The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index; 18 of the 59 sources its claims cite were checked for support.
Nonviral delivery of self-amplifying RNA vaccines
Open accessAbstract
Despite more than two decades of research and development on nucleic acid vaccines, there is still no commercial product for human use. Taking advantage of the recent innovations in systemic delivery of short interfering RNA (siRNA) using lipid nanoparticles (LNPs), we developed a self-amplifying RNA vaccine. Here we show that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA. This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors. Given the many positive attributes of nucleic acid vaccines, our results suggest that a comprehensive evaluation of nonviral technologies to deliver self-amplifying RNA vaccines is warranted.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Nonviral delivery of a 9-kb self-amplifying RNA encapsulated in lipid nanoparticles (LNP/RNA) increased reporter gene expression and immunogenicity compared with unformulated RNA. In mice and cotton rats, LNP/RNA elicited potent RSV-F-specific humoral and cellular responses and protection from RSV challenge comparable to viral replicon particle delivery.
Key findings
- LNP encapsulation protected self-amplifying RNA from RNase degradation and improved in vivo expression: 0.1 μg LNP/RNA increased serum SEAP over 1 μg naked RNA and reduced animal-to-animal variability.
- After two intramuscular immunizations, 0.1 μg LNP/RNA encoding RSV-F elicited F-specific IgG GMT 26,170 versus 2,292 for 1 μg naked RNA; 1 μg LNP/RNA was equivalent to 1 × 10⁶ IU VRPs (GMT 10,478), and seroconversion occurred after a single LNP/RNA dose as low as 0.01 μg RNA.
- In cotton rats, LNP/RNA boosted F-specific IgG approximately 8-fold (GMT 4,355 vs. 526) and RSV neutralization titers 10-fold (GMT 1,493 vs. 154) relative to the same dose of naked RNA, equivalent to 5 × 10⁶ IU VRPs (GMTs 5,861 and 1,690); all self-amplifying RNA vaccines reduced lung viral load >1,000-fold versus controls after intranasal RSV challenge.
- LNP/RNA elicited slightly elevated F-specific IgG2a relative to IgG1 and potent antigen-specific IFN-γ-producing CD4⁺ and CD8⁺ T cell responses; functional immune responses against HIV antigens were also observed (Fig. S5).
Methods
- Preclinical vaccine study using a self-amplifying RNA based on an alphavirus genome, produced by T7 RNA polymerase transcription from linear pDNA and encapsulated in lipid nanoparticles via an ethanol dilution process using DLinDMA, DSPC, cholesterol, and PEG-DMG 2000.
- Female BALB/c mice (8–10 wk, ~20 g) and female cotton rats were immunized intramuscularly on days 0 and 21; cotton rats were challenged intranasally with 1 × 10⁵ pfu RSV 4 wk after the final immunization.
- Main analyses included serum SEAP and luciferase bioluminescence, RSV-F-specific IgG/IgG1/IgG2a ELISA, RSV neutralization titers, T cell cytokine flow cytometry, and lung viral load; statistics used one-way ANOVA or Kruskal-Wallis with Dunn’s posttest at 95% confidence.
Limitations
- Stated: immunogenicity at submilligram doses in larger species “remains to be directly tested”; the mechanism of action is not fully elucidated, and studies are underway to identify transfected cells and explain why LNP delivery gives longer expression than VRP delivery.
- Stated: production of larger (~9 kb) self-amplifying RNA adds challenges, though the authors call them “not insurmountable.”
- Evident from the text: all efficacy and challenge data are from mice and cotton rats, with no human or nonhuman primate data reported for this LNP/RNA vaccine.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
31 Own result · 16 No full text of the sources · 14 Own interpretation · 7 Supported · 6 Partly supported · 5 No basis given · 2 Supported so far · 1 Own method · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, naked RNA vaccines suffer from limited potency, in part due to RNA instability in vivo, related to the presence of degradative enzymes in tissues (15).”
What the sources say
- Supportedcites [15] source
The Background states that ubiquitous ribonucleases rapidly degrade mRNA and that this instability limits the efficacy of mRNA-based therapies. The Conclusion applies that concern to mRNA vaccination, proposing protection from RNases to improve vaccine efficacy. (LLM, conf=0.92)
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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, for infant RSV vaccine development, safety considerations favor replicating (or selfamplifying) vaccine candidates over subunit approaches (33).”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
What the sources say
- Supportedcites [33] source
The “Subunit proteins” section says subunit vaccines face significant regulatory hurdles in seronegative infants and raises theoretical concerns about vaccine-enhanced disease relative to live-attenuated viruses or gene-based vectors. This supports the claim as a statement about safety considerations, not as proof that every replicating candidate is safe. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Similarly, EP-mediated delivery of pDNA has been shown to be broadly effective (26) and thus was used as the benchmark for pDNA delivery.”
What the sources say
- Supportedcites [26] source
The “Electroporation Enhanced DNA Vaccine Delivery” section reports a 100–1000-fold enhancement in plasmid delivery and gene expression compared with DNA delivery without EP. The “Translating In vivo Expression to Immunogenicity and Efficacy” section describes enhanced responses across numerous vaccine candidates and animal disease models. Together, these support the broad effectiveness attributed to EP-mediated pDNA delivery; page numbers were not supplied. (LLM, conf=0.91)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“VRPs have been shown to be potent in nonhuman primates and humans at a 100-fold higher dose (1 × 10 8 IU) (22,25), and thus we anticipate that this unique RNA vaccine will be immunogenic at submilligram doses in larger species, but this remains to be directly tested.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
What the sources say
- Partly supportedcites [22] sourceExperimental — accuracy not yet measured
Materials and Methods reports a VRP dose of 1 × 10^8 IU in rhesus macaques, and the Results and Discussion report immune responses and protection with a VRP-prime/Env-protein-boost regimen. The copy does not establish potency in humans or that this dose was 100-fold higher than a comparison dose; it also reports that VRP alone did not protect the macaques. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [25] 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The current costs of clinical manufacturing of pDNA are on the order of $50-100 per milligram (1-10 g scale) (26).”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
What the sources say
- Supportedcites [26] source
The “Prospects for Clinical Efficacy and Product Development Success” section states that current small-scale cGMP DNA manufacturing costs are approximately $50–100 per milligram at a 1–10 g manufacturing scale. This matches the cited claim about clinical pDNA manufacturing costs. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we show that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA.”
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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors.”
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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors.”
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.
A result the paper reports from its own data — 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 contrast, the naked control RNA was degraded by RNase A (Fig. 1C, lane 3 compared with lane 2).”
§ Nonviral delivery of self-amplifying RNA vaccines > Vaccine Formulation Characterization.
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Importantly, the immunogenicity and protective efficacy generated by 1 μg LNP/RNA was equivalent to the responses elicited by the VRP delivery technology.”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 38
- Probably not a substantial claim. 9
Every source the paper cites for this claim was checked and supports it.
In the paper
“Although plasmid DNA (pDNA) vaccines have proven to be a flexible platform and are broadly effective in small animal models, they have generally lacked potency in human clinical trials (2).”
What the sources say
- Supportedcites [2] source
The Preclinical studies section reports protective immunity against a broad range of pathogens in small-animal studies and describes applications beyond infectious disease. The DNA vaccine platform: room for improvement section says responses in humans have been significantly weaker than in mice, and Initial DNA vaccine studies in humans says greater potency is needed. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, with increasing life expectancy in high-income countries and newly emerging infections and poverty in low-income countries, new technologies will be required to address changing vaccine needs (1).”
What the sources say
- Supportedcites [1] source
The Main section identifies an aging society, emerging infections, and poverty in low-income countries as changing health needs. It also says emerging infections require appropriate technologies and that research into novel vaccine technologies remains a priority. No page numbers are available in our copy. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“VRPs are potent vaccines in mice (10,11), nonhuman primates (11,22), and humans (25).”
What the sources say
- Supportedcites [10] source
The Discussion reports potent vaccine responses in mice, and the Abstract states that VEE replicon particles induced potent, protective immune responses in primates. In the citing sentence, this source is cited for mice and nonhuman primates; the human claim is assigned to citation 25, not this paper. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [11] source
- Partly supportedcites [22] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports complete protection of rhesus macaques given an intramuscular VRP prime plus Env-protein boost, supporting the nonhuman-primate portion attributed to this source. It also says none of the macaques given VRP alone were protected, so the unqualified description of VRPs as potent vaccines overstates this study. The separate mice and humans citations are not being judged here. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [25] 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.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“There are limited published data on the in vivo delivery of self-amplifying RNA using nonviral delivery strategies (3,14,18), and none has taken advantage of the recently developed, clinically suitable delivery systems for siRNA (19,20).”
What the sources say
- Not checked — no full text of the sourcecites [3] source
- Supportedcites [14] source
This paper is cited for the first clause: examples of in vivo, nonviral delivery of self-amplifying RNA. The Discussion describes delivery of naked Semliki Forest virus RNA replicons and reports immune responses after intradermal delivery with electroporation. The separate claim about siRNA delivery systems is attached to other citations, not this paper. (LLM, conf=0.90)
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [19] source
- Supportedcites [20] source
The Main section (page unavailable) describes synthetic, nonviral siRNA delivery systems that have worked in vivo and says several clinical trials use delivery agents. This supports the cited description of clinically promising siRNA delivery systems; the statement that self-amplifying RNA studies had not used them is the citing authors’ comparison, not a finding attributed to this source. (LLM, conf=0.87)
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Injection of naked mRNA or self-amplifying RNA in vivo induces gene expression and generates immune responses (4, 11-13), with self-amplifying RNA being more efficient for gene expression in situ (13,14).”
What the sources say
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [11] source
- Not checked — no full text of the sourcecites [12] source
- Partly supportedcites [13] sourceExperimental — accuracy not yet measured
The in vivo gene-expression results report that injected replicative mRNA produced substantially more luciferase than non-replicative mRNA in muscle. The Discussion reports an immune response from prior CEA mRNA injections, but this study did not establish that its self-amplifying RNA generated an immune response; it discusses that possibility as a hypothesis (page not provided). (LLM, conf=0.87)
- Partly supportedcites [14] sourceExperimental — accuracy not yet measured
The Results section ('Relative expression levels and cellular immune response'; page unavailable) reports in vivo gene expression from both mRNA and replicon RNA, with lower, shorter-lived expression from mRNA. Replicon RNA elicited immune responses, but naked mRNA produced no detectable specific immune response in this study's single-injection experiments. The Introduction does report immune responses to mRNA vaccination in other studies, so the broad claim is supported only with that qualification. (LLM, conf=0.86)
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.
- Not matched
Every source the paper cites for this claim was checked and supports it.
In the paper
“The F protein of RSV is a conserved target of neutralizing antibodies and a promising antigen for RSV vaccine development (29).”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
What the sources say
- Supportedcites [29] source
The introductory passage following the Abstract explicitly calls RSV F “a conserved target of neutralizing antibodies” and “a promising antigen for RSV candidate vaccines.” The Discussion further reports that an engineered F antigen elicited high neutralizing antibody titers and protected cotton rats from RSV challenge. (LLM, conf=0.95)
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.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The neutralization titers elicited by LNP/RNA are above the titer of 380 that correlates with protection in cotton rats (30) and similar to passively acquired serum neutralizing titers that correlate with protection of human infants from severe RSV disease (31,32).”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
What the sources say
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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Currently there is no vaccine for RSV and, because of a history of disease enhancement upon natural infection after immunization with an RSV vaccine candidate that elicited T H 2-biased (and non-neutralizing) RSV-specific immune responses in RSV-naive infants, elicitation of a non-T H 2-biased RSV-specific response is considered an essential attribute for infant RSV vaccine candidates (33).”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
What the sources say
- Partly supportedcites [33] sourceExperimental — accuracy not yet measured
The Major hurdles section says adequate RSV vaccine options were unavailable and describes enhanced disease in infants after the formalin-inactivated vaccine. The Vaccine-enhanced disease section reports poor neutralizing antibody responses in those children, and the Role of T cells in vaccine-enhanced illness section recommends avoiding Th2 responses in RSV vaccines. However, it identifies clear Th2 induction in immunized animal models, not as a directly established response in the infants; their lung eosinophilia is cited as a reason for concern. (LLM, conf=0.86)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The shorter duration of expression in situ after RNA immunization compared with pDNA may be related to the induction of apoptosis of the transfected cell, which could occur during RNA amplification, leading to transient gene expression (12,13).”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
What the sources say
- Not checked — no full text of the sourcecites [12] source
- Partly supportedcites [13] sourceExperimental — accuracy not yet measured
The in vivo results report that replicative mRNA expression returned to baseline within 28 days, while plasmid DNA expression remained above baseline (Augmented gene expression in vivo). The Discussion proposes host-cell protein-synthesis inhibition and resulting cytopathogenicity as one possible explanation for the decline in mRNA-directed expression. It does not specifically identify apoptosis or establish that it occurs during RNA amplification. (LLM, conf=0.85)
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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recently, there has been an exponential growth in the development of clinically suitable nonviral delivery systems for siRNA (19,20); we have taken advantage of these innovations to develop the LNP/RNA formulation and have now embarked on a more extensive evaluation of other nonviral delivery systems.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
What the sources say
- Not checked — no full text of the sourcecites [19] source
- Partly supportedcites [20] sourceExperimental — accuracy not yet measured
The Main section describes advances in synthetic nonviral siRNA carriers and reports that some delivery agents are being used in clinical trials. It does not establish exponential growth, and it says safe, effective delivery remains a barrier rather than characterizing these systems generally as clinically suitable. Page numbers were not provided in our copy. (LLM, conf=0.85)
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.
A result the paper reports from its own data — 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 same self-amplifying RNA, when delivered using a VRP (1 × 10 6 IU), produced twice the bioluminescence at day 3 compared with LNP/RNA, but expression decayed much more rapidly and reached background levels by day 28 (Fig. 2B).”
§ Nonviral delivery of self-amplifying RNA vaccines > In Vivo Gene Expression at the Site of Injection.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“EP delivery of pDNA (at a high dose of 20 μg) elicited anti-F IgG titers (GMTs of 6,712) on average 3.9-fold less than those elicited by 0.1 μg of LNP/RNA, although not statistically different.”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the other hand, mice administered a pDNA-encoding luciferase (10 μg) delivered using EP in situ displayed the highest measurable bioluminescence at all time points tested, and this level remained high for at least 63 d (Fig. 2D).”
§ Nonviral delivery of self-amplifying RNA vaccines > In Vivo Gene Expression at the Site of Injection.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Encapsulation of a 10-fold lower dose of RNA (0.1 μg) in LNPs increased the serum SEAP concentration and reduced the variability between animals.”
§ Nonviral delivery of self-amplifying RNA vaccines > Vaccine Formulation Characterization.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Six days after intramuscular (i.m.) injection of 1 μg naked self-amplifying RNA encoding secreted alkaline phosphatase (SEAP), gene expression, as determined by serum SEAP concentration, was measurable but highly variable (Fig. 1D).”
§ Nonviral delivery of self-amplifying RNA vaccines > Vaccine Formulation Characterization.
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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This contrasted with what was observed for naked RNA, which required two vaccinations and microgram doses of RNA.”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
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 result the paper reports from its own data — 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 LNP/RNA was statistically superior to naked RNA and equivalent to the 5 ×10 6 IU of VRPs [GMTs 5,861 (F-specific IgG) and 1,690 (neutralization)].”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Addition of empty LNPs (without RNA) to naked RNA (0.1 μg) decreased the serum SEAP concentration relative to LNP-encapsulated RNA, indicating that RNA encapsulation was necessary for efficient RNA delivery and reporter gene expression.”
§ Nonviral delivery of self-amplifying RNA vaccines > Vaccine Formulation Characterization.
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.
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
“A recombinant F protein subunit vaccine formulated with alum was shown to be the most potent vaccine for induction of total and protective antibody responses.”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
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: 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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Bioluminescence intensity induced by LNP/RNA was substantially greater than naked RNA, pDNA, and pDNA launched RNA, and was comparable to the bioluminescence produced by 1 × 10 6 infectious units (IU) of VRPs.”
§ Nonviral delivery of self-amplifying RNA vaccines > In Vivo Gene Expression at the Site of Injection.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Agarose gel electrophoresis showed that RNA integrity was maintained during formulation (Fig. 1C, lane 4) and that the LNPs protected the RNA from degradation by RNase A (Fig. 1C, lane 5).”
§ Nonviral delivery of self-amplifying RNA vaccines > Vaccine Formulation Characterization.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — 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 an extended study (Fig. 2 B-D), mice injected with LNP/RNA (1 μg) showed measurable bioluminescence that was already high on day 3, peaked on day 7, and decreased to background by day 63 (Fig. 2C).”
§ Nonviral delivery of self-amplifying RNA vaccines > In Vivo Gene Expression at the Site of Injection.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The potency of this unique LNP/RNA vaccine in mice and cotton rats was comparable to a single-cycle alphavirus vector (VRP, 1 × 10 6 IU) at a reasonable dose of RNA (1 μg) and was generally comparable to pDNA delivered using EP at higher doses.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“All self-amplifying RNA vaccines provided protection from a nasal RSV challenge, reducing the lung viral load >1,000-fold compared with control animals (Fig. 5C) and these data are in agreement with previous reports for naked RNA (12).”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
What the sources say
- Not checked — no full text of the sourcecites [12] source
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — 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 LNP/RNA formulation boosted F-specific IgG titers approximately 8-fold (GMTs 4,355) and neutralization titers 10-fold (GMTs 1,493) relative to the same dose of naked RNA [GMTs of 526 (F-specific IgG) and 154 (neutralization)].”
§ Nonviral delivery of self-amplifying RNA vaccines > Virus Fusion Glycoprotien (RSV-F).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“An ethanol dilution process (28) was used to produce small uniform lipid particles with a high RNA encapsulation efficiency.”
§ Nonviral delivery of self-amplifying RNA vaccines > Vaccine Formulation Characterization.
What the sources say
- Not checked — no full text of the sourcecites [28] source
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — 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 number-weighted mean diameters ranged from 79 to 121 nm and Z-average diameters from 130 to 164 nm with a polydispersity index from 0.09 to 0.14.”
§ Nonviral delivery of self-amplifying RNA vaccines > Vaccine Formulation Characterization.
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — 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 ratio of F-specific IgG titer to RSV neutralization titer (Table S2) is low for the LNP/ RNA vaccine relative to the RSV-F subunit adsorbed on alum; thus it may be particularly suitable for development into a safe and effective infant RSV vaccine candidate.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — 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 LNP/RNA provides this benefit (Fig. 4) in addition to strong cellular immune responses.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“(iv) the generation of a humoral and cellular immune responses (both CD4 and CD8).”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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.
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
“Facilitated delivery of RNA, either by VRPs or LNPs, resulted in higher levels of reporter gene expression (SEAP and luciferase) than naked RNA delivery and considerably lower variability of expression between animals.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“However, many of the obstacles to mRNA vaccine development have been surmounted, and recently there has been a revival in the use of nonamplifying mRNA vaccines for cancer (6), allergy (7), and gene therapy (8).”
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Naturally transient and cytosolically active mRNA can now be produced at sufficient quantity and quality for human clinical trials (6) and is seen by many (9) as a safer and more potent alternative to pDNA for vaccination.”
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Viral vector-based technologies are generally regarded as the most efficient means to deliver nucleic acids into cells, but their utility can be restricted by preexisting or vaccine-induced antivector immunity that can decrease vaccine potency (12).”
What the sources say
- Not checked — no full text of the sourcecites [12] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Recombinant viral vector technologies have the advantage of efficient delivery of the nucleic acid payload, but their utility is often hampered by antivector immunity, production limitations, and safety concerns (3,4).”
What the sources say
- Not checked — no full text of the sourcecites [3] source
- Not checked — no full text of the sourcecites [4]
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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Various RNA vaccines have been evaluated in human clinical trials, including naked and formulated non-amplifying mRNA (37-39) and self-amplifying RNA packaged in VRPs (25).”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
What the sources say
plain- 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.
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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
“RNA vaccines avoid this rate-limiting step by using cytoplasmic amplification and expression, resulting in more efficient transfection of different cell types, including quiescent or slowly proliferating cells, such as vascular endothelia or myocytes.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“Therefore, the LNP formulation markedly enhances the potency of the self-amplifying RNA, thereby generating a robust and potentially generic vaccine technology.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Image acquisition times were kept constant as bioluminescence was measured with a cooled CCD camera.”
§ Nonviral delivery of self-amplifying RNA vaccines > RNA Synthesis.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Those studies showed RNA vaccines to be well tolerated and immunogenic.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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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, because the replication cycle of the self-amplifying RNA is strictly cytoplasmic, the need for codon modification is diminished, and the risks of splicing and destruction of the transcript are avoided.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“For an LNP/RNA vaccine, this sequestration might result in antigen production and/or stimulation of innate immune pathways within these immune cells.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
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. 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
“(ii) elimination of theoretical risks of generating infectious virus through recombination during production”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
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.
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 LNP delivery system may achieve these effects by a combination of increased transfection efficiency and protection of the RNA from enzymatic degradation at the site of injection.”
§ Nonviral delivery of self-amplifying RNA vaccines > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- 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 relies on this without support.
There is still no commercial product for human use for nucleic acid vaccines despite more than two decades of research and development.
“Despite more than two decades of research and development on nucleic acid vaccines, there is still no commercial product for human use.”
The paper relies on this without support.
mRNA-based vaccines must match the potency of viral vectors at doses of RNA that are not cost prohibitive to be commercially competitive as a platform technology.
“However, to be commercially competitive as a platform technology, mRNA-based vaccines must match the potency of viral vectors at doses of RNA that are not cost prohibitive.”
The paper relies on this without support.
The major limitation for delivery of pDNA is the nuclear barrier, and transport across the nuclear membrane is particularly inefficient in nondividing cells such as mature myocytes.
“The major limitation for delivery of pDNA is thought to be the nuclear barrier, and transport across the nuclear membrane seems to be particularly inefficient in nondividing cells, such as mature myocytes.”
The paper relies on this without support.
The immunogenicity and protection observed in mice and cotton rats are predictive of efficacy in humans.
“Thus, this technology has potential as a platform to address multiple disease targets.”
The paper relies on this without support.
The SAM vaccine platform can be applied to multiple disease targets.
“Thus, this technology has potential as a platform to address multiple disease targets.”
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
“Studies with self-amplifying mRNA vaccines investigated the effect of different formulations such as lipid-nanoparticles (LNP)10 or cationic nanoemulsion (CNE)11 on the immunogenicity of mRNA vaccines. Self-amplifying vaccines benefited from formulation with LNP or CNE and were able to induce protective antibody titers.”
From Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines (2017) · cites this paper as [10]
In the citing paper
“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”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [199]
In the citing paper
“Based on the potential toxicity of liposomes in clinical application,25,26 the success of the first approved small interfering RNA-lipid nanoparticle (LNP) therapeutic27 and mRNA COVID-19 vaccines originates only from their delivery using ionizable lipid-containing LNPs,28, 29, 30”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [30]
In the citing paper
“In preclinical studies, mRNA vaccines encoding either the native RSV F protein or the stabilized prefusion conformation were successfully delivered using cationic nanoemulsions109 and LNPs179,180 without any observed instances of VAED.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [180]
Citations
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Recent Advances in Messenger Ribonucleic Acid (mRNA) Vaccines and Their Delivery Systems: A Review
Belay, W. Y., Nibret, G., & Aschale, Y. (2023) · Clinical Pharmacology Advances and Applications · doi:10.2147/cpaa.s418314 · Cited by 16
Poly(2-oxazoline)/saRNA Polyplexes for Targeted and Nonviral Gene Delivery
Hayes, G., Barbieri, B. D., Yilmaz, G., Shattock, R. J., & Becer, C. R. (2023) · Biomacromolecules · doi:10.1021/acs.biomac.3c00683 · Cited by 14
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Self-citationRNA vaccines: A transformational advance
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“The concept of self-amplifying mRNA vaccine was first described in the early 2000s [16,17], but the large size of sa-mRNA, complex manufacturing and release processes, and lower stability compared with smaller mRNAs delayed the transition to the clinic.”
Self-amplifying RNA in lipid nanoparticles: a next-generation vaccine?
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“, electroporation(19) or formulation into lipid-nanoparticles.(20,21) Intriguingly, relatively little is known about the molecular”
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The Perspective on Bio-Nano Interface Technology for Covid-19
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“The mRNA and DNA based vaccines are straggled by the degradation of extracellular RNase and nucleases, hence the delivery vehicle is vital in both cases (Geall et al., 2012; Lung P. et al., 2020).”
BackgroundMaruggi, G., Shaw, C. A., Otten, G. R., Mason, P. W., & Beard, C. W. (2013) · Virology · doi:10.1016/j.virol.2013.07.021 · Cited by 14
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Nucleic acid vaccines: innovations, efficacy, and applications in at-risk populations
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Messenger RNA as a Novel Therapeutic Approach
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Nanomedicine & Nanotoxicology Future Could Be Reshaped Post-COVID-19 Pandemic
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Review: Development of SARS-CoV-2 immuno-enhanced COVID-19 vaccines with nano-platform
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“This unique feature allows sa-mRNA to achieve higher and more sustained activity with lower doses 18 .”
Advances in the development of lipid nanoparticles for ophthalmic therapeutics
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Clinical Development of mRNA Vaccines: Challenges and Opportunities
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“1 μg of these vectors injected intramuscularly was able to immunize mice [6].”
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“A critical problem is how to enhance transfection and entry into cells/nuclei of cells when applying DNA vaccines [24,25] or how to stabilize and protect RNA molecules until their delivery into the cytoplasm [26,27].”
BackgroundA Review of the Progress of COVID-19 Vaccine Development
Ullah, S., Al-Sehemi, A. G., Klemeš, J. J., SAQIB, S., GONDAL, S. M. A., SAQIB, S., ARSHAD, A., Saqib, H., Mukhtar, A., IBRAHIM, M., et al. (2021) · Düzce Tıp Fakültesi Dergisi · doi:10.18678/dtfd.890089 · Cited by 12
Nam, H. H., & Ison, M. G. (2021) · Seminars in Respiratory and Critical Care Medicine · doi:10.1055/s-0041-1736182 · Cited by 12
Jiskoot, W., Kersten, G. F. A., Mastrobattista, E., et al. (2019) · Springer eBooks · doi:10.1007/978-3-030-00710-2_14 · Cited by 12
Revolutionizing Cancer Vaccine: The Power of Advanced Nanotechnology
Udayakumar, S., Pandiarajan, S., Mercy, D. J., Suresh, J., kumar, J. R. J., Girigoswami, A., & Girigoswami, K. (2025) · Chemistry · doi:10.3390/chemistry7030097 · Cited by 11
Research progress of mRNA vaccines for infectious diseases
Zhang, Z., Du, J., Zhang, D., Han, R., Wu, X., & Liang, Y. (2025) · European journal of medical research · doi:10.1186/s40001-025-03060-x · Cited by 19
Aviña, A. E., Paz, D. D., Huang, S.-C., Chen, K., Chang, Y., Lee, C.-M., Lin, C.-H., Wei, F., & Wang, A. Y. L. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.02.016 · Cited by 12
Michels, C. A., Perrier, D., Kunadhasan, J., Clark, E., Gehrett, J., Gehrett, B., Kwiatek, K., Adams, S., Chandler, R. W., Stagno, L., et al. (2023) · International Journal of Vaccine Theory Practice and Research · doi:10.56098/ijvtpr.v3i1.85 · Cited by 11
Multimeric RNAs for efficient RNA-based therapeutics and vaccines
Kim, D., Han, S. W., Ji, Y., Moon, S., Nam, H., & Lee, J. B. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.03.052 · Cited by 11
Biodegradable Polyester Nanoparticle Vaccines Deliver Self‐Amplifying mRNA in Mice at Low Doses
Wilson, D. R., Tzeng, S. Y., Rui, Y., Neshat, S. Y., Conge, M., Luly, K. M., Wang, E. B., Firestone, J. L., McAuliffe, J., Maruggi, G., et al. (2023) · Advanced Therapeutics · doi:10.1002/adtp.202200219 · Cited by 12
Technologies for making new vaccines
Ellis, R. W., Rappuoli, R., & Ahmed, S. (2013) · Elsevier eBooks · doi:10.1016/b978-1-4557-0090-5.00013-6 · Cited by 11
Self-citationCell Reprogramming and Differentiation Utilizing Messenger RNA for Regenerative Medicine
Inagaki, M. (2023) · Journal of Developmental Biology · doi:10.3390/jdb12010001 · Cited by 11
“In 2012, Geall et al. successfully prepared the first LNPs encapsulating an mRNA vaccine [26].”
BackgroundKatopodi, T., Petanidis, S., Grigoriadou, E., Anestakis, D., Charalampidis, C., Chatziprodromidou, I. P., Floros, G., Eskitzis, P., Zarogoulidis, P., Koulouris, C., et al. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16040455 · Cited by 11
“Nucleic acid vaccines have exhibited benefits over conventional vaccinations, including safety, specificity for eliciting an immune response to the target antigen, elicitation of both humoral and cellular immunological responses, and relative affordability and simplicity of manufacturing [60].”
BackgroundCancer nanotechnology: a new approach to upgrade cancer diagnosis and therapy
Rad, D. M., Nazari, H., Naei, V. Y., Lotfi, M., Aref, A. R., & Warkiani, M. E. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15518-5.00013-6 · Cited by 11
Intradermal Electroporation of RNA
Knudsen, M. L., Ljungberg, K., Liljeström, P., & Johansson, D. X. (2014) · Methods in molecular biology · doi:10.1007/978-1-4614-9632-8_13 · Cited by 10
Li, X., Dai, X., Pan, Y., Sun, Y., Yang, B., Chen, K., Wang, Y., Xu, J., Dong, Y., Yang, Y. R., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c08930 · Cited by 9
Chen, J., Pan, L., Lu, Y. Z., Zhang, T., Xu, D., Yan, S., & Ouyang, Z. (2023) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2023.2276624 · Cited by 10
“21,22 23–28 Despite extensive efforts, no approvals were obtained during this period.”
BackgroundBonsmann, M. S. G., Niezold, T., Hannaman, D., Überla, K., & Tenbusch, M. (2016) · Vaccine · doi:10.1016/j.vaccine.2016.02.059 · Cited by 10
DeLong, R. K., & Curtis, C. B. (2016) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1415 · Cited by 10
Dendritic Cell Targets for Self-Replicating RNA Vaccines
(2014) · Journal of Blood & Lymph · doi:10.4172/2165-7831.1000132 · Cited by 10
“Although Alphavirus replicon RNA application was reported with lipid-based formulations [50], no interaction with DCs was demonstrated.”
BackgroundThe COVID-19 Vaccine Landscape
Koch, T., Fathi, A., & Addo, M. M. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-63761-3_31 · Cited by 11
Alphavirus vectors as tools in neuroscience and gene therapy
Lundstrom, K. H. (2015) · Virus Research · doi:10.1016/j.virusres.2015.08.015 · Cited by 10
Lipid Nanoparticle-based mRNA Therapeutics for Infectious Diseases
Kumar, R., Kommineni, N., Aadil, K. R., Desai, N., Bunekar, N., Salave, S., Bulusu, R., Kumar, D., & Vora, L. K. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.126420 · Cited by 12
The dawn of a new Era: mRNA vaccines in colorectal cancer immunotherapy
Song, J., Zhang, Y., Zhou, C., Zhan, J., Cheng, X., Huang, H., Mao, S., & Zong, Z. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112037 · Cited by 10
Anderluzzi, G., Mohamed, T., Moschetti, G., Favero, E. D., Rizzello, L., Magnaghi, V., Franzè, S., & Cilurzo, F. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s513568 · Cited by 9
“7 A range of nanoparticle-based systems have been developed for DNA delivery, with those based on cationic lipids (lipoplexes) and cationic polymers (polyplexes) being the most studied.”
The mRNA Vaccine Heralds a New Era in Vaccinology
Shinde, K., Bendre, S., Kale, N., & Gilda, S. (2022) · Asian Journal of Pharmacy and Technology · doi:10.52711/2231-5713.2022.00042 · Cited by 9
Yasmin, T., Adiba, M., Saba, A. A., et al. (2022) · Bioinformatics and Biology Insights · doi:10.1177/11779322221142122 · Cited by 9
Application of DNA Replicons in Gene Therapy and Vaccine Development
Lundstrom, K. H. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15030947 · Cited by 9
“Moreover, nanoparticle encapsulation of VEE RNA replicons (RNA/LNPs) has been compared to recombinant VEE, particles, naked RNA replicons, VEE DNA replicons, and conventional plasmid DNA by monitoring Luc reporter expression [70].”
MethodFongaro, B., Campara, B., Moscatiello, G. Y., Luigi, A. D., Panzeri, D., Sironi, L., Bigini, P., Carretta, G., Miolo, G., Pasut, G., et al. (2023) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2023.123319 · Cited by 12
Girard, M. P., Picot, V., Longuet, C., & Nabel, G. J. (2013) · Vaccine · doi:10.1016/j.vaccine.2013.02.068 · Cited by 9
Zika virus: An emerging infectious disease with serious perinatal and neurologic complications
Casale, T. B., Teng, M. N., Morano, J. P., Unnasch, T. R., & Lockwood, C. J. (2017) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.11.029 · Cited by 9
“Replicons have been developed from a range of RNA viruses, including alphaviruses, picornaviruses, and flaviviruses.(69,70) In mRNAvaccines the antigens of interest are expressed directly from RNA.”
BackgroundMeasuring the Adjuvant Activity of RNA Vaccines
Pardi, N., & Weissman, D. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6481-9_8 · Cited by 9
Technologies for Making New Vaccines
Ahmed, S. S., Ellis, R. W., & Rappuoli, R. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-35761-6.00066-3 · Cited by 10
Self-citationA Comprehensive Dataset of Lipid Nanoparticle Compositions and Properties for Nucleic Acid Delivery
Song, S., Baek, J., & Seo, S. (2025) · Scientific Data · doi:10.1038/s41597-025-06456-w · Cited by 13
Immunotherapeutic approaches for HPV-caused cervical cancer
Fatemi, S. A., Seifi, N., Rasekh, S., Amiri, S., Moezzi, S. M. I., Bagheri, A., Fathi, S., & Negahdaripour, M. (2022) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2021.11.002 · Cited by 8
Emerging trends of research on mRNA vaccines: A co-citation analysis
Chen, J., Zhang, T., Lu, Y. Z., Yang, X., & Ouyang, Z. (2022) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2022.2110409 · Cited by 10
“In 2012, scientists developed a SAM vaccine encapsulated within an LNP, the immunogenicity of which was increased substantially as compared to conventional mRNA vaccines.(37) In 2013, a rapidly produced SAM vaccine for H7N9 influenza was proved to be immunogenic in mice.”
ResultEvolution of Vaccines Formulation to Tackle the Challenge of Anti-Microbial Resistant Pathogens
Tognetti, F., Biagini, M., Denis, M., Berti, F., Maione, D., & Stranges, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512054 · Cited by 8
“An mRNA sequence is typically composed of an open reading frame which encodes the target antigen and is flanked by untranslated regions (UTRs), a five-prime (5′) cap, and a terminal poly (A) tail [80].”
BackgroundmRNA vaccines against infectious diseases and future direction
Aleem, M. T., Munir, F., Shakoor, A., & Gao, F. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112320 · Cited by 10
Treatment alternatives for multidrug-resistant fungal pathogens
Roe, K. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103596 · Cited by 10
In situproduction of therapeutic monoclonal antibodies
Suscovich, T. J., & Alter, G. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.1001375 · Cited by 9
“Furthermore, due to the selfpropagation of the replicon, the gene of interest continues to be expressed in cells irrespective of cell division, and long-term (>2 months) replicon-mediated gene expression has been observed [101,102].”
BackgroundHikke, M. C., & Pijlman, G. P. (2016) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-031716-032328 · Cited by 8
Qu, J., Wang, S., Chen, C., Zhang, Y., Lai, S., Gu, R., Xie, W., Feng, Y., Lang, J., Huang, J., et al. (2025) · ACS Nano · doi:10.1021/acsnano.5c01000 · Cited by 7
Engaging Broader Stakeholders to Accelerate Group A Streptococcus Vaccine Development
Kong, D., Pān, H., Wu, H., & Chen, J. (2025) · Vaccines · doi:10.3390/vaccines13070734 · Cited by 7
“…nucleic acid-based platforms (including mRNA-LNP constructs encoding multiple virulence factors [131,132] and self-amplifying RNA systems [133,134]) and live vector delivery systems (such as attenuated Salmonella typhi vectors [135,136] and rhabdovirus-based delivery platforms [137,138])…”
Recent Developments of RNA Vaccines and Therapeutics: Reagents, Formulations, and Characterization
Tomeh, M. A., Smith, R. K., & Watkinson, A. (2025) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.5c00670 · Cited by 8
Ikrar, T., Muchsin, W., & Sophian, A. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115019 · Cited by 10
mRNA as a Therapeutics: Understanding mRNA Vaccines
Oğuz, F., & Atmaca, H. (2021) · Advanced Pharmaceutical Bulletin · doi:10.34172/apb.2022.028 · Cited by 8
“They obtained env specific immune responses with CD8 T cell responses using different delivery systems.(37) In recent studies, self-amplifying RNA-LNP encoding HIV1 Env gp140 protein implemented to mice, as a result, antigen-specific IgG response was detected.”
BackgroundMethodMeldgaard, T. S., Blengio, F., Maffione, D., Sammicheli, C., Tavarini, S., Nuti, S., Kratzer, R., Medini, D., Siena, E., & Bertholet, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.757151 · Cited by 7
“RNA Synthesis and SAM-H1/CNE Formulation RNA was prepared as previously reported (33, 34).”
MethodApplications of self-replicating RNA
Lundstrom, K. H. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.03.006 · Cited by 7
Developing New Tools to Fight Human Pathogens: A Journey through the Advances in RNA Technologies
Costa, V., Costa, S. M., Saramago, M., Cunha, M. V., Arraiano, C. M., Viegas, S. C., & Matos, R. G. (2022) · Microorganisms · doi:10.3390/microorganisms10112303 · Cited by 8
Poultry Vaccine Technology Platforms
Bublot, M. (2023) · Avian Diseases · doi:10.1637/aviandiseases-d-23-99987 · Cited by 8
Patwa, A. N., Salgado, G. F. J., Dolé, F., et al. (2013) · Organic & Biomolecular Chemistry · doi:10.1039/c3ob41707g · Cited by 7
Modified mRNA-Based Vaccines Against Coronavirus Disease 2019
Wang, A. Y. L. (2022) · Cell Transplantation · doi:10.1177/09636897221090259 · Cited by 7
Banda, O. A., Adams, S. E., Omer, L., Jung, S. K., Said, H., Phoka, T., Tam, Y. K., Weissman, D., Rivella, S., Alameh, M., et al. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102423 · Cited by 6
On‐Chip De Novo Production of mRNA Vaccine in Lipid Nanoparticles
Zilberzwige‐Tal, S., Levin, A., Ezra, A., Elia, U., Finkelstein‐Zuta, G., Kreiser, T., Gershon, L., Goldsmith, M., Kon, E., Navon, Y., et al. (2025) · Small · doi:10.1002/smll.202500114 · Cited by 7
Evaluation of bird-adapted self-amplifying mRNA vaccine formulations in chickens
Comes, J. D. G., Doets, K., Zegers, T., Kessler, M., Slits, I., Ballesteros, N. A., van de Weem, N. M. P., Pouwels, H., van Oers, M. M., van Hulten, M. C. W., et al. (2024) · Vaccine · doi:10.1016/j.vaccine.2024.03.032 · Cited by 6
Potential and development of cellular vesicle vaccines in cancer immunotherapy
Zhao, W., Li, X., Guan, J., Yan, S., Teng, L., Sun, X., Dong, Y., Wang, H., & Tao, W. (2025) · Discover Oncology · doi:10.1007/s12672-025-01781-3 · Cited by 8
Viral Vector-Based Cancer Vaccines
Lundstrom, K. H. (2025) · Methods in molecular biology · doi:10.1007/978-1-0716-4542-0_9 · Cited by 6
Path to Success and Future Impact of Nucleic Acid Vaccines: DNA and mRNA
Ulmer, J. B., & Liu, M. A. (2021) · Molecular Frontiers Journal · doi:10.1142/s2529732521400022 · Cited by 6
Self-citationMiliotou, Α. N., Foltopoulou, P. F., Ingendoh‐Tsakmakidis, A., Tsiftsoglou, A. S., Vizirianakis, I. S., Pappas, I. S., & Papadopoulou, L. C. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15010286 · Cited by 7
Pascolo, S. (2023) · European Journal of Immunology · doi:10.1002/eji.202249941 · Cited by 6
Bera, K., Rojas-Gómez, R. A., Mukherjee, P., Snyder, C. E., Aksamitiene, E., Alex, A., Spillman, D. R., Marjanović, M., Shabana, A. A., Johnson, R., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-54697-3 · Cited by 6
“SAM is a synthetic mRNA vaccine platform that encodes the antigen of interest and the viral replication machinery required for intracellular RNA amplification 4 .”
BackgroundsiRNA and Gene Formulation for Efficient Gene Therapy
Ian, S., & Abdelkader, A. (2013) · InTech eBooks · doi:10.5772/55518 · Cited by 5
“This technology elicited broad, potent, and protective immune responses, comparable with those achieved by a viral delivery system, but without the inherent limitations of viral vectors [181].”
BackgroundNanoparticle-based delivery of self-amplifying RNA
Lundstrom, K. H. (2020) · Gene Therapy · doi:10.1038/s41434-020-0132-1 · Cited by 6
Vaccines and vaccine resistance: Past, present and future
Khardori, N. M. (2021) · Indian Journal of Medical Microbiology · doi:10.1016/j.ijmmb.2021.12.008 · Cited by 6
Harnessing nucleic acid technologies for human health on earth and in space
Sarli, S. L., & Watts, J. K. (2022) · Life Sciences in Space Research · doi:10.1016/j.lssr.2022.08.006 · Cited by 6
“These alphavirus genes code for nonstructural proteins that form the RNA-dependent RNA polymerase (RdRP) complex which amplifies and sus-tains in situ transgene expression (Geall et al. 2012, Bloom et al. 2021).”
Controlling Protein Expression by Delivery of RNA Therapeutics Using Lipid Nanoparticles
Lin, P. J. C., & Tam, Y. K. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814470-1.00009-5 · Cited by 6
Development of Gene-Based Vectors for Immunization
Weiner, D. B., & Nabel, G. J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-35761-6.00067-5 · Cited by 9
Marquez-Martinez, S., Salisch, N. C., Serroyen, J., Zahn, R. C., & Khan, S. (2024) · PLoS ONE · doi:10.1371/journal.pone.0299215 · Cited by 6
“RNA-based vaccines have been reported to express the SARS-COV-2 Spike transgene for over 9 days (mRNA) [41] or up to 63 days (saRNA) [26] in mice; and up to day 60 in humans [27].”
BackgroundEmerging lipid nanoparticle systems capable of efficient intramuscular RNA delivery
Raza, A., Zhang, R., Lu, R., Wen, J., & Wu, W. (2025) · Nanomedicine · doi:10.1080/17435889.2025.2555507 · Cited by 7
Canestrale, A. R., Kholia, S., Dimuccio, V., & Sanchez, M. B. H. (2025) · Journal of Personalized Medicine · doi:10.3390/jpm16010001 · Cited by 6
mRNA technology for the prevention and treatment of HIV-1 infection
Chuang, L. I. U., Yaremenko, A. V., Li, X., You, X., Zhu, X., Liu, N., Chen, W., Kong, N., Xie, T., Gaiha, G. D., et al. (2026) · Nature Reviews Bioengineering · doi:10.1038/s44222-025-00387-2 · Cited by 6
Immunological mechanisms of mRNA vaccines for infectious diseases
Locci, M., & Pardi, N. (2026) · Nature · doi:10.1038/s41586-026-10599-0 · Cited by 6
“It was demonstrated that LNPs can also be used for mRNA vaccines because they protect the mRNA from degradation and allow its efficient delivery into the cytosol of cells 31,52 .”
RNA-lipid nanoparticle therapeutics for women’s health
Nomani, A., Saraswat, A. L., Zhang, Y., Parenky, A. C., Kuo, C.-T. J., Brown, H., Hartford, S. A., Rayaprolu, B. M., Bhalla, A. S. B., & Shameem, M. (2025) · Frontiers in Nanotechnology · doi:10.3389/fnano.2025.1475969 · Cited by 7
Delivery Vehicles for Self-amplifying RNA
Bathula, N. V., Popova, P. G., & Blakney, A. K. (2022) · RNA technologies · doi:10.1007/978-3-031-08415-7_16 · Cited by 6
Duhen, R., Beymer, M., Jensen, S. M., Abbina, S., Abraham, S., Jain, N., Thomas, A. M., Geall, A. J., Hu, H., Fox, B. A., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.896310 · Cited by 5
Self-citation
Metadata
- Authors
- Geall, A. J., Verma, A., Otten, G. R., Shaw, C. A., Hekele, A., Banerjee, K., Cu, Y., Beard, C. W., Brito, L. A., Krucker, T., O’Hagan, D. T., Singh, M., Mason, P. W., Valiante, N. M., Dormitzer, P. R., Barnett, S. W., Rappuoli, R., Ulmer, J. B., & Mandl, C. W.
- Affiliations
- Novartis Vaccines and Diagnostics, Cambridge, MA 02139; and
- Novartis Institutes for BioMedical Research, Cambridge MA 02139
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08-20
- Volume
- 109
- Issue
- 36
- Pages
- 14604-14609
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3437863
- OpenAlex
- W2051665875
- Cited by
- 675
- References
- 41
- Citations by year
- 2026: 34 · 2025: 63 · 2024: 66 · 2023: 66 · 2022: 79 · 2021: 78 · 2020: 74 · 2019: 41 · 2018: 31 · 2017: 28 · 2016: 31 · 2015: 27 · 2014: 31 · 2013: 24 · 2012: 2
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (5P01 AI066287, P01AI066287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- self-amplifying RNA vaccine, lipid nanoparticles, siRNA delivery, nucleic acid vaccines, immunogenicity, protective immune response
- MeSH terms
- Alphavirus, Analysis of Variance, Animals, Electrophoresis, Agar Gel, Escherichia coli, Female, Fluorescent Antibody Technique, Humans, Lipids, Drug Delivery Systems, Statistics, Nonparametric, Vaccines, DNA, RNA, Small Interfering, Rats, Nanoparticles
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