Evaluation of mRNA-1273 SARS-CoV-2 vaccine in adolescents N. Engl. J. Med. 385 2021 2241 2251 10.1056/NEJMoa2109522 34379915 PMC8385554 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HPLC is a gold standard for mRNA purification in a lab setting; however, it presents challenges when scaling up.

    “HPLC is a gold standard for mRNA purification in a lab setting;100 however, it presents challenges when scaling up”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Karikó 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 10.1093/nar/gkr695 21890902 PMC3241667 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BioNTech/Pfizer's modRNA platform RNA sequence used for BNT162b2 consists of human α-globin 5′ untranslated region (UTR), amino-terminal enhancer of split (AES), and mtRNR1 3′ UTR motifs and a poly(A) tail consisting of A30LA70.

    “BioNTech/Pfizer's modRNA platform RNA sequence (used for BNT162b2) consists of human α-globin 5′ untranslated region (UTR), amino-terminal enhancer of split (AES), and mtRNR1 3′ UTR motifs91 and a poly(A) tail consisting of A30LA70 (linker [L]: GCAUAUGACU),81”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Orlandini von Niessen A.G. Poleganov M.A. Rechner C. Plaschke A. Kranz L.M. Fesser S. Diken M. Löwer M. Vallazza B. Beissert T. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3' UTRs identified by cellular library screening Mol. Ther. 27 2019 824 836 10.1016/j.ymthe.2018.12.011 30638957 PMC6453560 source

      Not checked in the free run.

    • cites [81] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans Nature 595 2021 572 577 10.1038/s41586-021-03653-6 34044428 source

      Not checked in the free run.

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

    Premisenone given

    One of the bottlenecks that required significant innovation was manufacturing, process development, and scale-up methods to meet supply demands for large-scale clinical trials and later worldwide marketing.

    “However, one of the bottlenecks that required significant innovation was manufacturing, process development, and scale-up methods to meet supply demands for large-scale clinical trials and later worldwide marketing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In multiple trials, neutralizing antibody titers after the second dose of mRNA-based vaccines were highly reduced for omicron compared with delta and especially compared with the wild-type variant, while the third dose significantly improved antibody neutralization titers.

    “In all cases, neutralizing antibody titers after the second dose of mRNA-based vaccines were highly reduced for omicron (B.1.1.529) compared with delta (B.1.617.2) and especially compared with the wild-type variant, while the third dose significantly improved antibody neutralization titers.110,112,113”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [110] Garcia-Beltran W.F. St Denis K.J. Hoelzemer A. Lam E.C. Nitido A.D. Sheehan M.L. Berrios C. Ofoman O. Chang C.C. Hauser B.M. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant Cell 2022 10.1016/j.cell.2021.12.033 PMC8733787 34995482 source

      Not checked in the free run.

    • cites [112] Pérez-Then E. Lucas C. Monteiro V.S. Miric M. Brache V. Cochon L. Vogels C.B.F. Malik A.A. La Cruz E.D. Jorge A. Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination Nat. Med. 2022 10.1038/s41591-022-01705-6 PMC8938264 35051990 source

      Not checked in the free run.

    • cites [113] Muik A. Lui B.G. Wallisch A.-K. Bacher M. Mühl J. Reinholz J. Ozhelvaci O. Beckmann N. La Güimil Garcia RdC. Poran A. Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine-elicited human sera Science 2022 eabn7591 10.1126/science.abn7591 PMC9836206 35040667 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 12- to 15-year-olds, two 30 μg doses of BNT162b2 showed a favorable safety profile and resulted in 100% vaccine efficacy.

    “In 12- to 15-year-olds, two 30 μg doses of BNT162b2 showed a favorable safety profile and resulted in 100% vaccine efficacy.80”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Frenck R.W. Klein N.P. Kitchin N. Gurtman A. Absalon J. Lockhart S. Perez J.L. Walter E.B. Senders S. Bailey R. Safety, immunogenicity, and efficacy of the BNT162b2 covid-19 vaccine in adolescents N. Engl. J. Med. 385 2021 239 250 10.1056/NEJMoa2107456 34043894 PMC8174030 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An Israeli study looking at the population ≥60 years of age receiving a single booster of BNT162b2 given at least 5 months after completion of the prime-boost primary regimen demonstrated 95% fewer reports of severe illness and significantly lower rate of confirmed COVID-19 cases.

    “An Israeli study looking at the population ≥60 years of age receiving a single booster of BNT162b2 given at least 5 months after completion of the p-b primary regimen demonstrated 95% fewer reports of severe illness and significantly lower rate of confirmed COVID-19 cases.111”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Bar-On Y.M. Goldberg Y. Mandel M. Bodenheimer O. Freedman L. Kalkstein N. Mizrahi B. Alroy-Preis S. Ash N. Milo R. Protection of BNT162b2 vaccine booster against covid-19 in Israel N. Engl. J. Med. 385 2021 1393 1400 10.1056/NEJMoa2114255 34525275 PMC8461568 source

      Not checked in the free run.

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

    Premisenone given

    All nucleoside-modified LNP-mRNAs referred to in Table 1 are administered intramuscularly in a prime-boost regimen with a 3 week interval for BNT162b2 and ChulaCov19, or a 4 week interval for mRNA-1273 and TAK-919.

    “All nucleoside-modified LNP-mRNAs referred to in Table 1 are administered i.m. in a prime-boost (p-b) regimen with a 3 week interval for BNT162b2 and ChulaCov19, or a 4 week interval for mRNA-1273 and TAK-919.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BNT162b2 and mRNA-1273 are composed of 1-methylpseudouridine-modified full-length spike mRNA, with proline substitutions, that is GC rich, codon optimized, and composed of standard mRNA components: cap, 5′ UTR, coding sequence, 3′ UTR, and a poly(A) tail.

    “BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna) are composed of 1-methylpseudouridine-modified full-length spike mRNA, with proline substitutions, that is GC rich, codon optimized, and composed of standard mRNA components: cap, 5′ UTR, coding sequence, 3′ UTR, and a poly(A) tail.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [91] Orlandini von Niessen A.G. Poleganov M.A. Rechner C. Plaschke A. Kranz L.M. Fesser S. Diken M. Löwer M. Vallazza B. Beissert T. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3' UTRs identified by cellular library screening Mol. Ther. 27 2019 824 836 10.1016/j.ymthe.2018.12.011 30638957 PMC6453560 source

      Not checked in the free run.

    • cites [92] Sahin U. Muik A. Derhovanessian E. Vogler I. Kranz L.M. Vormehr M. Baum A. Pascal K. Quandt J. Maurus D. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses Nature 586 2020 594 599 10.1038/s41586-020-2814-7 32998157 source

      Not checked in the free run.

    • cites [93] Xia X. Detailed dissection and critical evaluation of the Pfizer/BioNTech and Moderna mRNA vaccines Vaccines (Basel) 9 2021 10.3390/vaccines9070734 PMC8310186 34358150 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Application of a booster dose of mRNA vaccines may protect against highly transmissible variants and supports booster vaccine doses.

    “This suggests that application of a booster dose of mRNA vaccines may protect against these highly transmissible variants and supports booster vaccine doses, which are now being rolled out globally.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Full approval by the FDA was granted for BNT162b2 for individuals 16 years and older and mRNA-1273 for individuals 18 years and older on August 23, 2021, and January 31, 2022, respectively.

    “Full approval by the FDA was granted for BNT162b2 for individuals 16 years and older and mRNA-1273 for individuals 18 years and older on August 23, 2021, and on January 31, 2022, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PTX-COVID19-B had a tolerable safety profile at a dose of up to 100 μg among seronegative individuals and induced high neutralizing antibody levels in a phase I trial.

    “a successful phase I trial, which showed that it had a tolerable safety profile at a dose of up to 100 μg among seronegative individuals, and induced high neutralizing antibody levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Röltgen K. Nielsen S.C.A. Arunachalam P.S. Yang F. Hoh R.A. Wirz O.F. Lee A.S. Gao F. Mallajosyula V. Li C. mRNA vaccination compared to infection elicits an IgG-predominant response with greater SARS-CoV-2 specificity and similar decrease in variant spike recognition Preprint at medRxiv 2021 10.1101/2021.04.05.21254952 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The self-adjuvanting effect of saRNA triggers a broader immune response, which is considered to have potential to be effective with a single-dose inoculation.

    “This triggers a broader immune response, which was also considered to have potential to be effective with a single-dose inoculation.155,156”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Jensen S. Thomsen A.R. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion J. Virol. 86 2012 2900 2910 10.1128/JVI.05738-11 22258243 PMC3302314 source

      Not checked in the free run.

    • cites [156] Vogel A.B. Lambert L. Kinnear E. Busse D. Erbar S. Reuter K.C. Wicke L. Perkovic M. Beissert T. Haas H. Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses Mol. Ther. 26 2018 446 455 10.1016/j.ymthe.2017.11.017 29275847 PMC5835025 source

      Not checked in the free run.

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

    Premisecitation

    DS5670 has shown no relevant safety concerns in different age groups, with appropriate immunogenic response.

    “Recently, the company disclosed that no relevant safety concerns have been observed in different age groups, with appropriate immunogenic response.125”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Daichii Development progress of mRNA COVID19 vaccine in Japan: press release Updated October 21, 2021 https://www.daiichisankyo.com/files/news/pressrelease/pdf/202110/20211021_E.pdf

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

  • May combine two claims.

    Premisecitation

    circRNA can be translated in eukaryotic cells and, due to its closed-ring structure, is significantly more resistant to exonuclease-mediated degradation compared with linear mRNA.

    “circRNA (also called endless RNA) can be translated in eukaryotic cells48 and, due to its closed-ring structure, is significantly more resistant to exonuclease-mediated degradation compared with linear mRNA.151”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Chen C.Y. Sarnow P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs Science 268 1995 415 417 10.1126/science.7536344 7536344 source

      Not checked in the free run.

    • cites [151] Kristensen L.S. Andersen M.S. Stagsted L.V.W. Ebbesen K.K. Hansen T.B. Kjems J. The biogenesis, biology and characterization of circular RNAs Nat. Rev. Genet. 20 2019 675 691 10.1038/s41576-019-0158-7 31395983 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Based on an EMA review of multiple studies in pregnant women including about 65,000 pregnancies, no increased risk of pregnancy complications for expectant mothers and their unborn babies was found with mRNA-based COVID-19 vaccines, and effectiveness was not compromised compared with non-pregnant women.

    “Based on the results, the use of mRNA-based COVID-19 vaccines during pregnancy is encouraged, since no increased risk of pregnancy complications for expectant mothers and their unborn babies was found, and effectiveness was not compromised compared with non-pregnant women.119”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] EMA COVID-19: latest safety data provide reassurance about use of mRNA vaccines during pregnancy https://www.ema.europa.eu/en/news/covid-19-latest-safety-data-provide-reassurance-about-use-mrna-vaccines-during-pregnancy

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

  • May combine two claims.

    Premisecitation

    The limitations of unmodified mRNA vaccines are based on intrinsic immunogenicity of unmodified mRNA due to intracellular detection and type I interferon production, which inhibits translation, reduces CD8+ T cell activation, and inhibits T helper cell generation.

    “These limitations are based on the intrinsic immunogenicity of unmodified mRNA due to intracellular detection131,132 and type I interferon (IFN) production,34 which in turn is responsible for the inhibition of translation, the reduction of CD8+ T cell activation, and the inhibition of T helper cell generation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [131] Chen N. Xia P. Li S. Zhang T. Wang T.T. Zhu J. RNA sensors of the innate immune system and their detection of pathogens IUBMB Life 69 2017 297 304 10.1002/iub.1625 28374903 PMC7165898 source

      Not checked in the free run.

    • cites [132] Tatematsu M. Funami K. Seya T. Matsumoto M. Extracellular RNA sensing by pattern recognition receptors J. Innate Immun. 10 2018 398 406 10.1159/000494034 30404092 PMC6784046 source

      Not checked in the free run.

    • cites [34] Devoldere J. Dewitte H. Smedt S.C.D. Remaut K. Evading innate immunity in nonviral mRNA delivery: don't shoot the messenger Drug Discov. Today 21 2016 11 25 10.1016/j.drudis.2015.07.009 26210957 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a cohort of 131 pregnant or lactating women, BNT162b2 and mRNA-1273 led to robust humoral immunity with no significant differences in postvaccination reactogenicity between pregnant and non-pregnant women.

    “In a smaller patient cohort with 131 individuals, BNT162b2 and mRNA-1273 were studied in pregnant or lactating women, and both vaccines led to robust humoral immunity with no significant differences in postvaccination reactogenicity between pregnant and non-pregnant women.116”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Gray K.J. Bordt E.A. Atyeo C. Deriso E. Akinwunmi B. Young N. Baez A.M. Shook L.L. Cvrk D. James K. Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study Am. J. Obstet. Gynecol. 225 2021 303.e1 303.e17 10.1016/j.ajog.2021.03.023 33775692 PMC7997025

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    saRNA facilitates rapid candidate design and development, as well as cell-free molecule synthesis.

    “Similar to other mRNA vaccine platforms, saRNA facilitates rapid candidate design and development, as well as cell-free molecule synthesis.152”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Bloom K. van den Berg F. Arbuthnot P. Self-amplifying RNA vaccines for infectious diseases Gene Ther. 28 2021 117 129 10.1038/s41434-020-00204-y 33093657 PMC7580817 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CureVac further engineered the UTRs of the mRNA and showed a superior immunological profile in preclinical tests.

    “However, CureVac further engineered the UTRs of the mRNA and showed a superior immunological profile in preclinical tests,136,137”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [136] Gebre M.S. Rauch S. Roth N. Yu J. Chandrashekar A. Mercado N.B. He X. Liu J. McMahan K. Martinot A. Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine Nature 2021 10.1038/s41586-021-04231-6 PMC8770133 34794169 source

      Not checked in the free run.

    • cites [137] Roth N. Schön J. Hoffmann D. Thran M. Thess A. Mueller S.O. Petsch B. Rauch S. CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats 10.1101/2021.05.13.443734 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Uridine depletion to reduce counterproductive immune reactions can be achieved by replacement of uridine by codon optimization, but this must be balanced with regard to transfer RNA abundance.

    “Uridine depletion to reduce counterproductive immune reactions can be achieved by the replacement of uridine by codon optimization, but this must be balanced with regard to transfer RNA abundance.120, 121, 122”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [120] Linares-Fernández S. Lacroix C. Exposito J.-Y. Verrier B. Tailoring mRNA vaccine to balance innate/adaptive immune response Trends Mol. Med. 26 2020 311 323 10.1016/j.molmed.2019.10.002 31699497 source

      Not checked in the free run.

    • cites [121] Gustafsson C. Govindarajan S. Minshull J. Codon bias and heterologous protein expression Trends Biotechnol. 22 2004 346 353 10.1016/j.tibtech.2004.04.006 15245907 source

      Not checked in the free run.

    • cites [122] Heil F. Hemmi H. Hochrein H. Ampenberger F. Kirschning C. Akira S. Lipford G. Wagner H. Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8 Science 303 2004 1526 1529 10.1126/science.1093620 14976262 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a preclinical study, a circRNA candidate administered to mice intramuscularly at 10 and 50 μg in a prime-boost regimen 2 weeks apart elicited high-titer neutralizing antibodies in a dose-dependent manner, with Th1-biased T cell responses.

    “In the preclinical study, the candidate was administered to mice i.m. at two different doses (10 and 50 μg) in a p-b regimen 2 weeks apart, which elicited a high titer of neutralizing antibodies in a dose-dependent manner, with Th1-biased T cell responses.59”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Qu L. Yi Z. Shen Y. Xu Y. Wu Z. Tang H. Xiao X. Dong X. Guo L. Yisimayi A. Circular RNA vaccines against SARS-CoV-2 and emerging variants: Qu et al CircRNA COVID-19 vaccine https://www.biorxiv.org/content/10.1101/2021.03.16.435594v1 PMC8971115 35460644 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    mRNA-based therapeutics have key advantages in versatility and adaptability, which could lead to promising therapeutics not only for infectious diseases but also for other indications such as cancer, warranting further research and investment.

    “In summary, mRNA-based therapeutics have key advantages in terms of their versatility and adaptability, which could lead to promising therapeutics not only for infectious diseases but for other indications such as cancer, and thus, further research and investment into this technology is warranted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    circRNA represents a favorable concept, but further improvement is necessary prior to continuing its development as drug candidates.

    “circRNA represents a favorable concept, but it seems that further improvement is necessary prior to continuing their development as drug candidates.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The functionality of an IRES element in combination with modified nucleosides is yet to be demonstrated.

  • May combine two claims.

    Premisecitation

    In the LNP-nCoVsaRNA phase I/II trial, doses of 0.1-10 μg showed a dose-dependent immune response, but there was no seroconversion in a significant portion of participants, all seronegative at inclusion, and clinical development was halted.

    “Doses of 0.1–10 μg showed a dose-dependent immune response; however, there was no seroconversion in a significant portion of the trial participants, all of whom were seronegative at inclusion for SARS-CoV-2 infection159 and, accordingly, the clinical development process was halted.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Pollock K.M. Cheeseman H.M. Szubert A.J. Libri V. Boffito M. Owen D. Bern H. O’Hara J. McFarlane L.R. Lemm N.-M. Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial: COVAC1 human phase I study https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3859294 PMC8759012 35043093

      Not checked in the free run.

69 of 69

  • The paper relies on this without support.

    Initial clinical trials of COVID-19 vaccines included healthy volunteers and did not include pregnant women.

    “While initial clinical trials included healthy volunteers, an important aspect is the safety and efficacy in pregnant women, who were not included.”

  • The paper relies on this without support.

    Profound immunogenicity data for therapeutic usage in non-inflammatory environments is still missing.

    “Profound immunogenicity data for therapeutic usage in non-inflammatory environments is still missing.”

  • The paper relies on this without support.

    The functionality of an IRES element in combination with modified nucleosides is yet to be demonstrated.

    “to our knowledge, the functionality of an IRES element in combination with modified nucleosides is yet to be demonstrated.”

  • The paper relies on this without support.

    The large size of saRNA, due to its non-structural protein encoding sequence, is a main obstacle for the saRNA platform.

    “One of the main obstacles concerning the platform is the large size of the saRNA, as it contains the non-structural protein encoding sequence derived from the alphavirus genome necessary for replicative activity.”

  • The paper relies on this without support.

    The length of saRNA substantially influences its stability and ease of delivery.

    “The length of the RNA substantially influences the stability and ease of delivery.”
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 has emerged as a promising therapeutic molecule with numerous clinical applications in treating central nervous system disorders, tumors, COVID-19, and other diseases.

    “Messenger RNA (mRNA) has emerged as a promising therapeutic molecule with numerous clinical applications in treating central nervous system disorders, tumors, COVID-19, and other diseases.”

    From Exosome for mRNA delivery: Strategies and therapeutic applications (2024) · cites this paper as [5]

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.

  • MRT5500 trial doses disagree

    Major

    Table 3 lists a 7.5 μg dose for MRT5500, but the text says the phase I/II trial administered 15, 45, or 135 μg.

  • Trial NCT04470427 is assigned to two different vaccines

    Minor

    Table 2 labels the Moderna-sponsored NCT04470427 entry BNT162b2, whereas Table 1 identifies that trial as an mRNA-1273 trial.

  • IVT is expanded inconsistently

    Minor

    The Figure 1 caption defines IVT as "in vitro translation," but the text introduces it as in vitro mRNA transcription.

3 of 3

The citation lists haven’t been fetched yet

References 163 · Cited by 308

Authors
Szabó, G. T., Mahiny, A. J., & Vlatkovic, I.
Affiliations
BioNTech (Germany) (DE)
Corresponding author
Szabó, Gábor Tamás
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2022-05
Volume
30
Issue
5
Pages
1850-1868
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2022.02.016
PMC
PMC8856755
OpenAlex
W4213123920
Cited by
308
References
163
Citations by year
2026: 59 · 2025: 77 · 2024: 80 · 2023: 57 · 2022: 34 · 2021: 1
FWCI
9.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
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
COVID-19 mRNA vaccine, SARS-CoV-2, nucleoside-modified mRNA, self-amplifying RNA vaccine, vaccine safety and efficacy, real-world evidence, mRNA therapeutics, cancer vaccines
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, Humans, Nucleosides, RNA, Messenger, Vaccines, Synthetic

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.

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