The DOI matches its Crossref record; 217 of the 218 references it cites were found in a registry or an index; none of the 187 sources its claims cite is checked for support yet.
Three decades of messenger RNA vaccine development
Open accessAbstract
Abstract In the early nineties, pioneering steps were taken in the use of mRNA as a therapeutic tool for vaccination. In the following decades, an improved understanding of the mRNA pharmacology, together with novel insights in immunology have positioned mRNA-based technologies as next-generation vaccines. This review outlines the history and current state-of-the-art in mRNA vaccination, while presenting an immunological view on mRNA vaccine development. As such, we highlight the challenges in vaccine design, testing and administration, key considerations in the design of mRNA-based vaccines and new opportunities that arise when packaging mRNA in nanoparticulate vaccines. Finally, we discuss the mRNA self-adjuvant effect as a critical, but dichotomous parameter that determines the safety, efficacy and strength of the evoked immune response.
Overview
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Written from the paper’s full text.
TL;DR
This narrative review traces three decades of mRNA vaccine development, from early liposomal and naked mRNA expression studies to lipid-nanoparticle-formulated clinical candidates. It argues that the central challenge is balancing mRNA translation capacity against the mRNA self-adjuvant type I IFN response to achieve safe and effective immunity.
Key findings
- Early work showed mRNA could be delivered in vivo: liposomal mRNA transfected eukaryotic cells, and intramuscular naked mRNA produced encoded protein for a couple of days; mRNA encoding influenza nucleoprotein elicited virus-specific CTLs, and mRNA encoding carcinoembryonic antigen induced anti-tumoral antibody responses.
- mRNA is intrinsically immunostimulatory via endosomal TLR3/7/8 and cytosolic RIG-I/MDA5, inducing type I IFN and pro-inflammatory cytokines; this self-adjuvant effect supports DC maturation and T cell activation but also inhibits mRNA translation and antigen expression.
- Nucleoside-modified mRNA improves stability and translation—e.g., 25% thio-uridine and 25% 5-methylcytidine mRNA encoding Epo gave five times higher Epo levels than untreated mice two weeks after i.m. administration—but can reduce CTL responses due to lower type I IFN; unmodified mRNA may favor CTL responses while modified mRNA favors antibody responses.
- Delivery route and formulation matter: in rhesus macaques, i.d. delivery of ionizable LNP with nucleoside-modified mRNA gave earlier skin DC activation, more efficient migration to draining LNs, prolonged antigen availability, and superior antibody titers and CD4+ T cell activation versus i.m.; nanoparticles up to 200 nm can enter lymphatic vessels, and a <50 nm calcium-phosphate/DOTAP/DSPE-PEG mRNA system showed mRNA in draining LN as early as 4 h after s.c. injection.
Methods
- Narrative review synthesizing historical, immunological, delivery, and clinical literature on mRNA vaccines; no primary experimental data are reported.
- Data include published preclinical and clinical studies, with a table summarizing selected clinical trial results across CureVac, BioNTech, Moderna, and eTheRNA platforms.
- Main analysis is qualitative: it discusses mRNA pharmacology, innate immune sensing, nanoparticle design, administration routes, type I IFN effects, and combination with checkpoint inhibitors.
Limitations
- Stated in the paper: clinical patient numbers are still limited; detailed studies on biomolecular corona formation and dynamics on LNPs are still very limited; how type I IFN signaling relates to mRNA vaccine design requires further investigation.
- Evident from the text: as a narrative review, it lacks systematic search/selection criteria and quantitative synthesis; Table 1 combines heterogeneous platforms, doses, routes, and trial phases, limiting direct comparisons.
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Claims the paper makes
148 Not checked yet · 39 Own interpretation · 23 No basis given
In the paper
“In a phase I/IIa trial of a RNactive ® -based vaccine for non-small cell lung carcinoma (NSCLC), common diagnostic indicators for autoimmunity were found to be elevated up to 20% of the patients after a RNactive ® schedule of five intradermal injections (dose of 400-1600 µg) [187].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
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- Not checked yetcites [187] source
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In the paper
“Another study testing the safety and immunogenicity of the RNactive ® platform as prophylactic vaccine against rabies, elicited a moderate case of Bell's palsy one week after a second i.m. administration of the highest dose of 640 µg (1/37 patients).”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
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In the paper
“They demonstrated that mRNA packaged within a liposomal nanoparticle could successfully transfect mRNA into a variety of eukaryotic cells [1].”
§ Three decades of messenger RNA vaccine development > 1. Introduction: the first steps in mRNA vaccine development
What the sources say
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In the paper
“These preliminary data provided the first evidence that in vitro transcribed (IVT) mRNA could deliver the genetic information to produce proteins within living tissue.”
§ Three decades of messenger RNA vaccine development > 1. Introduction: the first steps in mRNA vaccine development
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In the paper
“As pioneers, Martinon et al. showed that liposomes containing mRNA encoding the influenza virus nucleoprotein elicited virus-specific cytotoxic T lymphocytes (CTLs) [3].”
§ Three decades of messenger RNA vaccine development > 1. Introduction: the first steps in mRNA vaccine development
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In the paper
“Conry et al. demonstrated the activation of humoral immune responses, as they confirmed that a prophylactic vaccine consisting of mRNA encoding a carcinoembryonic antigen resulted in the induction of anti-tumoral antibody responses [4].”
§ Three decades of messenger RNA vaccine development > 1. Introduction: the first steps in mRNA vaccine development
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In the paper
“A few months later, Wolff et al. reported on their experiments where 'naked', unprotected mRNA was directly administrated in the muscle of mice.”
§ Three decades of messenger RNA vaccine development > 1. Introduction: the first steps in mRNA vaccine development
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In the paper
“In small and large animal models, mRNA vaccines were able to elicit immunity against emerging infections such as zika, ebola and HIV [19][20][21][22][23].”
§ Three decades of messenger RNA vaccine development > 2.1. mRNA as an attractive source of antigen
What the sources say
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In the paper
“By comparison with protein-based vaccines, it was recently found that the extended antigen availability that can be obtained via mRNA had a profound effect on the magnitude and the affinity maturation of antibody responses, resulting in a more durable protection [11][12][13].”
§ Three decades of messenger RNA vaccine development > 2.1. mRNA as an attractive source of antigen
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In the paper
“Interestingly, they found that the strongly reduced immune-modulatory capacity of endogenous mRNA could be attributed to the presence of modified nucleotides in the mRNA construct, such as methylated nucleosides or pseudouridine.”
§ Three decades of messenger RNA vaccine development > 2.3. The paradigm for mRNA vaccine development
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a proof-of-concept study, we demonstrated that nucleoside-modified mRNA can be co-delivered with the clinically approved TLR agonist MPLA, achieving functional CTL responses like unmodified mRNA, but with strongly reduced type I IFN responses [157].”
§ Three decades of messenger RNA vaccine development > 5. Beyond the type I IFN response
What the sources say
- Not checked yetcites [157] source
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In the paper
“By the dual”
§ Three decades of messenger RNA vaccine development > 5. Beyond the type I IFN response
What the sources say
- Not checked yetcites [196]
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In the paper
“Indeed, as the mRNA molecules only have to reach the cytosol in order to be translated at the ribosomes, they avert the risk of being integrated into the host genome.”
§ Three decades of messenger RNA vaccine development > 1. Introduction: the first steps in mRNA vaccine development
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In the paper
“In contrast, no significant changes were detected with unmodified mRNA, which only evoked a substantial immune activation [44].”
§ Three decades of messenger RNA vaccine development > 2.3. The paradigm for mRNA vaccine development
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The fact that preparing a new mRNA construct tailored to a specific disease can be done in a straightforward and fast way, makes mRNA also an ideal candidate to trigger immunity against infectious diseases.”
§ Three decades of messenger RNA vaccine development > 2.1. mRNA as an attractive source of antigen
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In 2004, Karikó and colleagues observed, while exposing ex vivo human DCs to mRNA from different sources, that these cells tolerated mammalian mRNA, while strong inflammatory cytokine responses were detected upon the delivery of mRNA derived from bacteria, necrotic mammalian cells and IVT mRNA [39,40].”
§ Three decades of messenger RNA vaccine development > 2.3. The paradigm for mRNA vaccine development
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In the paper
“For one, mRNA can code full-length proteins, thus avoiding restrictions concerning a patient's MHC haplotype.”
§ Three decades of messenger RNA vaccine development > 2.1. mRNA as an attractive source of antigen
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
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In the paper
“Interestingly, also the MHC class II pathway can be targeted using mRNA as a source of antigen: this either after the secretion and recycling of the mRNA expressed proteins, or via direct shuttling of antigens from the cytosol to the lysosomes, e.g., promoted by the incorporation of a lysosomal targeting sequence in the mRNA construct [9,10].”
§ Three decades of messenger RNA vaccine development > 2.1. mRNA as an attractive source of antigen
What the sources say
- Not checked yetcites [9]
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plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One of the key advantages of using antigen-encoding mRNA, is that it provides an easy way to evoke MHC-I presentation and elicit CTL responses.”
§ Three decades of messenger RNA vaccine development > 2.1. mRNA as an attractive source of antigen
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In turn, type I IFNs bind autocrine or paracrine receptors, activating the Janus kinase-signal transducer activator of transcription (JAK-STAT) pathway, which regulates the gene expression of hundreds of proteins involved in antiviral immunity [35,36].”
§ Three decades of messenger RNA vaccine development > 2.2. mRNA as danger signal
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- Not checked yetcites [35]
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In the paper
“Antigen signalling by DCs can either originate from the cytoplasm, which involves the presentation of antigenic peptides in major histocompatibility complex (MHC) class I molecules, or alternatively from the lysosomes that harbour fragments of endo-or phagocytized antigens which are loaded into MHC class II.”
§ Three decades of messenger RNA vaccine development > 2. An immunological view on mRNA vaccines
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In the paper
“DCs are specialized in the uptake, processing and presentation of protein antigens to lymphocytes, which links innate and adaptive immune responses.”
§ Three decades of messenger RNA vaccine development > 2. An immunological view on mRNA vaccines
What the sources say
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In the paper
“A first-in-human trial demonstrated the clinical feasibility and safety of this approach for advanced melanoma cancers: all vaccinated patients developed CD4 + and CD8 + T cell responses against the selected antigens, with some patients showing objective antitumor responses [15].”
§ Three decades of messenger RNA vaccine development > 2.1. mRNA as an attractive source of antigen
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In the paper
“Antireverse cap (ARCA) modifications can ensure the correct cap orientation at the 5' end, which yields almost complete fractions of mRNA that can efficiently bind the ribosomes [54].”
§ Three decades of messenger RNA vaccine development > 2.3. The paradigm for mRNA vaccine development
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In the paper
“The company CureVac AG found that by stabilizing the mRNA with either a phosphorothioate backbone, or by its precipitation with the cationic protein protamine, antigen expression was diminished, but stronger immune-stimulating capacities could be obtained [62,63].”
§ Three decades of messenger RNA vaccine development > 2.3. The paradigm for mRNA vaccine development
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In the paper
“Correlations were found between the elongation of the poly(A) tail of mRNA and the duration of expression, and specific modifications at the 3' UTR were reported that can slow-down the decay of the poly(A) tail by deadenylation [57,58].”
§ Three decades of messenger RNA vaccine development > 2.3. The paradigm for mRNA vaccine development
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In the paper
“Taken together, these findings resulted in a paradigm of the design of mRNA formulations for vaccination.One strategy is to use mRNA which is fully optimized to obtain a strong adjuvant effect, another is to work with 'modified' mRNA with high translation capacity, and thus improved antigen bio-availability [43,62].”
§ Three decades of messenger RNA vaccine development > 2.3. The paradigm for mRNA vaccine development
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In the paper
“As such, the cytosolic presence of a few mRNA molecules can ensure extensive antigen presentation to CTLs, while proteins have to rely on less efficient cross-presentation pathways.”
§ Three decades of messenger RNA vaccine development > 2.1. mRNA as an attractive source of antigen
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In the paper
“The binding of mRNA molecules to these danger sensors leads to downstream signalling via specific adaptor molecules (i.e.MyD88 for TLR7/8 and TRIF for TLR3), eventually resulting in the production of type I IFN and other pro-inflammatory cytokines (e.g., IL-6 and TNF-α).”
§ Three decades of messenger RNA vaccine development > 2.2. mRNA as danger signal
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In the paper
“Moreover, using a high throughput system, Paunovska et al. were able to test hundreds of LNPs for the nucleic acid delivery to macrophages or endothelial cells after i.v.delivery, but found almost no in vitro-in vivo correlations [91].”
§ Three decades of messenger RNA vaccine development > 3.3. Advanced delivery systems for mRNA 3.3.1. Nanoparticles: opening new avenues
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- Not checked yetcites [91]
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In the paper
“These ionizable lipids (pKa < 7), originally optimized for siRNA delivery, have a neutral to mildly cationic charge under physiological pH conditions.This offers certain benefits over the permanently-charged lipids, the foremost of which is that ionizable lipids have been associated with a reduced toxicity and a prolonged blood circulation lifetime [100,101].”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
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In the paper
“Intradermal injections of granulocyte-macrophage colony-stimulating factor (GM-CSF) contributed to the infiltration of monocytes, and to the migration of mRNA-transfected, matured DCs to the LNs [86,87].”
§ Three decades of messenger RNA vaccine development > 3.2. Naked, or unprotected mRNA vaccines for local delivery
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In the paper
“Only years later, the involvement of immune cells in the uptake of unformulated mRNA was identified: skin-resident DCs were capable of engulfing naked mRNA via macropinocytosis and could trigger T cell immunity in mice [78].”
§ Three decades of messenger RNA vaccine development > 3.2. Naked, or unprotected mRNA vaccines for local delivery
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- Not checked yetcites [78]
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In the paper
“The addition of saturated phospholipids, such as DPPC and DSPC, increases the phase transition temperature of the cationic liposomes and supports the formation of such a lamellar lipid bilayer structure [102].”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
What the sources say
- Not checked yetcites [102] source
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In the paper
“Upon i.d.application, both vaccine components, sequence-engineered mRNA and protamine-complexed mRNA, were taken up by both immune cells and non-immune cells, with the highest frequencies detected within macrophages, DCs and neutrophils [79].”
§ Three decades of messenger RNA vaccine development > 3.2. Naked, or unprotected mRNA vaccines for local delivery
What the sources say
- Not checked yetcites [79] source
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In the paper
“They concluded that APCs could take up antigens that were produced by the transfected muscle cells, and that cross-presentation of the myocyte-expressed antigens was the mechanism leading to the induction of CTL responses [85].”
§ Three decades of messenger RNA vaccine development > 3.2. Naked, or unprotected mRNA vaccines for local delivery
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- Not checked yetcites [85]
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The earliest studies have explored the i.m., subcutaneous (s.c.), and intradermal (i.d.) routes, showing detectable protein expression levels at the injection site, which also resulted in adaptive immune responses [4,51,75].”
§ Three decades of messenger RNA vaccine development > 3.2. Naked, or unprotected mRNA vaccines for local delivery
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plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Over the years, it became clear that the chosen injection route plays a major role regarding the cell types that come in contact with the mRNA and the potency of the evoked immune response.”
§ Three decades of messenger RNA vaccine development > 3.2. Naked, or unprotected mRNA vaccines for local delivery
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Indeed, tumor-infiltrating CD8a + cross-presenting DCs were mainly responsible for mRNA uptake after injection in different subcutaneous murine tumor models, resulting in mRNA expression for >5 days [83,84].”
§ Three decades of messenger RNA vaccine development > 3.2. Naked, or unprotected mRNA vaccines for local delivery
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In the paper
“Recently, an i.n.administered TriMix mRNA vaccine was shown to be safe and well tolerated in a doseescalation clinical study against HIV-1 infection, while obtaining moderate HIV-specific T cell responses at high doses (total mRNA dose of 1.2 mg) [89].”
§ Three decades of messenger RNA vaccine development > 3.2. Naked, or unprotected mRNA vaccines for local delivery
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- Not checked yetcites [89]
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Notwithstanding, the potency of this self-adjuvant effect of mRNA must be weighed against the risk of any adverse reaction inherent to it, including inflammation reactions and auto-immune events [68].”
§ Three decades of messenger RNA vaccine development > 2.3. The paradigm for mRNA vaccine development
What the sources say
- Not checked yetcites [68]
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Since mRNAs are large and polyanionic molecules, they cannot passively diffuse across the cell membrane.Therefore, mRNA molecules rely on active transportation via endocytic uptake mechanisms.”
§ Three decades of messenger RNA vaccine development > 3.1. The in vivo approach
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Note that the physicochemical and structural characteristics of mRNA LNPs will depend on the lipid composition, the ratio of mRNA to the total amount of (cationic) lipids, and the LNP synthesis (for a detailed review on these parameters also see [107]).”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
What the sources say
- Not checked yetcites [107] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“They proposed that in the rapid-mixing step at acidic pH, (”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, depending on the administration route, specific extracellular barriers might be encountered which prompts specific particle optimizations.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“Although all of these cell types were able to internalize mRNA LNPs, only monocytes and myeloid DCs showed high translation of the mRNA.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [127] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although this was not further investigated in this study, prior reports have linked the occurrence of cholesterol nanocrystals to an improved transfection efficiency [114,115].”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
What the sources say
- Not checked yetcites [114]
- Not checked yetcites [115]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Notably, bench-top microfluidic mixing devices are available for the production of unloaded liposomes or mRNA LNPs via this ethanol-dilution principle, with the potential to be scaled up for clinical or industrial purposes [116].”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
What the sources say
- Not checked yetcites [116] source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In another study, Yanez Arteta et al. indicated that the structural arrangement of mRNA LNPs based on D-Lin-MC3-DMA, DSPC, cholesterol and a PEG-lipid exhibited a disordered inverse hexagonal phase containing D-Lin-MC3-DMA, cholesterol, water and mRNA.”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
What the sources say
- Not checked yetcites [113] source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The mechanism of the formation of these ionizable LNP systems (with different nucleic acid payloads) has recently been elucidated by Kulkarni and colleagues [111,112].”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“With respect to the resulting immune response, they showed that i.d.delivery resulted in an earlier activation of skin DCs and a more efficient migration to draining LNs, as well as a prolonged antigen availability at the injection site.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [127] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Furthermore, this has also supported the discovery of new lead ionizable lipids holding greatly improved potency and safety for mRNA transfection [117][118][119].”
§ Three decades of messenger RNA vaccine development > 3.3.2. Designing and preparing lipid nanoparticles for mRNA delivery
What the sources say
- Not checked yetcites [117][118][119]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Together, this resulted in a superior immunogenicity compared to i.m. delivery, as i.d.injection resulted in the highest antibody titers and CD4 + T cell activation.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [127] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This may reduce the colloidal stability of the mRNA LNPs, followed by the aggregation of the particles and a premature release of the mRNA cargo [139,140].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [139]
- Not checked yetcites [140]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Recently, Vu et al. elucidated how nanoparticles mediate complement activation, and found this to be quite universal over a range of clinically approved liposomes [148].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [148]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“These PEG-lipids can gradually diffuse out of the LNPs, and thus temporarily confer stealth properties to the LNP system, while achieving higher transfection efficiencies compared to the longer, persistent PEG-lipids [139,144].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [139]
- Not checked yetcites [144]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These mRNA nanoparticles had a relatively small particle size (<50 nm), and an uncharged, strongly PEGylated outer-surface.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [135] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the specific case of cancer immunotherapy, it was proven essential to evoke a systemic immune response to obtain antitumor immunity, which makes i.v.delivery a highly appealing administration route for mRNA-based cancer vaccines [92,136,137].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Merely a few surface-bound immunoglobulin molecules are sufficient to trigger complement activation.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Alternatively, the incorporation of PEGylated lipids is widely used to provide a”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [143]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is also possible to tweak the serum stability of LNPs by modifying their helper lipid composition.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“However, PEGylation also has its limitations: in patients with pre-existing anti-PEG antibodies, infusion of PEGylated LNPs is contra-indicated, as this could lead to an even stronger complement activation as well as an accelerated blood clearance of PEGylated nanoparticles.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [143]
- Not checked yetcites [148]
- Not checked yetcites [155]
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Reports suggest that nanoparticles up to 200 nm are able to enter the lymphatic vessels, whereas larger particles are withheld at the injection site [128][129][130].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [128][129][130]
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, recent findings suggest that these nanoparticle-mediated infusion reactions are triggered by an acute intoxication of pulmonary intravascular macrophages [152][153][154].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [152][153][154]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Perche et al. prepared mannosylated nanoparticles loaded with mRNA, which could be used as an active targeting strategy to enhance the transfection of splenic DCs [126].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [126]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While it is possible that the observed site-specific targeting could be attributed to the LNP surface charge, the involvement of a different biomolecular corona cannot be excluded.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Here, it was found that chronic activation of the type I IFN pathway leads to the induction of regulatory DCs, the deletion of virus-specific B cells and strongly impaired T cells responses [180][181][182].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [180][181][182]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“If type I IFNs are produced after recognition of MHC-presented antigens by T cells, they act as a strong 3 rd signal cytokine to stimulate T cell activation and proliferation.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Indeed, type I IFN signalling induces DC maturation, improved antigen processing and presentation, and enhances DC migration to enriched T cell zones (e.g., via CCR7) [172][173][174][175].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [172][173][174][175]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“By regulating other pro-inflammatory cytokines, type I IFNs are also involved in the regulation of other immune cell types, such as Natural Killer (NK) cell responses [179].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [179]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For a self-amplifying mRNA LNP vaccine, Pepini et al. reported that the antigen expression was dramatically enhanced in the absence of IFN-α/β, which correlated with improved immunogenicity and IgG antibody responses [167].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [167]
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Comparative studies performed by our research group and others demonstrated that nucleoside-modified mRNA LNPs outperformed unmodified mRNA LNPs in translation capacity, but failed to elicit successful CTL responses due to the drastically reduced production of type I IFNs [119,157].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [119]
- Not checked yetcites [157] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In an opinion article, De Beuckelaer et al. suggested that the type I IFN response by mRNA vaccines might have dual effects on naïve T cells, depending on the duration and relative timing between type I IFN signalling and T cell priming [169].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [169]
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, by lowering the lipid-to-mRNA ratio to a lower lipid content, Kranz et al. demonstrated that DOTMA-DOPE mRNA LNPs become negatively charged and specifically target DCs in the spleen [92,158].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [92] source
- Not checked yetcites [158]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This might explain why the early type I IFN response induced by an mRNA vaccine, might not only limit the mRNA-encoded antigen expression, but even exert deleterious effects on T cell responses [169].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [169]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In humoral immunity, type I IFNs promote the generation of long-lived antibody responses by the indirect enhancement of helper T cell responses and by direct immune-stimulatory effects on B cells [177,178].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [177]
- Not checked yetcites [178]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, this sparks opportunity for combining mRNA vaccines with PD-1 checkpoint inhibitor treatments.”
§ Three decades of messenger RNA vaccine development > 6. Combination of mRNA cancer vaccines with checkpoint therapies
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Breckpot and colleagues demonstrated the reprogramming of DCs after the intratumoral administration of TriMix mRNA (i.e.CD40L, caTLR4 and CD70), or using mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II [84,202].”
§ Three decades of messenger RNA vaccine development > 5. Beyond the type I IFN response
What the sources say
- Not checked yetcites [84]
- Not checked yetcites [202]
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Indeed, the expression of the MLKL provokes a type of immunogenic cell death, called necroptosis, which enables the release of tumor-specific antigens and natural DAMPs that trigger antitumor responses.”
§ Three decades of messenger RNA vaccine development > 5. Beyond the type I IFN response
What the sources say
- Not checked yetcites [204]
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, it is of crucial importance to keep a close eye on several immunosuppressive mechanisms that might hamper the evoked immunity.”
§ Three decades of messenger RNA vaccine development > 6. Combination of mRNA cancer vaccines with checkpoint therapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“This is a condition of temporary facial paralysis, which has been linked to autoimmunity [188].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [188]
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“By the localized expression of these immunomodulatory molecules, this strategy was able to break DC tolerance and to activate tumor-specific T cell responses.”
§ Three decades of messenger RNA vaccine development > 5. Beyond the type I IFN response
What the sources say
- Not checked yetcites [203] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“To give two examples, Thran et al. evaluated an LNP formulation of sequence-engineered mRNA coding for prophylactic or therapeutic antibodies.This could provide protection against rabies infection, botulinum intoxication, and tumors [201].”
§ Three decades of messenger RNA vaccine development > 5. Beyond the type I IFN response
What the sources say
- Not checked yetcites [201] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There is, however no doubt that distinct mRNA vaccines, varying in mRNA design, formulation and administration route, will exhibit differences in kinetics and cell-specificity for both mRNA expression and innate immune activation.”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“This includes the generation of transgenic reporter mouse strains, such as the IFN-β reporter mice and Cre recombinase (mRNA) reporter mice, as well as the development of fluorescent imaging mRNA probes that allow to detect mRNA at high resolution [90,158,[192][193][194][195].”
§ Three decades of messenger RNA vaccine development > 3.3.3. The administration of mRNA LNPs
What the sources say
- Not checked yetcites [90,158,[192][193][194][195]
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This mRNA platform represented a valid alternative to classic mRNA cancer vaccines, providing a strong infiltration of T cells able to eliminate tumors in mice.”
§ Three decades of messenger RNA vaccine development > 5. Beyond the type I IFN response
What the sources say
- Not checked yetcites [197] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Firstly, it is essential to ensure adequate intracellular delivery of mRNA molecules, preferably by targeting APCs in vivo.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Two papers showed that the i.v.administration of unmodified mRNA LNPs triggered a rapid and systemic induction of type I IFNs, which involved the selective targeting of DCs and macrophages and the activation of the TLR7 pathway[92,136].”
§ Three decades of messenger RNA vaccine development > 8. Acknowledgements
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both parameters are of crucial importance to the vaccine outcome, but are inherently linked to the structural properties of the mRNA molecule itself.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, it is still waiting for a more extended clinical experience on how patients respond to mRNA vaccines, including more comparative research to select for the best suited mRNA platform and administration route, as well as to show clear therapeutic benefits over other vaccine strategies.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We discussed that the design of these LNPs asks for a multi-objective solving approach in which the overall mRNA transfection capacity will depend on trade-offs between different requirements to cross the extra-and intracellular barriers, while precautions are needed to prevent potential nanoparticle inherent (immune) toxicities.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mRNA represents an attractive source of antigen in vaccination approaches”
§ Three decades of messenger RNA vaccine development > 8. Acknowledgements
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both parameters are of crucial importance to the vaccine outcome, but are inherently linked to the structural properties of the mRNA molecule itself.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Nowadays, there appears to be a trend towards the use of lipid-based nanoparticles for both localized and systemic delivery of mRNA.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nanoformulation widens the administration and delivery options for mRNA vaccines”
§ Three decades of messenger RNA vaccine development > 8. Acknowledgements
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fundamental research should further focus on how to control the type I IFN activity of mRNA vaccines, which might vary depending on the mRNA formulation, administration route, the individual patient and the intended therapeutic application.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For clinical translation of these mRNA LNP systems, it will also be critical to meet pharmaceutical-and regulatory product requirements, going from scale-up manufacturing under GMP conditions, quality control of these products, stability testing, and good safety and efficacy assessments during the pre-clinical stage in relevant animal models.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Over the years, a fairly large knowledge gap about the in vivo behaviour of mRNA has been filled, both after the delivery of naked mRNA or when formulated in nanoparticles, and this for various immunization routes.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For prophylactic mRNA vaccines against infectious diseases, (pre-)clinical studies (in non-human primates) show accumulating evidence that mRNA vaccination is feasible, generally well-tolerated, and potentially beneficial over other traditional vaccine approaches.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“More specifically, although the mRNA-induced type I IFN response might add to the immunogenicity of the mRNA vaccine, it also interferes with the mRNA-encoded antigen expression and possibly even lead to deleterious immune effects.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The self-adjuvant effect of mRNA is a double-edged sword for vaccine efficacy”
§ Three decades of messenger RNA vaccine development > 8. Acknowledgements
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Each of these elements can be optimized and modified in order to modulate the stability, translation capacity, and immune-stimulatory profile of mRNA.”
§ Three decades of messenger RNA vaccine development > 8. Acknowledgements
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Both unformulated and nanoparticulate mRNA are used for direct in vivo vaccination”
§ Three decades of messenger RNA vaccine development > 8. Acknowledgements
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The choice of the amino lipids (cationic or ionizable lipids) and helper lipids will have an impact on the structural arrangement and functional properties of the formulated mRNA LNPs.”
§ Three decades of messenger RNA vaccine development > 8. Acknowledgements
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, mRNA approaches which do not necessarily rely on the self-adjuvant effect of mRNA are one the rise, such as the replacement of type I IFN responses by more controllable adjuvant systems, or using mRNA for passive immunization approaches.”
§ Three decades of messenger RNA vaccine development > 7. Conclusions and perspectives
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Therefore, the establishment of effective combination therapies that could increase the response rate of checkpoint inhibitors is an area of intensive investigation [220,221].”
§ Three decades of messenger RNA vaccine development > 6. Combination of mRNA cancer vaccines with checkpoint therapies
What the sources say
- Not checked yetcites [220]
- Not checked yetcites [221]
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Contradictory results have been reported about the role of type I IFN responses on the immunogenicity of mRNA vaccines (see also section 2.3).”
§ Three decades of messenger RNA vaccine development > 8. Acknowledgements
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The authors state this as an assumption.
When mRNA LNPs are prepared by admixing mRNA with pre-formed monolamellar liposomes containing a permanently-charged lipid, the liposomes reorganize to form a multi-lamellar structure in which mRNA molecules are sandwiched between concentric lipid bilayers.
“When mRNA LNPs are prepared by admixing mRNA with pre-formed (monolamellar) liposomes containing a permanently-charged lipid, it is assumed that the liposomes reorganize to form a multi-lamellar structure in which mRNA molecules are”
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?
The cited source says what the claim attributes to it.
In the citing paper
“The modified nucleosides escape the type interferons (IFNs) induced antiviral pathways and are targeted to break and block invading mRNA; therefore they can be used to create mRNA vaccines with significantly improved translation efficiency (Verbeke et al. 2019).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Verbeke et al. 2019
The cited source says what the claim attributes to it.
In the citing paper
“The modified nucleosides escape the type interferons (IFNs) induced antiviral pathways and are targeted to break and block invading mRNA; therefore they can be used to create mRNA vaccines with significantly improved translation efficiency (Verbeke et al. 2019).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Verbeke et al. 2019
The cited source says what the claim attributes to it.
In the citing paper
“The basic structure of mRNA, same as eukaryotic mRNA, is made up of (i) protein encoding ORF, surrounded by (ii) 5′ and 3′ UTRs, and (iii) a 7-methyl guanosine 5′ cap structure and (iv) a 3′poly(A) tail at the end sides (Verbeke et al. 2019; Schlake et al. 2012; Sahin et al. 2014) (Fig. 1).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Verbeke et al. 2019
The cited source says what the claim attributes to it.
In the citing paper
“mRNA transcripts containing modified nucleosides, also known as nucleoside-modified mRNAs, are created with lower immunostimulatory activity and a better safety profile.”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Verbeke et al. 2019
In the citing paper
“Another interesting finding by Arteta et al. is that the shell of their mRNA-LNPs is a monolayer (Yanez Arteta et al., 2018, Verbeke et al., 2019).”
From mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability (2021) · cites this paper as Verbeke et al., 2019
In the citing paper
“research into the use of mRNA as a source of protein has been around for three decades [1]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [1]
In the citing paper
“several research groups underlined that the type I IFN response can act as a driving force for mRNA vaccines to elicit cytotoxic T cell responses [1,60,61]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [1]
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Self-citationmRNA vaccines for infectious diseases: principles, delivery and clinical translation
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Metadata
- Authors
- Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H.
- Affiliations
- Ghent University Hospital (BE)
- Vrije Universiteit Brussel (BE)
- Venue
- Nano Today
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 28
- Pages
- 100766
- ISSN
- 1748-0132 (ISSN-L)
- OpenAlex
- W2969814123
- Semantic Scholar
- 708a4fdc49c5e158058dfd9f2bb4267f0d3981f8
- Cited by
- 342
- References
- 218
- Citations by year
- 2026: 50 · 2025: 45 · 2024: 48 · 2023: 61 · 2022: 55 · 2021: 69 · 2020: 14
- FWCI
- 13.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nano Today (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Funders
- Agentschap voor Innovatie door Wetenschap en Technologie
- Fonds Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- mRNA vaccines, mRNA, vaccine design, vaccine safety and efficacy, vaccine administration
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