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Cited by 601SARS-CoV-2 and COVID-19 ResearchRNA Interference and Gene DeliverySARS-CoV-2 detection and testing

Advances in COVID-19 mRNA vaccine development

Open access
Fang, Enyue, Liu, Xiaohui, Li, Miao, Zhang, Zelun, Song, Lifang, Zhu, Baiyu, Wu, Xiaohong, Liu, Jingjing +2 more·2022·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-022-00950-yPMC PMC8940982
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Abstract

To date, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has determined 399,600,607 cases and 5,757,562 deaths worldwide. COVID-19 is a serious threat to human health globally. The World Health Organization (WHO) has declared COVID-19 pandemic a major public health emergency. Vaccination is the most effective and economical intervention for controlling the spread of epidemics, and consequently saving lives and protecting the health of the population. Various techniques have been employed in the development of COVID-19 vaccines. Among these, the COVID-19 messenger RNA (mRNA) vaccine has been drawing increasing attention owing to its great application prospects and advantages, which include short development cycle, easy industrialization, simple production process, flexibility to respond to new variants, and the capacity to induce better immune response. This review summarizes current knowledge on the structural characteristics, antigen design strategies, delivery systems, industrialization potential, quality control, latest clinical trials and real-world data of COVID-19 mRNA vaccines as well as mRNA technology. Current challenges and future directions in the development of preventive mRNA vaccines for major infectious diseases are also discussed.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes the structural design, antigen engineering, delivery systems, clinical trial results, and manufacturing/quality-control landscape of COVID-19 mRNA vaccines as of early 2022. It argues that mRNA platforms offer short development cycles, easy industrialization, and flexibility against new variants, while flagging ultra-cold-chain storage and long-term durability as open problems.

Key findings

  • As of February 8, 2022, WHO listed 337 COVID-19 vaccine candidates in development, of which 47 were mRNA vaccines and 23 had entered clinical trials.
  • BNT162b2 (30 μg, two doses 21 days apart) showed 95% efficacy against COVID-19 in individuals aged 16+, with efficacy of 91.3% over six months; a booster trial in over 5,000 people showed 95.6% protection. Real-world Qatar data showed effectiveness of 89.5% against Alpha, 75.0% against Beta, and 51.9% against Delta.
  • mRNA-1273 (100 μg, two doses 28 days apart) showed 94.1% efficacy in a phase III trial of 30,420 participants; real-world effectiveness was 100% against Alpha, 96.4% against Beta, and 73.1% against Delta, and 95.2% against Delta vs 62.5% against Omicron after three doses.
  • CureVac's CVnCoV (12 μg, unmodified nucleosides) showed only 48.2% overall efficacy and its rolling review was terminated by EMA; saRNA vaccines require far lower doses (0.1–10 μg) than mRNA-1273 (100 μg) or BNT162b2 (30 μg), but clinical seroconversion rates were incomplete (e.g., 8–61% for Imperial College London's LNP-nCoVsaRNA; ARCT-021 did not reach 100% seroconversion).
  • The mRNA vaccine production cycle from IVT to mRNA-LNP complex is approximately 10 days, with product potentially marketable within 40 days; storage requirements differ (mRNA-1273 six months at −20 °C; BNT162b2 six months at −60 to −80 °C; CVnCoV three months at −60 °C).

Methods

  • Design: narrative review of the literature on COVID-19 mRNA vaccine technology, covering mRNA types (non-replicating, saRNA, taRNA, circRNA), antigen design, delivery systems, clinical trials, production, and quality control.
  • Data: no primary data collection; the review synthesizes published preclinical studies, clinical trial registrations and results, real-world effectiveness data, and regulatory actions, with tables compiling UTR designs, antigen design strategies, and clinical trial candidates.
  • Analysis: descriptive synthesis; no meta-analysis or statistical pooling is reported.

Limitations

  • The paper does not state explicit limitations of its own review.
  • Evident from the text: this is a narrative (non-systematic) review with no stated search strategy, inclusion criteria, or risk-of-bias assessment, so selection of cited trials and real-world studies may be selective.
  • Evident from the text: clinical trial participant numbers and locations are noted as subject to change ("Clinical trials are regularly updated, therefore locations and the number of participants of clinical trials reported above are subjected to change"), and the review's data cut off in early 2022, predating later variant and durability data.

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

Integrity signals

Registry

Crossref · 10.1038/s41392-022-00950-y

Cites

416 of 416 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Findingcitation

    All five BioNTech/Pfizer COVID-19 mRNA vaccine candidates have entered clinical trials.

    “Till now, all of these candidates have entered clinical trials (Table 5).130,376,377”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [130] Sahin, U., Muik, A., Derhovanessian, E., Vogler, I. & Türeci, Z. Publisher Correction: COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature, 590, E17 (2021). source

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    • cites [376] Mulligan, M. J. et al. Phase 1/2 study to describe the safety and immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in adults 18 to 55 years of age: interim report. medRxiv, https://doi.org/10.1101/2020.06.30.20142570 (2020). source

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    • cites [377] Li, J. et al. 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, 1062–1070 (2021). source

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  • Findingcitation

    Five mRNA vaccines for influenza virus encoding the HA antigen have entered clinical trials: mRNA-1851, mRNA-1440, and mRNA-1010 from Moderna; MRT-5400 and MRT-5401 co-developed by Sanofi and Translate Bio.

    “Currently, five mRNA vaccines for influenza virus encoding the HA antigen have entered clinical trials: mRNA-1851, mRNA-1440, and mRNA-1010368,369 from Moderna; MRT-5400 and MRT-5401 co-developed by Sanofi and Translate Bio.370”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [368] A seasonal flu investigational vaccine clinical trial for healthy adults, https://trials.modernatx.com/study/?id=mRNA-1010-P101 (2021).

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    • cites [369] Abbasi, J. Moderna’s mRNA vaccine for seasonal flu enters clinical trials. JAMA 326, 1365–1365 (2021).

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    • cites [370] Sanofi and Translate Bio Initiate Phase 1 Clinical Trial of mRNA Influenza Vaccine, https://translatebio.gcs-web.com/news-releases/news-release-details/sanofi-and-translate-bio-initiate-phase-1-clinical-trial-mrna (2021).

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  • Findingcitation

    Several mRNA vaccine candidates for viral agents other than SARS-CoV-2 have entered clinical trials, including CMV, influenza virus, rabies virus, Zika virus, RSV, and human metapneumovirus (hMPV).

    “Several mRNA vaccine candidates for viral agents other than SARS-CoV-2 have entered clinical trials (Table 4), including CMV,359 influenza virus,288,360 rabies virus,86,88 Zika virus,90,361–364 RSV,365,366 human metapneumovirus (hMPV).367”
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  • Premisecitation

    Non-replicating mRNA vaccines deliver exclusively genetic information coding for the target antigen, containing 5′-cap, 5′ UTR, 3′ UTR, and 3′-poly(A) tail regions.

    “Non-replicating mRNA vaccines deliver exclusively genetic information coding for the target antigen, thus containing the 5′-cap, 5′ untranslated region (UTR), 3′ UTR, and 3′-poly(A) tail regions.108”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines—a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source

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  • Premisecitation

    saRNA vaccines can deliver genetic information encoding the target antigen and other genes, e.g., viral RNA polymerase, to enable mRNA to self-replicate.

    “saRNA vaccines can deliver genetic information encoding the target antigen and other genes, e.g., viral RNA polymerase, to enable mRNA to self-replicate.109,110”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [109] Blakney, A. K., Ip, S. & Geall, A. J. An update on self-amplifying mRNA vaccine development. Vaccines 9, 97 (2021). source

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    • cites [110] Atasheva, S. et al. Enhancement of protein expression by alphavirus replicons by designing self-replicating subgenomic RNAs. Proc. Natl Acad. Sci. USA 111, 10708–10713 (2014). source

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  • Classified as probably not a substantial claim. 33
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  • The quote only partly states this claim. 1

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    Premisecitation

    mRNA vaccines can be categorized as non-replicating mRNA, self-amplifying mRNA (saRNA), and circular RNA (circRNA) based on their genetic characteristics.

    “mRNA vaccines can be categorized as non-replicating mRNA, self-amplifying mRNA (saRNA) and circular RNA (circRNA) based on their genetic characteristics (Fig. 3).107”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Iavarone, C., O’hagan, D. T., Yu, D., Delahaye, N. F. & Ulmer, J. B. Mechanism of action of mRNA-based vaccines. Expert Rev. Vaccines 16, 871–881 (2017). source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    COVID-19 mRNA vaccines have advantages including short development cycle, easy industrialization, simple production process, flexibility to respond to new variants, and capacity to induce better immune response.

    “Among these, the COVID-19 messenger RNA (mRNA) vaccine has been drawing increasing attention owing to its great application prospects and advantages, which include short development cycle, easy industrialization, simple production process, flexibility to respond to new variants, and the capacity to induce better immune response.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    When poly(A) tail size increases to 120 bp, the expression level of the corresponding protein increases accordingly; however, when poly(A) tail size is greater than 120 bp, the expression level of the corresponding protein did not increase.

    “Studies have shown that when poly(A) tail size increases to 120 bp, the expression level of the corresponding protein increases accordingly. However, when poly(A) tail size is greater than 120 bp, the expression level of the corresponding protein did not increase.152”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Kormann, M. S. et al. Expression of therapeutic proteins after deliveryof chemically modified mRNA in mice. Nat. Biotechnol. 29, 154–157 (2011). source

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    Premisecitation

    The cap1 structure can be used as a signature of self-RNA, thus reducing activation of pattern recognition receptor (PRR) and improving translation efficiency of mRNA in vivo.

    “Since the cap1 structure has only been described to date in eukaryotic mRNAs, it can be used as a signature of self-RNA, thus reducing the activation of pattern recognition receptor (PRR) and consequently improving translation efficiency of mRNA in vivo.119”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Hyde, J. L. & Diamond, M. S. Innate immune restriction and antagonism of viral RNA lacking 2׳-O methylation. Virology 479, 66–74 (2015). source

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    Premisecitation

    The 5′-cap structure prevents mRNA from degradation by exonucleases, thereby maintaining mRNA stability and enabling translation initiation.

    “The 5′-cap structure prevents mRNA from degradation by exonucleases, thereby maintaining mRNA stability and enabling translation initiation.115”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Kwon, H. et al. Emergence of synthetic mRNA: in vitro synthesis of mRNA and its applications in regenerative medicine. Biomaterials 156, 172–193 (2018). source

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    Premisenone given

    At present, the cap1 structure is most commonly applied for capping mRNA vaccines.

    “At present, the cap1 structure is most commonly applied for capping mRNA vaccines.”
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    Premisecitation

    Co-transcriptional capping is the most commonly used method in IVT for mRNA.

    “Co-transcriptional capping is the most commonly used method in IVT for mRNA,115”
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    • cites [115] Kwon, H. et al. Emergence of synthetic mRNA: in vitro synthesis of mRNA and its applications in regenerative medicine. Biomaterials 156, 172–193 (2018). source

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    Premisenone given

    Non-replicating mRNA vaccines have advantages including simple structure and shorter length, and optimized or modified mRNA can have greatly enhanced biological activity.

    “The advantages of non-replicating mRNA vaccines include the use of an RNA molecule of simple structure and shorter length. An optimized or modified mRNA can have greatly enhanced biological activity.”
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    Premisecitation

    The poly(A) tail plays an important role in maintaining mRNA stability and translation efficiency.

    “The poly(A) tail plays an important role in maintaining mRNA stability and translation efficiency.116”
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    • cites [116] Gallie, D. R. The cap and poly (A) tail function synergistically to regulate mRNA translational efficiency. Genes Dev. 5, 2108–2116 (1991). source

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    Premisecitation

    At present, the 3′ UTR is mainly derived from hemoglobin subunit α (HBA) and subunit β (HBB) genes, but it can also be derived from albumin (ALB), heat-shock protein 70 (Hsp70), tyrosine hydroxylase (TH), and collagen alpha 1 (COL1A1) genes.

    “At present, the 3′ UTR is mainly derived from hemoglobin subunit α (HBA) and subunit β (HBB) genes,140 but it can also be derived from albumin (ALB), heat-shock protein 70 (Hsp70), tyrosine hydroxylase (TH), and collagen alpha 1 (COL1A1) genes.141–143”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [140] Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C. & Thakur, A. Opportunities and challenges in the delivery of mRNA-based vaccines. Pharmaceutics 12, 102 (2020). source

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    • cites [141] Zhang, B. Vaccines and compositions based on S antigen protein of SARS-CoV-2. CN112480217A (2021).

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    • cites [142] Karikó, K., Muramatsu, H., Keller, J. M. & Weissman, D. Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin. Mol. Ther. 20, 948–953 (2012). source

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    • cites [143] Sepac, A. et al. Comparison of cardiomyogenic potential among human ESC and iPSC lines. Cell Transpl. 21, 2523–2530 (2012). source

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    Premisecitation

    In mammalian cells, actively translated mRNAs generally contain 100-250 adenosine residues.

    “In mammalian cells, actively translated mRNAs generally contain 100–250 adenosine residues.117,150”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [117] To, K. K. & Cho, W. C. An overview of rational design of mRNA-based therapeutics and vaccines. Expert Opin. Drug Discov. 16, 1307–1317 (2021). source

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    • cites [150] Tang, T. T. & Passmore, L. A. Recognition of poly (A) RNA through its intrinsic helical structure. Cold Spring Harb. Symp. Quant. Biol. 84, 21–30 (2019). source

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    Premisecitation

    The 5′ UTR is mainly involved in translation of its downstream ORF sequence, and the Kozak sequence is generally added after the 5′ UTR sequence to improve translation efficiency.

    “The 5′ UTR is mainly involved in translation of its downstream ORF sequence.132,133 The Kozak sequence is generally added after the 5′ UTR sequence to improve translation efficiency.134”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] Balzer, Le,S., Onsager, I., Lorentzen, J. A. & Lale, R. Dual UTR-A novel 5′ untranslated region design for synthetic biology applications. Synth. Biol. 5, ysaa006 (2020). source

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    • cites [133] Leppek, K., Das, R. & Barna, M. Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat. Rev. Mol. Cell Biol. 19, 158–174 (2018). source

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    • cites [134] Nance, K. D. & Meier, J. L. Modifications in an emergency: the role of N1-Methylpseudouridine in COVID-19 vaccines. ACS Cent. Sci. 7, 748–756 (2021). source

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    Premisecitation

    The vaccinia capping enzyme (VCE) integrates the enzymatic activity of RTPase, GTase, and G-N7 MTase, which can be capped to generate a cap0 structure, and then 2′-O-MTase can be used to generate a methylated cap1 structure, thus reaching a capping efficiency of 100%.

    “The vaccinia capping enzyme (VCE) integrates the enzymatic activity of RTPase, GTase, and G-N7 MTase, which can be capped to generate a cap0 structure, and then 2′-O-MTase can be used to generate a methylated cap1 structure, thus reaching a capping efficiency of 100%.52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Linares-Fernández, S., Lacroix, C., Exposito, J. Y. & Verrier, B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol. Med. 26, 311–323 (2019). source

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    Premisecitation

    The COVID-19 vaccine mRNA-1273 developed by Moderna employs the capping enzyme described above.

    “Of note, it has been reported that the COVID-19 vaccine mRNA-1273 developed by Moderna employs the capping enzyme described above.28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). source

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    Premisecitation

    A non-replicating mRNA contains an open reading frame (ORF) encoding the gene coding for the target antigen flanked by 5′ and 3′ UTR; the 5′ end contains a 7-methylguanosine cap structure, whereas the 3′ end contains a poly(A) tail structure.

    “A non-replicating mRNA contains an open reading frame (ORF) encoding the gene coding for the target antigen flanked by 5′ and 3′ UTR. The 5′ end contains a 7-methylguanosine cap structure (5′-cap, m7G), whereas the 3′ end contains a poly(A) tail structure.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [113] Schlake, T., Thess, A., Fotin-Mleczek, M. & Kallen, K.-J. Developing mRNA-vaccine technologies. RNA Biol. 9, 1319–1330 (2012). source

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    • cites [114] Youn, H. & Chung, J. K. Modified mRNA as an alternative to plasmid DNA (pDNA) for transcript replacement and vaccination therapy. Expert Opin. Biol. Ther. 15, 1–12 (2015). source

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

    Premisecitation

    The poly(A) tail can bind to multiple poly(A)-binding proteins (PABPs) while working synergistically with 5′ m7G cap sequences to regulate translational efficiency.

    “The poly(A) tail can also bind to multiple poly(A)-binding proteins (PABPs) while working synergistically with 5′ m7G cap sequences to regulate translational efficiency.146,147”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [146] Goss, D. J. & Kleiman, F. E. Poly (A) binding proteins: are they all created equal? Wiley Interdiscip. Rev.: RNA 4, 167–179 (2013). source

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    • cites [147] Wang, Z. & Kiledjian, M. The poly (A)-binding protein and an mRNA stability protein jointly regulate an endoribonuclease activity. Mol. Cell. Biol. 20, 6334–6341 (2000). source

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  • May combine two claims.

    Premisecitation

    The CleanCap® cap analogs can be co-transcribed with the target mRNA to obtain the cap1 structure, thus solving the issues of low efficiency and high enzyme costs of traditional capping methods.

    “The current new generation of cap analogs is the CleanCap® cap analogs developed by TriLink BioTechnologies (San Diego, CA, USA),126 which can be co-transcribed with the target mRNA to obtain the cap1 structure, thus solving the issues of low efficiency and high enzyme costs of traditional capping methods.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Henderson, J. M. et al. Cap 1 messenger RNA synthesis with co-transcriptional CleanCap® analog by in vitro transcription. Curr. Protoc. 1, e39 (2021). source

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    Premisenone given

    saRNA vaccines are currently in preclinical and clinical trials.

    “Lastly, saRNA vaccines are currently in preclinical and clinical trials.”
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    Premisecitation

    Adenylate-uridylate-rich elements are involved in mRNA degradation, and degradation rate and translation life cycle can be adjusted by replacing adenylate-uridylate-rich sequences found in the 3′ UTR.

    “Studies have shown that adenylate-uridylate-rich elements are involved in mRNA degradation. Degradation rate and translation life cycle can be adjusted by replacing adenylate-uridylate-rich sequences found in the 3′ UTR.137–139”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [137] Mayr, C. What are 3′ UTRs doing?. Cold Spring Harb. Perspect. Biol. 11, a034728 (2018). source

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    • cites [138] Fotin-Mleczek, M. et al. Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity. J. Immunother. 34, 1–15 (2011). source

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    • cites [139] Eberhardt, W., Doller, A., Akool, E.-S. & Pfeilschifter, J. Modulation of mRNA stability as a novel therapeutic approach. Pharmacol. Ther. 114, 56–73 (2007). source

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    Premisecitation

    The function of the 3′ UTR is to maintain mRNA stability.

    “Conversely, the function of the 3′ UTR is to maintain mRNA stability.135,136”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [135] Mayr, C. Regulation by 3′-untranslated regions. Annu. Rev. Genet. 51, 171–194 (2017). source

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    • cites [136] Matoulkova, E., Michalova, E., Vojtesek, B. & Hrstka, R. The role of the 3’untranslated region in post-transcriptional regulation of protein expression in mammalian cells. RNA Biol. 9, 563–576 (2012). source

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

    Premisecitation

    mRNA contains 5′ and 3′ UTRs, whose functions are related, respectively, to regulating translation and maintaining mRNA stability.

    “mRNA contains 5′ and 3′ UTRs, whose functions are related, respectively, to regulating translation and maintaining mRNA stability.131”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Zarghampoor, F., Azarpira, N., Khatami, S. R., Behzad-Behbahani, A. & Foroughmand, A. M. Improved translation efficiency of therapeutic mRNA. Gene 707, 231–238 (2019). source

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    Premisecitation

    The use of CleanCap® cap analogs reduces the probability of reverse capped, uncapped, and cap0 intermediates, and the co-transcribed mRNA only possesses a cap1 structure, therefore capping rate can be 90% or higher.

    “The use of CleanCap® cap analogs reduces the probability of reverse capped, uncapped, and cap0 intermediates, and the co-transcribed mRNA only possesses a cap1 structure, therefore capping rate can be 90% or higher.52,126”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Linares-Fernández, S., Lacroix, C., Exposito, J. Y. & Verrier, B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol. Med. 26, 311–323 (2019). source

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    • cites [126] Henderson, J. M. et al. Cap 1 messenger RNA synthesis with co-transcriptional CleanCap® analog by in vitro transcription. Curr. Protoc. 1, e39 (2021). source

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    Premisecitation

    An mRNA of cap 0 is likely to be recognized as exogenous RNA by the host, which could stimulate the innate immune response and trigger inflammatory responses.

    “however, an mRNA of cap 0 is likely to be recognized as exogenous RNA by the host, which could stimulate the innate immune response of the host and ultimately trigger inflammatory responses.117”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] To, K. K. & Cho, W. C. An overview of rational design of mRNA-based therapeutics and vaccines. Expert Opin. Drug Discov. 16, 1307–1317 (2021). source

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    Premisecitation

    The RNActive® platform designed by CureVac combines the use of co-delivered RNA and protamine (a polycationic peptide) complex as adjuvant, which has been shown to effectively trigger innate immune responses and enhance vaccine immunogenicity.

    “A vaccine platform (RNActive®) was designed by CureVac186 combining the use of co-delivered RNA and protamine (a polycationic peptide) complex as adjuvant, which has been shown to effectively trigger innate immune responses and enhance vaccine immunogenicity.186–189”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [186] Rauch, S., Lutz, J., Kowalczyk, A., Schlake, T. & Heidenreich, R. RNActive® technology: generation and testing of stable and immunogenic mRNA vaccines. Methods Mol. Biol. 1499, 89–107 (2017). source

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    • cites [187] Edwards, D. K. et al. Adjuvant effects of a sequence-engineered mRNA vaccine: translational profiling demonstrates similar human and murine innate response. J. Transl. Med 15, 1–18 (2017). source

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    • cites [188] Kallen, K.-J. et al. A novel, disruptive vaccination technology: self-adjuvanted RNActive® vaccines. Hum. Vaccine Immunother. 9, 2263–2276 (2013). source

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    • cites [189] Kowalczyk, A. et al. Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity. Vaccine 34, 3882–3893 (2016). source

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  • May combine two claims.

    Interpretationreasoning

    The full length of a saRNA sequence is usually above 9 kb, which might hinder cloning construction.

    “In addition, considering that the length of nsP1–4 sequence is approximately 7 kb, the full length of a saRNA sequence is usually above 9 kb, which might hinder cloning construction.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Two different saRNA vaccines developed independently by Arcturus Therapeutics and Imperial College London have shown favorable immune responses against SARS-CoV-2, and have entered clinical trials.

    “Recently, two different saRNA vaccines developed independently by Arcturus Therapeutics and Imperial College London have shown favorable immune responses against SARS-CoV-2, and have entered clinical trials.211–213”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [211] McKay, P. F. et al. Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat. Commun. 11, 1–7 (2020). source

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    • cites [212] Pollock, K. M. et al. Safety and Immunogenicity of a Self-Amplifying RNA Vaccine Against COVID-19: COVAC1, a Phase I, Dose-Ranging Trial. EClinicalMedicine, https://doi.org/10.1016/j.eclinm.2021.101262 (2022). source

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    • cites [213] de Alwis, R. et al. A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice. Mol. Ther. 29, 1970–1983 (2021). source

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    Premisecitation

    Adding modified nucleosides during IVT of mRNA can significantly reduce the host inflammatory response without affecting protein expression.

    “To avoid this, Karikó and colleagues found that adding modified nucleosides during IVT of mRNA can significantly reduce the host inflammatory response without affecting protein expression.81,159”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005). source

      Not checked in the free run.

    • cites [159] Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The segmented poly(A) tail extends mRNA half-life and improves translation efficiency compared to the long-chain poly(A) tail.

    “Current studies have shown that the segmented poly(A) tail extends mRNA half-life and improves translation efficiency compared to the long-chain poly(A) tail.154”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [154] Trepotec, Z., Geiger, J., Plank, C., Aneja, M. K. & Rudolph, C. Segmented poly(A) tails significantly reduce recombination of plasmid DNA without affecting mRNA translation efficiency or half-life. RNA 25, 507–518 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    saRNA vaccines have shortcomings including the risk of excessive activation of the inflammatory response, and the production of viral nsP produced by the alphavirus replicon that may interfere with normal signal transduction in target host cells.

    “saRNA vaccines have nonetheless certain shortcomings, including the risk of excessive activation of the inflammatory response, and the production of viral nsP produced by the alphavirus replicon that may interfere with normal signal transduction in target host cells.214,215”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [214] Maruggi, G., Zhang, C., Li, J., Ulmer, J. B. & Yu, D. mRNA as a transformative technology for vaccine development to control infectious diseases. Mol. Ther. 27, 757–772 (2019). source

      Not checked in the free run.

    • cites [215] Jensen, S. & Thomsen, A. R. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. J. Virol. 86, 2900–2910 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nucleoside-modified mRNA can reduce the activation of TLRs, retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2′-5′-oligoadenylate synthetase (OAS); additionally, nucleoside modification increases translation activity and resistance against RNase L-mediated degradation.

    “Nucleoside-modified mRNA can reduce the activation of TLRs, retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2′-5′-oligoadenylate synthetase (OAS). Additionally, nucleoside modification increases translation activity and resistance against RNase L-mediated degradation.54,81,173–176”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [54] Hornung, V. et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006). source

      Not checked in the free run.

    • cites [81] Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005). source

      Not checked in the free run.

    • cites [173] Andries, O. et al. N1-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J. Control. Rel. 217, 337–344 (2015). source

      Not checked in the free run.

    • cites [174] Anderson, B. R. et al. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res 38, 5884–5892 (2010). source

      Not checked in the free run.

    • cites [175] Anderson, B. R. et al. Nucleoside modifications in RNA limit activation of 2′-5′-oligoadenylate synthetase and increase resistance to cleavage by RNase L. Nucleic Acids Res 39, 9329–9338 (2011). source

      Not checked in the free run.

    • cites [176] Svitkin, Y. V. et al. N1-methyl-pseudouridine in mRNA enhances translation through eIF2α-dependent and independent mechanisms by increasing ribosome density. Nucleic Acids Res 45, 6023–6036 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Replacing original nucleosides with m6A and s2U inhibits activation of TLR3, whereas activation of TLR7 and TLR8 is blocked when using ψ, 5-methyluridine (m5U), m6A, and s2U, thereby inhibiting the innate immune responses and improving protein translation efficiency.

    “Studies have found that replacing original nucleosides with m6A and s2U inhibits activation of TLR3, whereas activation of TLR7 and TLR8 is blocked when using ψ, 5-methyluridine (m5U), m6A, and s2U, thereby inhibiting the innate immune responses and improving protein translation efficiency.81,159,171”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [81] Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005). source

      Not checked in the free run.

    • cites [159] Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008). source

      Not checked in the free run.

    • cites [171] Yan, K. et al. Toll-like receptor 3 and RIG-I-like receptor activation induces innate antiviral responses in mouse ovarian granulosa cells. Mol. Cell. Endocrinol. 372, 73–85 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kormann and colleagues replaced 25% of mRNA cytosine with m5C and 25% of uridine with s2U, which improved mRNA stability and increased protein translation in mice.

    “Kormann and colleagues152 replaced 25% of mRNA cytosine with m5C and 25% of uridine with s2U, which improved mRNA stability and increased protein translation in mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Kormann, M. S. et al. Expression of therapeutic proteins after deliveryof chemically modified mRNA in mice. Nat. Biotechnol. 29, 154–157 (2011). source

      Not checked in the free run.

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

    Premisenone given

    Both Moderna and BioNTech use pseudouridine modifications to ensure mRNA stability in their COVID-19 vaccine formulation.

    “Both Moderna and BioNTech use pseudouridine modifications to ensure mRNA stability in their COVID-19 vaccine formulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    dsRNA can activate PRR such as TLR3, whereas ssRNA activates TLR7 and TLR8 to produce IFN-I, thus inducing inflammation in the host and interrupting mRNA translation.

    “dsRNA can activate PRR such as TLR3,52,156 whereas ssRNA activates TLR7 and TLR8 to produce IFN-I, thus inducing inflammation in the host and interrupting mRNA translation.157,158”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [52] Linares-Fernández, S., Lacroix, C., Exposito, J. Y. & Verrier, B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol. Med. 26, 311–323 (2019). source

      Not checked in the free run.

    • cites [156] 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, e142–e142 (2011). source

      Not checked in the free run.

    • cites [157] Vaidyanathan, S. et al. Uridine depletion and chemical modification increase Cas9 mRNA activity and reduce immunogenicity without HPLC purification. Mol. Ther. Nucleic Acids 12, 530–542 (2018). source

      Not checked in the free run.

    • cites [158] Isaacs, A., Cox, R. & Rotem, Z. Foreign nucleic acids as the stimulus to make interferon. Lancet, 282, 113–116 (1963). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Li and colleagues developed an in vitro evolution strategy, and six mutations (A1979G, G3936C, A4311G, A4758G, G4796T, G4944A) were identified in the nsP2 and nsP3 of the VEEV replicon, which were shown to promote expression of subgenomic RNA in cells.

    “Li and colleagues developed an in vitro evolution strategy, and six mutations (namely A1979G, G3936C, A4311G, A4758G, G4796T, G4944A) were identified in the nsP2 and nsP3 of the VEEV replicon, which were shown to promote expression of subgenomic RNA in cells.210”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [210] Li, Y. et al. In vitro evolution of enhanced RNA replicons for immunotherapy. Sci. Rep. 9, 1–10 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Currently, nucleoside-modified mRNA vaccines employ 100% chemically modified nucleosides replacing natural nucleosides, and m1ψ is often used to replace uridine during IVT to improve the safety and stability of mRNA vaccines.

    “Currently, nucleoside-modified mRNA vaccines employ 100% chemically modified nucleosides replacing natural nucleosides, and m1ψ is often used to replace uridine during IVT to improve the safety and stability of mRNA vaccines.52,134,172”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [52] Linares-Fernández, S., Lacroix, C., Exposito, J. Y. & Verrier, B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol. Med. 26, 311–323 (2019). source

      Not checked in the free run.

    • cites [134] Nance, K. D. & Meier, J. L. Modifications in an emergency: the role of N1-Methylpseudouridine in COVID-19 vaccines. ACS Cent. Sci. 7, 748–756 (2021). source

      Not checked in the free run.

    • cites [172] Mauger, D. M., Cabral, B. J., Presnyak, V., Su, S. V. & Mcfadyen, I. J. mRNA structure regulates protein expression through changes in functional half-life. Proc. Natl Acad. Sci. USA 116, 201908052 (2019). source

      Not checked in the free run.

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

    Premisecitation

    The idea of using in vitro synthesized saRNA as a preventive vaccine was first proposed by Zhou and colleagues in 1994, using a modified Semliki Forest virus (SFV) replicon to express the nucleoprotein (NP) of the influenza virus.

    “The idea of using in vitro synthesized saRNA as a preventive vaccine was first proposed by Zhou and colleagues in 1994, using a modified Semliki Forest virus (SFV) replicon to express the nucleoprotein (NP) of the influenza virus.197”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Zhou, X. et al. Self-replicating Semliki Forest virus RNA as recombinant vaccine. Vaccine 12, 1510–1514 (1994). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Geall and colleagues were the first to use LNP to encapsulate a saRNA chimera composed of the Venezuelan equine encephalitis virus (VEEV) and Sindbis virus (SINV) replicons into a vaccine which was used to immunize mice, and immunogenicity was significantly improved compared with unencapsulated group.

    “Decades later, Geall and colleagues were the first to use LNP to encapsulate a saRNA chimera composed of the Venezuelan equine encephalitis virus (VEEV) and Sindbis virus (SINV) replicons into a vaccine which was used to immunize mice, and immunogenicity was significantly improved compared with unencapsulated group.199”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Geall, A. J. et al. Nonviral delivery of self-amplifying RNA vaccines. Proc. Natl Acad. Sci. USA 109, 14604–14609 (2012). source

      Not checked in the free run.

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

    Interpretationreasoning

    With its highly stable properties without nucleotide modification, circRNA can potentially become a novel platform for vaccine and drug development.

    “With its highly stable properties without nucleotide modification, circRNA can potentially become a novel platform for vaccine and drug development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Studies have found that the S protein prefusion conformation induces better immunogenicity and can be considered an ideal target antigen.

    “Studies have found that the S protein prefusion conformation induces better immunogenicity and can be therefore considered an ideal target antigen.237”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [237] Yadav, T. et al. Recombinant vaccines for COVID-19. Hum. Vaccin Immunother. 16, 2905–2912 (2020). source

      Not checked in the free run.

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

    Interpretationnone given

    CircRNA has emerged as an important new class of non-coding RNAs.

    “In summary, although considered a byproduct of the mRNA splicing process, circRNA has now emerged as an important new class of non-coding RNAs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Codon preference varies extensively in different organisms; adjusting the balance between codon usage frequency and host tRNA availability can significantly improve translation efficiency and in vivo expression of the target antigen.

    “Codon preference varies extensively in different organisms,249 therefore adjusting the balance between codon usage frequency and host tRNA availability can significantly improve translation efficiency and in vivo expression of the target antigen.250,251”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [249] Sharp, P. M. & Li, W. H. The codon Adaptation Index–a measure of directional synonymous codon usage bias, and its potential applications. Nucl. Acids Res 15, 1281–1295 (1987). source

      Not checked in the free run.

    • cites [250] Wu, Q. et al. Translation affects mRNA stability in a codon-dependent manner in human cells. elife 8, e45396 (2019). source

      Not checked in the free run.

    • cites [251] Gustafsson, C., Govindarajan, S. & Minshull, J. Codon bias and heterologous protein expression. Trends Biotechnol. 22, 346–353 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The S1 subunit comprises SP, RBD, NTD, CTD1, CTD2, and primarily interacts with ACE2 via RBD.

    “The S1 subunit comprises the signal peptide (SP), RBD, N-terminal domain (NTD), C-terminal domain 1 (CTD1), and C-terminal domain 2 (CTD2), and primarily interacts with the cellular angiotensin-converting enzyme 2 (ACE2) receptor via RBD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CircRNA prepared with sequences of Delta strains resulted in broad-spectrum protection and production of neutralizing antibodies against both Delta and Omicron.

    “the results revealed that circRNA prepared with sequences of Delta strains resulted in broad-spectrum protection and production of neutralizing antibodies against both Delta and Omicron.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [227] Qu, L. et al. Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants. BioRxiv, https://doi.org/10.1101/2021.03.16.435594 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The S2 subunit comprises FP, HR, CH, CD, TMD, CT, and is responsible for mediating fusion between virus and host cell membrane.

    “The S2 subunit comprises the fusion peptide (FP), double heptad repeat (HR), central helix region (CH), connector domain (CD), transmembrane domain (TMD), and cytoplasmic tail (CT), and the S2 subunit is responsible for mediating the fusion between the virus and the host cell membrane233–236”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [233] Wang, Q. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181, 894–904. e899 (2020). source

      Not checked in the free run.

    • cites [234] Shang, J. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221–224 (2020). source

      Not checked in the free run.

    • cites [235] Singh, S. P., Pritam, M., Pandey, B. & Yadav, T. P. Microstructure, pathophysiology and potential therapeutics of COVID-19: A comprehensive review. J. Med. Virol. 93, 275–299 (2020). source

      Not checked in the free run.

    • cites [236] Cai, Y. et al. Distinct conformational states of SARS-CoV-2 spike protein. Science 369, 1586–1592 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vaccines produced with circRNA prepared based on Omicron sequences provided a narrower protection, and produced neutralizing antibodies could protect only against Omicron but not against Delta.

    “However, vaccines produced with circRNA prepared based on Omicron sequences provided a narrower protection, and produced neutralizing antibodies could protect only against Omicron but not against Delta.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [227] Qu, L. et al. Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants. BioRxiv, https://doi.org/10.1101/2021.03.16.435594 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most neutralizing antibodies are molded based on epitopes of S protein in prefusion conformation, which is covered once the S protein acquires the postfusion conformation, thus reducing the production of neutralizing antibodies.

    “Most neutralizing antibodies are molded based on epitopes of S protein in prefusion conformation, which is covered once the S protein acquires the postfusion conformation, thus reducing the production of neutralizing antibodies.238”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [238] Walls, A. C. et al. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181 (2020). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    CircRNA is a highly stable single-stranded RNA with a covalently closed loop structure.

    “CircRNA is a highly stable single-stranded RNA with a covalently closed loop structure (Fig. 3), including a large category of non-coding RNAs generated by backsplicing in eukaryotic cells.218–220”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [218] Zhang, X.-O. et al. Complementary sequence-mediated exon circularization. Cell 159, 134–147 (2014). source

      Not checked in the free run.

    • cites [219] Kristensen, L. S. et al. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 20, 675–691 (2019). source

      Not checked in the free run.

    • cites [220] Chen, L.-L. The biogenesis and emerging roles of circular RNAs. Nat. Rev. Mol. Cell Biol. 17, 205–211 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The S1/S2 cleavage site strategy employs direct deletion of the sequence Q677TNSPRRARYSV687 to Q677TILRYSV683 or mutation of amino acids (RRAR to GGSG) that prevent S protein cleavage in the host cell, thus maintaining its structural stability and inducing stronger immune responses.

    “The S1/S2 cleavage site strategy employs direct deletion of the sequence Q677TNSPRRARYSV687 in wild-type SARS-CoV-2 protein S to Q677TILRYSV683238 or mutation of amino acids (RRAR to GGSG)141 that ultimately prevent the S protein from cleavage in the host cell, thus maintaining its structural stability and inducing stronger immune responses.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [238] Walls, A. C. et al. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181 (2020). source

      Not checked in the free run.

    • cites [141] Zhang, B. Vaccines and compositions based on S antigen protein of SARS-CoV-2. CN112480217A (2021).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After immunizing mice with the circRNA vaccine, long-lasting neutralizing antibodies and Th1-biased cellular immune responses were produced.

    “After immunizing mice with the obtained vaccine, long-lasting neutralizing antibodies and Th1-biased cellular immune responses were produced.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Qu, L. et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. BioRxiv, https://doi.org/10.1101/2021.03.16.435594 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Although the optimized chemical structure of PEI has higher gene transfection efficiency, it still induces strong cytotoxicity due to the high cationic charge density.

    “Although the optimized chemical structure of PEI has higher gene transfection efficiency, it still induces strong cytotoxicity due to the high cationic charge density.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The mRNA vaccine BNT111 developed by BioNTech's FixVac platform to treat advanced melanoma has entered phase II clinical trials and was assigned the FDA Fast Track designation on November 19, 2021.

    “The mRNA vaccine BNT111 developed by BioNTech’s FixVac platform to treat advanced melanoma has entered phase II clinical trials and was assigned the FDA Fast Track designation on November 19, 2021.349”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [349] BioNTech Receives FDA Fast Track Designation for its FixVac Candidate BNT111 in Advanced Melanoma, https://investors.biontech.de/news-releases/news-release-details/biontech-receives-fda-fast-track-designation-its-fixvac (2021).

      Not checked in the free run.

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

    Premisecitation

    Helper phospholipids are amphiphilic lipids that support the lipid bilayer structure, help promote fusion with endosomal membranes, and determine the specificity of target organs.

    “Helper phospholipids are amphiphilic lipids that support the lipid bilayer structure, help promote fusion with endosomal membranes, and determine the specificity of target organs.293,294”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [293] Cheng, X. & Lee, R. J. The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery. Adv. Drug Deliv. Rev. 99, 129–137 (2016). source

      Not checked in the free run.

    • cites [294] Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020). source

      Not checked in the free run.

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

    Premisenone given

    LNPs is a nano-scale vesicle which simulates the lipid structure of the cell membrane and can encapsulate mRNA in its cavity, being considered the most investigated mRNA vaccine delivery system.

    “LNPs is a nano-scale vesicle which simulates the lipid structure of the cell membrane and can encapsulate mRNA in its cavity, being considered the most investigated mRNA vaccine delivery system.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Moderna's mRNA personalized cancer vaccine mRNA-4157 is comprised of 34 unique neoantigen genes combined in a single mRNA vaccine; this vaccine was proven safe and tolerable in combination with pembrolizumab in phase I clinical trials.

    “Moderna’s mRNA personalized cancer vaccine mRNA-4157 is comprised of 34 unique neoantigen genes (encoded by tumor-specific mutated genes) combined in a single mRNA vaccine; this vaccine was proven safe and tolerable in combination with pembrolizumab in phase I clinical trials.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [355] Moderna Announces Clinical Updates on Personalized Cancer Vaccine Program, https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-clinical-updates-personalized-cancer-vaccine (2020).

      Not checked in the free run.

    • cites [356] Burris, H. A. et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. J. Clin. Oncol. 37, 2523 (2019). source

      Not checked in the free run.

    • cites [357] Bauman, J. et al. 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. J. Immunother. Cancer 8, A846–A846 (2020).

      Not checked in the free run.

    • cites [358] Burris, H. A. III et al. A phase 1, open-label, multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with pembrolizumab in subjects with unresectable solid tumors (Keynote-603). J. Clin. Oncol. 37, 2523–2523 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Yang and colleagues applied similar LPP technology to encapsulate mRNA in two steps using ionizable lipid, DOPE and PEG-lipid to generate COVID-19 mRNA vaccine with a core-shell structure, which showed significant protection in mice and non-human primates.

    “Yang and colleagues330 applied similar LPP technology to encapsulate mRNA in two steps using ionizable lipid, DOPE and PEG-lipid to generate COVID-19 mRNA vaccine with a core-shell structure, which showed significant protection in mice and non-human primates.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [330] Yang, R. et al. A core-shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity. Signal Transduct. Target. Ther. 6, 1–10 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The di-linoleic alkyl tail in DLin-MC3-DMA is prone to degradation, and repeated booster doses can potentially lead to cumulative toxicity.

    “However, it was later found that the di-linoleic alkyl tail in DLin-MC3-DMA is prone to degradation, and repeated booster doses can potentially lead to cumulative toxicity.289”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [289] Buschmann, M. D. et al. Nanomaterial delivery systems for mRNA vaccines. Vaccines 9, 65 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Moderna has developed an ionizable lipid (Lipid H, SM-102), whose tail adopts larger branches which increases potency, and whose introduced ester bonds increase biodegradability.

    “Based on these observations, Moderna has developed an ionizable lipid (namely Lipid H, SM-102), whose tail adopts larger branches which in turn increases potency, and whose introduced ester bonds increase biodegradability (Fig. 7).290,291”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [290] Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26, 1509–1519 (2018). source

      Not checked in the free run.

    • cites [291] Hassett, K. J. et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol. Ther. Nucleic Acids 15, 1–11 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ionizable lipids are neutral at physiological pH, thus making them safer and more stable for use as delivery systems in vaccines.

    “Ionizable lipids are neutral at physiological pH, thus making them safer and more stable for use as delivery systems in vaccines.285”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [285] Cullis, P. R. & Hope, M. J. Lipid nanoparticle systems for enabling gene therapies. Mol. Ther. 25, 1467–1475 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous studies have demonstrated that the use of BNT111 alone or in combination with PD-1 antibody can activate tumor antigen-specific CD4+ and CD8+ T cells and elicit durable immune responses.

    “Previous studies have demonstrated that the use of BNT111 alone or in combination with PD-1 antibody can activate tumor antigen-specific CD4+ and CD8+ T cells and elicit durable immune responses.345,350–352”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [345] Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020). source

      Not checked in the free run.

    • cites [350] Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 66, 1078–1094 (2021). source

      Not checked in the free run.

    • cites [351] Tay, B. Q. et al. Evolution of cancer vaccines—challenges, achievements, and future directions. Vaccines 9, 535 (2021). source

      Not checked in the free run.

    • cites [352] Jin, M.-Z. & Wang, X.-P. Immunogenic cell death-based cancer vaccines. Front. Immunol. 12, 697964 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The overall response rate (ORR) for the treatment of 10 cases of HPV-negative head and neck squamous cell carcinoma (HPV-HNSCC) with the mRNA-4157 vaccine was 50%, of which 2 cases achieved complete remission (CR).

    “Finally, the overall response rate (ORR) for the treatment of 10 cases of HPV-negative head and neck squamous cell carcinoma (HPV-HNSCC) with the mRNA-4157 vaccine was 50%, of which 2 cases achieved complete remission (CR).355–358”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [355] Moderna Announces Clinical Updates on Personalized Cancer Vaccine Program, https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-clinical-updates-personalized-cancer-vaccine (2020).

      Not checked in the free run.

    • cites [356] Burris, H. A. et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. J. Clin. Oncol. 37, 2523 (2019). source

      Not checked in the free run.

    • cites [357] Bauman, J. et al. 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. J. Immunother. Cancer 8, A846–A846 (2020).

      Not checked in the free run.

    • cites [358] Burris, H. A. III et al. A phase 1, open-label, multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with pembrolizumab in subjects with unresectable solid tumors (Keynote-603). J. Clin. Oncol. 37, 2523–2523 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LPPs have higher stability, low cytotoxicity, cell delivery and endosomal escape efficiency.

    “LPPs have higher stability, low cytotoxicity, cell delivery and endosomal escape efficiency.327–329”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [327] Rezaee, M., Oskuee, R. K., Nassirli, H. & Malaekeh-Nikouei, B. Progress in the development of lipopolyplexes as efficient non-viral gene delivery systems. J. Control. Rel. 236, 1–14 (2016). source

      Not checked in the free run.

    • cites [328] Guevara, M. L., Jilesen, Z., Stojdl, D. & Persano, S. Codelivery of mRNA with α-Galactosylceramide using a new lipopolyplex formulation induces a strong antitumor response upon intravenous administration. ACS Omega 4, 13015–13026 (2019). source

      Not checked in the free run.

    • cites [329] Kaczmarek, J. C. et al. Polymer–lipid nanoparticles for systemic delivery of mRNA to the lungs. Angew. Chem. Int Ed. Engl. 128, 14012–14016 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mRNA vaccines have shown good efficacy in the treatment of acute myelocytic leukemia (AML), non-small cell lung cancer (NSCLC), and melanoma.

    “mRNA vaccines have shown good efficacy in the treatment of acute myelocytic leukemia (AML),339–341 non-small cell lung cancer (NSCLC),342,343 and melanoma344–348 (Table 3).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [339] Van Tendeloo, V. F. et al. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination. Proc. Natl Acad. Sci. USA 107, 13824–13829 (2010). source

      Not checked in the free run.

    • cites [340] Anguille, S. et al. Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia. Blood 130, 1713–1721 (2017). source

      Not checked in the free run.

    • cites [341] Khoury, H. J. et al. Immune responses and long-term disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia. Cancer 123, 3061–3072 (2017). source

      Not checked in the free run.

    • cites [342] Sebastian, M. et al. Messenger RNA vaccination and B-cell responses in NSCLC patients. J. Clin. Oncol. 30, 2573–2573 (2012). source

      Not checked in the free run.

    • cites [343] Sebastian, M. et al. A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer. Cancer Immunol. Immunother. 68, 799–812 (2019). source

      Not checked in the free run.

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

    Premisenone given

    LNPs are composed of four components: ionizable lipids, helper phospholipids, cholesterol, and PEGylated lipids, among which ionizable lipids are considered the key components.

    “LNPs are composed of four components: ionizable lipids, helper phospholipids, cholesterol, and PEGylated lipids, among which, ionizable lipids are considered the key components.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Specific immune responses against at least one antigen were detected in 63% of patients after treatment, and the frequency of activated IgD+ CD38hi B cells increased by more than two-fold in 60% of evaluated patients.

    “Specific immune responses against at least one antigen were detected in 63% of patients after treatment, and the frequency of activated IgD+ CD38hi B cells increased by more than two-fold in 60% of evaluated patients.343,353,354”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [343] Sebastian, M. et al. A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer. Cancer Immunol. Immunother. 68, 799–812 (2019). source

      Not checked in the free run.

    • cites [353] Tang, X. et al. Therapeutic prospects of mRNA-based gene therapy for glioblastoma. Front. Oncol. 9, 1208 (2019). source

      Not checked in the free run.

    • cites [354] Jarzebska, N. T., Mellett, M., Frei, J., Kuendig, T. M. & Pascolo, S. Protamine for RNA transfection: from heparin antagonist to RNA delivery. Pharmaceutics 13, 877 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In LNPs formulations, cholesterol increases stability by filling gaps among LNPs molecules and aiding fusion with endosomal membranes, thereby promoting uptake of the vaccine complex.

    “In LNPs formulations, cholesterol increases stability by filling gaps among LNPs molecules and aiding fusion with endosomal membranes, thereby promoting uptake of the vaccine complex.302”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [302] Yang, S.-T., Kreutzberger, A. J., Lee, J., Kiessling, V. & Tamm, L. K. The role of cholesterol in membrane fusion. Chem. Phys. Lipids 199, 136–143 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Moreover, this LPP-based mRNA vaccine exhibited intrinsic adjuvant activity, which stimulates dendritic cells (DCs) to secrete cytokines and inhibit tumor growth by activating the TLR7/8 signaling pathway, resulting in a significant antitumor activity.

    “Moreover, this LPP-based mRNA vaccine exhibited intrinsic adjuvant activity, which stimulates dendritic cells (DCs) to secrete cytokines and inhibit tumor growth by activating the TLR7/8 signaling pathway, resulting in a significant antitumor activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [326] Persano, S. et al. Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination. Biomaterials 125, 81–89 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The efficacy of BNT162b2 at preventing COVID-19 infection in individuals aged 16 was 95%, and over the six subsequent months, vaccine efficacy was 91.3%.

    “The efficacy of the vaccine at preventing COVID-19 infection in individuals aged 16 was 95%, and over the six subsequent months, vaccine efficacy was 91.3%.385–387”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [385] Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). source

      Not checked in the free run.

    • cites [386] Thomas, S. J. et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months. N. Engl. J. Med., NEJMoa2110345, https://doi.org/10.1056/NEJMoa2110345 (2021). source

      Not checked in the free run.

    • cites [387] Tober-Lau, P. et al. Long-term immunogenicity of BNT162b2 vaccination in the elderly and in younger health care workers. medRxiv, https://doi.org/10.1101/2021.08.26.21262468 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    On September 22, 2021, the FDA approved the BNT162b2 vaccine for administration in high-risk populations as a booster, then expanded eligibility on November 19, 2021 as a single booster of both BNT162b2 and mRNA-1273 to individuals aged 18 and older after completion of the primary vaccination scheme with any FDA-authorized or previously approved COVID-19 vaccine.

    “On September 22, 2021, the FDA approved the BNT162b2 vaccine for administration in high-risk populations as a booster,395 then expanded eligibility on November 19, 2021 as a single booster of both BNT162b2 and mRNA-1273 to individuals aged 18 and older after completion of the primary vaccination scheme with any FDA-authorized or previously approved COVID-19 vaccine.396”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [395] FDA. FDA Authorizes Booster Dose of Pfizer-BioNTech COVID-19 Vaccine for Certain Populations, https://www.fda.gov/news-events/press-announcements/fda-authorizes-booster-dose-pfizer-biontech-covid-19-vaccine-certain-populations (2021).

      Not checked in the free run.

    • cites [396] FDA. Coronavirus (COVID-19) Update: FDA Expands Eligibility for COVID-19 Vaccine Boosters, https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-expands-eligibility-covid-19-vaccine-boosters (2021).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The BNT162b2 mRNA vaccine was added to the WHO Emergency Use Listing on December 31, 2020, and approved on May 10 and May 28, 2021 by the US government and the European Union, respectively, for administration in adolescents aged 12 to 15.

    “The BNT162b2 mRNA vaccine was then added to the WHO Emergency Use Listing (EUL) on December 31, 2020,383 and approved on May 10 and May 28, 2021 by the US government and the European Union, respectively, for administration in adolescents aged 12 to 15.384”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [383] World Health Organisation. WHO issues its first emergency use validation for a COVID-19 vaccine and emphasizes need for equitable global access, https://www.who.int/news/item/31-12-2020-who-issues-its-first-emergency-use-validation-for-a-covid-19-vaccine-and-emphasizes-need-for-equitable-global-access (2020).

      Not checked in the free run.

    • cites [384] Coronavirus (COVID-19) Update: FDA Authorizes Pfizer-BioNTech COVID-19 Vaccine for Emergency Use in Adolescents in Another Important Action in Fight Against Pandemic, https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-pfizer-biontech-covid-19-vaccine-emergency-use (2021).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The incidence of anaphylaxis after BNT162b2 vaccination in Japan was higher, pointing towards considering race-related adverse effects.

    “indicated that the incidence of anaphylaxis after BNT162b2 vaccination in Japan was higher, which points towards considering race-related adverse effects401 whose underlying causes are still unknown.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [401] Hashimoto, T. et al. High anaphylaxis rates following vaccination with the Pfizer BNT162b2 mRNA vaccine against COVID-19 in Japanese healthcare workers: a secondary analysis of initial post-approval safety data. J. Travel Med. 28, taab090 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Real-world data from Qatar indicated that the BNT162b2 vaccine had 51.9% effectiveness against the Delta variant, significantly lower than 75.0% against Beta and 89.5% against Alpha.

    “Real-world data from Qatar indicated that the BNT162b2 vaccine had only 51.9% effectiveness against the Delta variant, which was significantly lower compared to 75.0% and 89.5% effectiveness conferred by the vaccine against Beta and Alpha variants, respectively.102”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Tang, P. et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar. Nat. Med. 27, 2136–2143 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The protective effect of BNT162b2 against SARS-CoV-2 infection peaks after the second dose and then quickly declines, with the humoral immune response sharply decreasing.

    “Studies have shown that the protective effect of BNT162b2 against SARS-CoV-2 infection peaks after the second dose and then quickly declines, with the humoral immune response sharply decreasing.388–391”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [388] Chemaitelly, H. et al. Waning of BNT162b2 vaccine protection against SARS-CoV-2 infection in Qatar. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2114114 (2021). source

      Not checked in the free run.

    • cites [389] Levin, E. G. et al. Waning Immune humoral response to BNT162b2 Covid-19 vaccine over 6 months. N. Engl. J. Med. 385, e84 (2021). source

      Not checked in the free run.

    • cites [390] Moustsen-Helms, I. R. et al. Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 Vaccine in long-term care facility residents and healthcare workers–a Danish cohort study. MedRxiv, https://doi.org/10.1101/2021.03.08.21252200 (2021). source

      Not checked in the free run.

    • cites [391] Levine-Tiefenbrun, M. et al. Viral loads of Delta-variant SARS-CoV2 breakthrough infections following vaccination and booster with the BNT162b2 vaccine. medRxiv, https://doi.org/10.1101/2021.08.29.21262798 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BioNTech/Pfizer proceeded with BNT162b2 in global phase II/III clinical trials on July 27, 2020, and it received EUA by the US government on December 11, 2020, and European Union conditional marketing authorization on December 21, 2020.

    “BioNTech/Pfizer proceeded with BNT162b2 in global phase II/III clinical trials on July 27, 2020, which received EUA by the US government on December 11, 2020379,380 as well as the European Union conditional marketing authorization (CMA) on December 21, 2020.381,382”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [379] Lamb, Y. N. BNT162b2 mRNA COVID-19 Vaccine: First Approval. Drugs 81, 495-501, https://doi.org/10.1007/s40265-021-01480-7 source

      Not checked in the free run.

    • cites [380] FDA takes key action in fight against COVID-19 by issuing emergency use authorization for first COVID-19 Vaccine, https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19 (2020).

      Not checked in the free run.

    • cites [381] Pfizer and BioNTech receive authorization in the European Union for COVID-19 vaccine, https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-receive-authorization-european-union (2020).

      Not checked in the free run.

    • cites [382] Cavaleri, M., Enzmann, H., Straus, S. & Cooke, E. The European Medicines Agency’s EU conditional marketing authorisations for COVID-19 vaccines. Lancet. (2021). source

      Not checked in the free run.

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

    Premisecitation

    The FDA granted BNT162b2 emergency approval for use in children and adolescents aged 5 to 11 on October 29, 2021.

    “The FDA granted BNT162b2 emergency approval for use in children and adolescents aged 5 to 11 on October 29, 2021.103,106”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [103] Walter, E. B. et al. Evaluation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years of age. N. Engl. J. Med 386, 35–46 (2021). source

      Not checked in the free run.

    • cites [106] FDA Authorizes Pfizer-BioNTech COVID-19 Vaccine for Emergency Use in Children 5 through 11 Years of Age, https://www.fda.gov/news-events/press-announcements/fda-authorizes-pfizer-biontech-covid-19-vaccine-emergency-use-children-5-through-11-years-age (2021). source

      Not checked in the free run.

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

    Premisecitation

    The US FDA officially authorized BNT162b2 for vaccination of individuals aged 16 and older on August 23, 2021.

    “The US FDA officially authorized BNT162b2 for vaccination of individuals aged 16 and older on August 23, 2021.105”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] FDA Approves First COVID-19 Vaccine | FDA, https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine (2021).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mRNA-1440 vaccine against H10N8 and the mRNA-1851 vaccine against H7N9 influenza viruses were well tolerated and elicited robust humoral immune responses when tested separately.

    “Current clinical trials showed that the mRNA-1440 vaccine against H10N8 and the mRNA-1851 vaccine against H7N9 influenza viruses were well tolerated and elicited robust humoral immune responses when tested separately (Table 4).360”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [360] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Six months after two mRNA-1273 injections, booster with 50 μg mRNA-1273, mRNA-1273.211, or mRNA-1273.351 induced neutralization against Beta, Gamma, and Delta comparable to wild-type D614G.

    “The neutralization effect of the booster in each immunization group against SARS-CoV-2 variants Beta, Gamma and Delta reached a level comparable to that observed against the wild-type D614G strain.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [415] Choi, A. et al. Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis. Nat. Med., https://doi.org/10.1038/s41591-021-01527-y (2021). source

      Not checked in the free run.

    • cites [416] Wu, K. et al. Preliminary analysis of safety and immunogenicity of a SARS-CoV-2 variant vaccine booster. Medrxiv, https://doi.org/10.1101/2021.05.05.21256716 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ARCoV is reportedly safe and well-tolerated at 15 μg, and induced high titers of neutralizing antibodies approximately two-fold higher than those of patients who had recovered from COVID-19 infection.

    “ARCoV is reportedly safe and well-tolerated at an amount of 15 μg, which induced high titers of neutralizing antibodies titers (approximately two-fold higher that those of patients which had recovered from COVID-19 infection).439”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [438] A Phase III Clinical Study of a SARS-CoV-2 Messenger Ribonucleic Acid (mRNA) vaccine candidate against COVID-19 in population aged 18 years and above, https://clinicaltrials.gov/ct2/show/NCT04847102 (2021).

      Not checked in the free run.

    • cites [439] Chen, G.-L. et al. Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Microbe., https://doi.org/10.1016/s2666-5247(21)00280-9 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical trials showed MRT5500 induced a Th1-biased immune response in mice and non-human primates and prevented Th2-bias response which can induce vaccine-related enhanced respiratory disease (VAERD).

    “Results of preclinical trials showed that MRT5500 induced a Th1-biased immune response in mice and non-human primates and prevented Th2-bias response which can induce vaccine-related enhanced respiratory disease (VAERD).433–435”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [433] Graham, B. S. Rapid COVID-19 vaccine development. Science 368, 945–946 (2020). source

      Not checked in the free run.

    • cites [434] Kalnin, K. V. et al. Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models. npj Vaccines 6, 61 (2021). source

      Not checked in the free run.

    • cites [435] Kalnin, K. V. et al. Immunogenicity of novel mRNA COVID-19 vaccine MRT5500 in mice and non-human primates. BioRxiv, https://doi.org/10.1101/2020.10.14.337535 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Real-world data showed mRNA-1273 effectiveness against Alpha was 100%, against Beta 96.4%, and against Delta 73.1%.

    “Real-world data showed that effectiveness of mRNA-1273 against Alpha and Beta variants was 100% and 96.4%, respectively,417,418 whereas effectiveness against Delta was slightly lower (73.1%).102”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [417] Chemaitelly, H. et al. mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar. Nat. Med. 27, 1614–1621 (2021). source

      Not checked in the free run.

    • cites [418] Günl, F. et al. Shooting at a moving target—effectiveness and emerging challenges for SARS-CoV-2 vaccine development. Vaccines 9, 1052 (2021). source

      Not checked in the free run.

    • cites [102] Tang, P. et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar. Nat. Med. 27, 2136–2143 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    No serious safety concerns have been identified for mRNA-1273 so far, and most adverse events were mild or moderate.

    “No serious safety concerns have been identified so far, and most adverse events were mild or moderate”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [410] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). source

      Not checked in the free run.

    • cites [411] Moderna announces TeenCOVE study of its COVID-19 vaccine in adolescents meets primary endpoint and plans to submit data to regulators in early June, https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-teencove-study-its-covid-19-vaccine (2021).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of three doses of mRNA-1273 provided high and durable protection against Delta infection (95.2%) but lower protection against Omicron (62.5%).

    “administration of three doses of mRNA-1273 provided a high and durable protection against Delta infection (95.2%) but lower protection against Omicron (62.5%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [421] Tseng, H. F. et al. Effectiveness of mRNA-1273 against SARS-CoV-2 omicron and delta variants. medRxiv, 2022.2001.2007.22268919, https://doi.org/10.1101/2022.01.07.22268919 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In preclinical trials, CVnCoV induced high levels of neutralizing antibodies in rodents and non-human primates, outbalancing immune responses mediated by CD4+ and CD8+ T cells, and showed better efficacy against SARS-CoV-2 D614G variant.

    “In previously preclinical trials, CVnCoV was shown to induce high levels of neutralizing antibodies in rodents and non-human primates, outbalancing immune responses mediated by CD4+ and CD8+ T cells as well as showing better efficacy against SARS-CoV-2 D614G variant.426”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [426] Rauch, S. et al. mRNA-based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus-neutralising antibodies and mediates protection in rodents. npj Vaccines 6, 57 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phase I clinical data showed CVnCoV has acceptable tolerance and high immunogenicity.

    “Phase I clinical data showed that CVnCoV has acceptable tolerance and high immunogenicity.29,427”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Kremsner, P. G. et al. Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2: A phase 1 randomized clinical trial. Wien. Klin. Wochenschr. 133, 931–941 (2021). source

      Not checked in the free run.

    • cites [427] Gebre, M. et al. Optimization of non-coding regions improves protective efficacy of an mRNA SARS-CoV-2 vaccine in nonhuman primates. BioRxiv, https://doi.org/10.1101/2021.08.13.456316 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In phase II clinical trials, 228 COVID-19 cases were reported, 204 were sampled for whole-genome sequencing, only 3% had wild-type SARS-CoV-2, and 14 variants were identified in the remaining patients.

    “In phase II clinical trials, 228 COVID-19 cases were reported, from which 204 have been sampled for whole-genome sequencing, which showed that only 3% of the patients had been infected by wild-type SARS-CoV-2, whereas 14 variants have been identified in the remaining patients.425”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [425] Kremsner, P. G. et al. Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial. Lancet Infect. Dis., https://doi.org/10.1016/s1473-3099(21)00677-0 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preliminary results from phase IIb/III clinical trials showed overall efficacy of CVnCoV was 48.2%, which failed to meet prespecified success criteria.

    “Preliminary results from phase IIb/III clinical trials showed that the overall efficacy of the vaccine was 48.2% (Table 5), which failed to meet prespecified success criteria.425”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [425] Kremsner, P. G. et al. Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial. Lancet Infect. Dis., https://doi.org/10.1016/s1473-3099(21)00677-0 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Abnormal transcription products can activate the host innate immune response, thereby causing inflammation and reducing the translation efficiency of delivered mRNA.

    “Abnormal transcription products can activate the host innate immune response, thereby causing inflammation and reducing the translation efficiency of delivered mRNA.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    After over 30 years of research, mRNA vaccines have become a promising technology platform for vaccine development.

    “After over 30 years of research, mRNA vaccines have become a promising technology platform for vaccine development.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Purified mRNA is not suitable for clinical use unless it is protected by a delivery formulation.

    “Purified mRNA is not suitable for clinical use unless it is protected by a delivery formulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Compared with traditional production methods for inactivated, subunit, or viral vector vaccines, mRNA vaccine technology avoids complicated and time-consuming production steps, while also reducing the risk of contamination from cell sources.

    “Compared with the traditional production methods for inactivated, subunit, or viral vector vaccines, mRNA vaccine technology avoids complicated and time-consuming production steps, while also reducing the risk of contamination from cell sources.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Phase I/II clinical trials of ARCT-021 indicated production of robust anti-spike specific antibodies when 5.0-7.5 μg was administered per dose group, but it failed to reach 100% seroconversion rate.

    “the results of phase I/II clinical trials of the saRNA vaccine ARCT-021 developed by Arcturus Therapeutics indicated the production of robust anti-spike specific antibodies when 5.0–7.5 μg was administered per dose group, but it also failed to reach 100% seroconversion rate.441,442”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [441] Arcturus therapeutics announces positive interim ARCT-021 (LUNAR-COV19) Phase 1/2 study results for both single shot and prime-boost regimens, and up to $220 million in additional financial commitments from Singapore | Arcturus Therapeutics, Inc, https://ir.arcturusrx.com/news-releases/news-release-details/arcturus-therapeutics-announces-positive-interim-arct-021-lunar (2020).

      Not checked in the free run.

    • cites [442] Low, J. G. et al. A phase 1/2 randomized, double-blinded, placebo controlled ascending dose trial to assess the safety, tolerability and immunogenicity of ARCT-021 in healthy adults. medRxiv, https://doi.org/10.1101/2021.07.01.21259831 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    mRNA is highly susceptible to degradation by ubiquitous RNases, therefore ultra-low temperature storage is recommended to limit RNase activity whilst ensuring mRNA stability effectively.

    “Studies showed that mRNA is highly susceptible to degradation by the ubiquitous RNases, therefore ultra-low temperature storage is recommended to limit RNase activity whilst ensuring mRNA stability effectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Proper mRNA capping plays a critical role in mRNA transcription and translation efficiency, as well as in reducing inflammation response.

    “Proper mRNA capping plays a critical role in mRNA transcription and translation efficiency, as well as in reducing inflammation response.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Most advanced mRNA vaccines employ LNPs as delivery systems.

    “Most advanced mRNA vaccines employ LNPs as delivery systems.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The safety and protection conferred by current mRNA vaccines are satisfactory.

    “We believe that the safety and protection conferred by current mRNA vaccines are satisfactory, but their long-term protection will only be determined after additional clinical studies are performed.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Prior to the emergence of COVID-19, mRNA technology was mostly used for developing novel cancer therapeutic drugs showing promising results.

    “Prior to the emergence of COVID-19, mRNA technology was mostly used for developing novel cancer therapeutic drugs showing promising results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Determining mRNA capping efficiency is critical for quality control of mRNA vaccines, which is usually determined by liquid chromatography and mass spectrometry (LC-MS).

    “As a result, determining mRNA capping efficiency is critical for quality control of mRNA vaccines, which is usually determined by liquid chromatography and mass spectrometry (LC-MS).467”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [467] Beverly, M., Dell, A., Parmar, P. & Houghton, L. Label-free analysis of mRNA capping efficiency using RNase H probes and LC-MS. Anal. Bioanal. Chem. 408, 5021–5030 (2016). source

      Not checked in the free run.

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

    Interpretationnone given

    At the moment, COVID-19 mRNA vaccines are playing a key role in limiting the spread of the current pandemic.

    “At the moment, COVID-19 mRNA vaccines are playing a key role in limiting the spread of the current pandemic.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Delivery of mRNA has evolved from its naked form to LNP-based delivery.

    “Moreover, delivery of mRNA has evolved from its naked form to LNP-based delivery.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    mRNA vaccines, unlike traditional vaccines, may enable adjustment of antigen design and even allow combining sequences from several variants to respond to new mutations in the virus genome.

    “mRNA vaccines, unlike traditional vaccines, may enable adjustment of antigen design and even allow combining sequences from several variants to respond to new mutations in the virus genome.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Safety, efficacy, and quality control of vaccine production are determined by measuring critical process parameters (CPPs) and intermediate critical quality attributes (IQAs).

    “Safety, efficacy, and quality control of vaccine production are determined by measuring critical process parameters (CPPs) and intermediate critical quality attributes (IQAs).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Freeze-drying for mRNA vaccine conservation was shown to effectively reduce storage requirements and is considered a promising technique to improve mRNA vaccine stability.

    “A more recent storage approach involves employing freeze-drying to mRNA vaccine conservation, which was shown to effectively reduce storage requirements, being thus considered a promising technique to improve mRNA vaccine stability.472,473”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [472] Stitz, L. et al. A thermostable messenger RNA based vaccine against rabies. PLoS Negl. Trop. Dis. 11, e0006108 (2017). source

      Not checked in the free run.

    • cites [473] Studies to address new formulations, https://www.pfizer.com/science/coronavirus/vaccine/studies-address-new-formulations (2022).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LNP-nCoVsaRNA showed seroconversion rate from 8% to 61% by ELISA when 0.1-10.0 μg was administered per dose group, and demonstrated inferior immunogenicity in humans compared to mice.

    “the saRNA vaccine LNP-nCoVsaRNA developed by the Imperial College London showed seroconversion rate from 8% to 61% as determined by ELISA when 0.1–10.0 μg was administered per dose group, demonstrated inferior immunogenicity in humans compared to that observed in mice.212”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [212] Pollock, K. M. et al. Safety and Immunogenicity of a Self-Amplifying RNA Vaccine Against COVID-19: COVAC1, a Phase I, Dose-Ranging Trial. EClinicalMedicine, https://doi.org/10.1016/j.eclinm.2021.101262 (2022). source

      Not checked in the free run.

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

    Premisereasoning

    The COVID-19 pandemic has fostered the growth of mRNA vaccine platforms as a means to prevent and treat several infectious diseases, and a new generation of vaccines has progressively reached the public and gained increasing attention.

    “The COVID-19 pandemic has fostered the growth of mRNA vaccine platforms as a means to prevent and treat several infectious diseases, and a new generation of vaccines has progressively reached the public and gained increasing attention.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Production of mRNA vaccines does not require culturing cells or viruses as in traditional vaccine production, relying instead on in vitro synthesis; therefore the production cycle is shorter and easy to scale up, offering quick industrialization.

    “Production of mRNA vaccines does not require culturing cells or viruses as in traditional vaccine production technology, relying instead on in vitro synthesis technology. Therefore, the production cycle is shorter and easy to scale up, hence offering the possibility of quick industrialization of vaccine production.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The entire production cycle for an mRNA vaccine from IVT of mRNA to preparation of mRNA-LNP complexes might last approximately 10 days, and including qualification and release, the product can be available on the market within 40 days.

  • May combine two claims.

    Premisecitation

    Storage conditions and stability vary among vaccine manufacturers: mRNA-1273 maintains effectiveness for six months at −20 °C; BNT162b2 for six months at −60 to −80 °C; CVnCoV can be stored at −60 °C for three months.

    “For instance, the mRNA-1273 vaccine from Moderna maintains its effectiveness for six months at −20 °C, whereas the effectiveness of the BNT162b2 vaccine from BioNTech is maintained for six months when stored at −60 to −80 °C. Conversely, the CVnCoV vaccine from CureVac can be stored at −60 °C for three months.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [469] Uddin, M. N. & Roni, M. A. Challenges of storage and stability of mRNA-Based COVID-19 vaccines. Vaccines 9, https://doi.org/10.3390/vaccines9091033 (2021). source

      Not checked in the free run.

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

    Interpretationnone given

    The long-term protection of current mRNA vaccines will only be determined after additional clinical studies are performed.

    “We believe that the safety and protection conferred by current mRNA vaccines are satisfactory, but their long-term protection will only be determined after additional clinical studies are performed.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The requirement for storage at ultra-low temperature conditions might represent a challenge in transportation and storage of mRNA vaccines.

    “However, the requirement for storage at ultra-low temperature conditions might represent a challenge in transportation and storage of mRNA vaccines.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Due to its advantages, such as a quick development cycle, no requirement for cell culture, and high immunogenicity, an mRNA vaccine has become the world's first COVID-19 vaccine authorized by the FDA.

    “Due to its advantages, such as a quick development cycle, no requirement for cell culture, and high immunogenicity, an mRNA vaccine has become the world’s first COVID-19 vaccine authorized by the FDA.”
    Quote in the paperNot a substantial claim
110 of 110

  • The paper relies on this without support.

    Vaccination is the most effective and economical intervention for controlling the spread of epidemics and saving lives.

    “Vaccination is the most effective and economical intervention for controlling the spread of epidemics, and consequently saving lives and protecting the health of the population.”

  • The paper relies on this without support.

    Currently, no specific drug has been identified for COVID-19 prevention or treatment.

    “Currently, no specific drug has been identified for COVID-19 prevention or treatment, and vaccination is the most economical and effective intervention to limit the spread of SARS-CoV-2.”

  • The paper relies on this without support.

    mRNA is a negatively charged and unstable molecule.

    “Since mRNA is a negatively charged and unstable molecule, it is generally encapsulated in a delivery vehicle in order to enter the target cell.”

  • The paper relies on this without support.

    Among 37 people who presented anaphylaxis after BNT162b2 vaccination, 57% had a history of allergy and four had a history of cosmetic allergy.

    “This is related to the fact 57% of the 37 people who presented anaphylaxis had a history of allergy, and four had a history of cosmetic allergy, suggesting a potential role for PEG in inducing anaphylaxis.”

  • The paper relies on this without support.

    The entire production cycle for an mRNA vaccine from IVT of mRNA to preparation of mRNA-LNP complexes might last approximately 10 days, and including qualification and release, the product can be available on the market within 40 days.

    “From IVT of mRNA to preparation of mRNA-LNP complexes, the entire production cycle for an mRNA vaccine might last approximately 10 days. Considering also the time required for qualification and release, the product can be available on the market within 40 days.”

  • The paper relies on this without support.

    mRNA vaccine technology is broadly compatible with any mRNA sequences and virtually all vaccines based on proteins can be produced using this technology.

    “As a technology platform, mRNA vaccine technology is broadly compatible with any mRNA sequences and virtually all vaccines based on proteins can be produced using this technology.”

  • The paper relies on this without support.

    mRNA is highly susceptible to degradation by ubiquitous RNases.

    “Studies showed that mRNA is highly susceptible to degradation by the ubiquitous RNases, therefore ultra-low temperature storage is recommended to limit RNase activity whilst ensuring mRNA stability effectively.”
7 of 7

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 [3]

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.

  • ARCoV is classified as both nucleoside-modified and unmodified

    Major

    The text lists ARCoV among vaccines with unmodified nucleosides, but Table 2 marks its nucleotide modification as positive.

  • Two different Qatar estimates are given for Moderna effectiveness against Beta

    Minor

    Table 5 gives 95.7% effectiveness against the Beta-lineage variant in Qatar, while the text gives 96.4% for the same vaccine, variant and setting.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 9

  1. Qu, L. et al. Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants. BioRxiv, https://doi.org/10.1101/2021.03.16.435594 (2022). · DOI · Paper page
  2. Zhang, H. et al. Lineardesign: Efficient algorithms for optimized mrna sequence design. arXiv preprint arXiv:2004.10177, https://arxiv.org/abs/2004.10177 (2021). · arXiv
  3. Walsh, E. E. et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N. Engl. J. Med 383, 2439–2450 (2020). · DOI · Paper page
  4. Burris, H. A. III et al. A phase 1, open-label, multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with pembrolizumab in subjects with unresectable solid tumors (Keynote-603). J. Clin. Oncol. 37, 2523–2523 (2019). · DOI · Paper page
  5. Mulligan, M. J. et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 586, 589–593 (2020). · DOI · Paper page
  6. Pfizer and BioNTech receive authorization in the European Union for COVID-19 vaccine, https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-receive-authorization-european-union (2020).
  7. Pfizer. Pfizer and BioNTech announce Phase 3 trial data showing high efficacy of a booster dose of their COVID-19 vaccine, https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-phase-3-trial-data-showing (2021).
  8. Sanofi to focus its COVID-19 development efforts on the recombinant vaccine candidate, https://www.sanofi.com/en/media-room/press-releases/2021/2021-09-28-18-44-47-2304800 (2021).
  9. Sanofi announces positive Phase 1/2 study interim results for its first mRNA-based vaccine candidate, https://www.sanofi.com/en/media-room/press-releases/2021/2021-09-28-08-00-00-2304069 (2021).

Cited by

Sorted by citations

Related

Authors
Fang, E., Liu, X., Li, M., Zhang, Z., Song, L., Zhu, B., Wu, X., Liu, J., Zhao, D., & Li, Y.
Affiliations
  • National Institutes for Food and Drug Control (CN)
  • Texas A&M University (US)
Corresponding author
Li, Yuhua
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-03-23
Volume
7
Issue
1
Pages
94-94
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-022-00950-y
PMC
PMC8940982
OpenAlex
W4220852564
Cited by
601
References
416
Citations by year
2026: 81 · 2025: 158 · 2024: 186 · 2023: 134 · 2022: 42
FWCI
20.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
Keywords
COVID-19 pandemic, SARS-CoV-2, mRNA vaccines, vaccine development, antigen design, mRNA delivery systems, vaccine quality control, clinical trials, real-world data, mRNA technology, prophylactic vaccines
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, Humans, RNA, Messenger, Vaccines, Synthetic, 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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