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Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial
Open accessAbstract
Introduction In a first-in-human study immune responses to rabies virus glycoprotein (RABV-G)-mRNA vaccine were dependent on the route of administration, necessitating specialized devices. Following successful preclinical studies with mRNA encapsulated in lipid nanoparticles (LNP), we tested an mRNA-LNP formulation (CV7202).Methods In this phase 1, multi-center, controlled study in Belgium and Germany we enrolled 55 healthy 18-40-year-olds to receive intramuscular injections of 5 μg (n = 10), 1 μg (n = 16), or 2 μg (n = 16) CV7202 on Day 1; subsets (n = 8) of 1 μg and 2 μg groups received second doses on Day 29. Controls (n = 10) received rabies vaccine, Rabipur, on Days 1, 8 and 29. Safety and reactogenicity were assessed up to 28 days post-vaccination using diary cards; immunogenicity was measured as RABV-G-specific neutralizing titers (VNT) by RFFIT and IgG by ELISA.Results As initially tested doses of 5 μg CV7202 elicited unacceptably high reactogenicity we subsequently tested 1 and 2 μg doses which were better tolerated. No vaccine-related serious adverse events or withdrawals occurred. Low, dose-dependent VNT responses were detectable from Day 15 and by Day 29%, 31% and 22% of 1, 2 and 5 μg groups, respectively, had VNTs ≥ 0·5 IU/mL, considered an adequate response by the WHO. After two 1 or 2 μg doses all recipients had titers ≥ 0.5 IU/mL by Day 43. Day 57 GMTs were not significantly lower than those with Rabipur, which elicited adequate responses in all vaccinees after two doses. CV7202-elicited VNT were significantly correlated with RABV-G-specific IgG antibodies (r 2 = 0.8319, p < 0.0001).Conclusions Two 1 μg or 2 μg doses of CV7202 were well tolerated and elicited rabies neutralizing antibody responses that met WHO criteria in all recipients, but 5 μg had unacceptable reactogenicity for a prophylactic vaccine. ClinicalTrials.gov Identifier: NCT03713086.
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TL;DR
In a phase 1 first-in-human trial, an unmodified mRNA rabies vaccine encapsulated in lipid nanoparticles (CV7202) was tested in healthy adults; 5 μg caused unacceptable reactogenicity, while two 1 μg or 2 μg doses were better tolerated and elicited rabies neutralizing antibody responses meeting WHO criteria in all recipients. The authors conclude this supports the mRNA-LNP platform for low-dose prophylactic vaccines.
Key findings
- The initially tested 5 μg dose elicited high early-onset reactogenicity in 9/10 (90%) participants, including severe solicited systemic AEs in 6/10 (60%); 1 μg and 2 μg doses were better tolerated, with no vaccine-related serious adverse events or withdrawals.
- After two 1 μg or 2 μg CV7202 doses, all recipients had virus-neutralizing titers (VNT) ≥ 0.5 IU/mL by Day 43; Day 57 GMTs were not significantly lower than those with three doses of Rabipur (p = 0.2831 for 1 μg, p = 0.3507 for 2 μg).
- Peak VNT GMTs at Day 43 were 4.8 IU/mL (95% CI 1.77–13.0) for 1 μg and 4.2 IU/mL (95% CI 1.02–17.2) for 2 μg; Rabipur peaked at 13.5 IU/mL (95% CI 5.95–30.6) at Day 15.
- CV7202-elicited VNT were significantly correlated with RABV-G-specific IgG antibodies after two doses (r² = 0.8319, p < 0.0001).
Methods
- Non-randomized, open-label, controlled, dose-escalation, multi-center phase 1 study at University Hospital LMU Munich, Germany and University of Ghent, Belgium; 55 healthy 18–40-year-olds enrolled, with 53 assigned to CV7202 5 μg (n = 10), 2 μg (n = 16), 1 μg (n = 16), or Rabipur control (n = 11 per Table 1; abstract states n = 10 controls).
- Participants received intramuscular CV7202 on Day 1; subsets (n = 8) of the 1 μg and 2 μg groups received a second dose on Day 29; controls received Rabipur on Days 1, 8, and 29.
- Safety/reactogenicity were assessed through 28 days post-vaccination by diary cards; immunogenicity measured RABV-G-specific neutralizing titers by RFFIT and IgG by ELISA; analyses were descriptive only, with no confirmatory statistical inference.
Limitations
- The paper states this is a small trial and an interim report presenting immune responses only up to four weeks after the second dose; participants are to be monitored for two years for long-term safety and persistence of immune response.
- The authors state further investigations are needed for booster responses, long-term immune memory, avidity, IgG subclasses, and B cell responses, and note that direct comparison of kinetics with Rabipur is complicated by different vaccination schedules and no second 5 μg dose.
- Evident from the text: the study was non-randomized and open-label, used descriptive statistics without confirmatory inference, had small group sizes, and enrolled a predominantly White population; no efficacy or challenge data are reported.
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Claims the paper makes
73 Own result · 10 Own interpretation · 6 Own method · 4 Partly supported · 4 No full text of the sources · 2 Supported · 1 Couldn’t confirm · 1 Sources not found · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These transient changes were not considered to represent toxicity but rather redistribution of lymphocytes due to the vaccine’s mode of action as has been observed for other vaccines [12], [13].”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
What the sources say
- Partly supportedcites [12] Hopkins R.J. Daczkowski N.F. Kaptur P.E. Randomized, double-blind, placebo-controlled, safety and immunogenicity study of 4 formulations of Anthrax Vaccine Adsorbed plus CPG 7909 (AV7909) in healthy adult volunteers Vaccine 31 2013 3051 3058 23701746 PMC3687017 sourceExperimental — accuracy not yet measured
The Discussion reports transient lymphopenia after AV7909 and says it may result from altered lymphocyte trafficking; it also notes similar findings in other trials using CPG 7909 as a vaccine adjuvant. It does not establish redistribution as the cause or say the changes were not toxicity. The Results > Safety section classifies lymphopenia as a vaccination-related adverse event, including one severe case. (LLM, conf=0.87)
- Partly supportedcites [13] Kløverpris H.N. Akil Jackson A. Handley A. Non-immunogenicity of overlapping Gag peptides pulsed on autologous cells after vaccination of HIV infected individuals PLoS ONE 8 2013 e74389 PMC3790804 24124451 sourceExperimental — accuracy not yet measured
The Results section reports transient lymphopenia after OPAL-HIV-Gag(c) vaccination, and the Discussion says the rapid recovery suggests redistribution of lymphocytes. The paper presents redistribution as an inference, not an established mechanism; the passages do not explicitly classify the changes as non-toxic or say they were observed with other vaccines. Page numbers are unavailable in our copy. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Intracellular delivery of oligonucleotides can be improved by encapsulating them in lipid nanoparticles (LNP) [9], [23]”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
What the sources say
- Supportedcites [9] Lutz J. Lazzaro S. Habbeddine M. Schmidt K.E. Baumhof P. Mui B.L. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines npj Vaccines 2 2017 29 29263884 PMC5648897 source
The Discussion says LNPs can enhance cellular delivery of nucleic acids by improving uptake and facilitating endosomal escape. The Results provide a direct example: LNP-formulated mRNA produced significantly higher expression in mouse muscle than unformulated mRNA. (LLM, conf=0.91)
- Supportedcites [23] Reichmuth A.M. Oberli M.A. Jaklenec A. Langer R. Blankschtein D. mRNA vaccine delivery using lipid nanoparticles Ther Deliv 7 2016 319 334 27075952 PMC5439223 source
The passage labeled Abstract (page not supplied) says LNP lipids facilitate oligonucleotide release in the cytosol and mRNA uptake and endosomal escape into the cytoplasm. This supports the claim that LNP encapsulation can improve intracellular delivery. (LLM, conf=0.89)
plaindirect- 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
“preclinical studies showed that protecting the mRNA by lipid encapsulation significantly enhanced the response to the CV7201 [9], [24].”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
What the sources say
- Partly supportedcites [9] Lutz J. Lazzaro S. Habbeddine M. Schmidt K.E. Baumhof P. Mui B.L. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines npj Vaccines 2 2017 29 29263884 PMC5648897 sourceExperimental — accuracy not yet measured
The Results section (‘LNP-formulated mRNA induces strong humoral and cellular responses in mice’; page unavailable) reports substantially higher rabies-neutralizing antibody titers and stronger cellular responses with LNP-formulated RABV-G mRNA than with non-formulated mRNA. The Discussion says LNPs protect mRNA from RNases. Our copy does not identify the LNP-formulated vaccine as CV7201, so the CV7201-specific part of the claim is not established. (LLM, conf=0.86)
- Partly supportedcites [24] Armbruster N. Jasny E. Petsch B. Advances in RNA vaccines for preventive indications: A case study of a vaccine against rabies Vaccines (Basel) 7 2019 pii: E132 PMC6963972 31569785 sourceExperimental — accuracy not yet measured
Section 3 reports that lipid-nanoparticle encapsulation substantially increased antibody responses to rabies-glycoprotein mRNA in mice compared with plain mRNA. But Section 2.1 identifies CV7201 as a protamine-formulated vaccine, while Section 3 identifies the LNP formulation as CV7202. The enhanced response is therefore supported for the LNP-formulated rabies mRNA, not for CV7201 as named in the claim. (LLM, conf=0.88)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Partly 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
“There were no immediate reactions or AEs during the four-hour post-vaccination surveillance period in any participant”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plain- 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
“There were single cases of severe AEs—neck stiffness, excessive sweating, hip stiffness, pre-syncopal episode, hot flushes, thirst, lack of thirst, perceived dehydration, weakness, and lethargy—some in the same participant.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
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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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
“As initially tested doses of 5 μg CV7202 elicited unacceptably high reactogenicity”
- Also stated in: § Safety · plain
“following the administration of one dose of vaccine in the 5 μg group there was a high rate of early onset reactogenicity which affected 9 (90%) of the 10 participants (Table 2 ).”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Abstract > Results
plaindirectn = 10- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Safety · plain
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
“No participant withdrew from the study due to an AE.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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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
“we subsequently tested 1 and 2 μg doses which were better tolerated.”
- Also stated in: § Safety · plain
“Following the study hiatus, 1 and 2 μg dosages of CV7202 were administered and were associated with a much lower reactogenicity profile (Table 3 ).”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Abstract > Results
plaincorrelationaln = 16- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Safety · plain
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
“Day 43 GMTs after two doses of CV7202 were not statistically significantly lower than those achieved with three doses of Rabipur (p = 0.2831 for 1 µg, p = 0.3507 for 2 µg; Mann-Whitney test).”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – Neutralizing antibodies
plain- 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
“which elicited adequate responses in all vaccinees after two doses.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 47
- Probably not a substantial claim. 16
- The quote only partly states this claim. 1
Every source the paper cites for this claim was checked and supports it.
In the paper
“Further preclinical research in animal models has found that formulation of the mRNA in lipid nanoparticles (LNP) protects the mRNA and enhances the immune response [9].”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Introduction
What the sources say
- Supportedcites [9] Lutz J. Lazzaro S. Habbeddine M. Schmidt K.E. Baumhof P. Mui B.L. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines npj Vaccines 2 2017 29 29263884 PMC5648897 source
The Discussion states that LNPs protect mRNA from RNases and that LNP-formulated mRNA produced strong immune responses in mice. The Results section reports substantially higher antibody titers and stronger cellular responses in mice than with non-formulated mRNA. Page numbers were not provided in our copy. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Rabies virus-specific serum neutralizing titers (VNT) were measured using the WHO-recommended rapid fluorescent focus inhibition test (RFFIT) [13] at the accredited Kansas State University Rabies Laboratory.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Methods > Virus-neutralizing antibodies
What the sources say
- Could not verifycites [13] Kløverpris H.N. Akil Jackson A. Handley A. Non-immunogenicity of overlapping Gag peptides pulsed on autologous cells after vaccination of HIV infected individuals PLoS ONE 8 2013 e74389 PMC3790804 24124451 sourceExperimental — accuracy not yet measured
The Methods sections describe HIV Gag-specific IFNγ ELIspot and intracellular cytokine staining assays, not rabies-virus neutralization testing. Searches for RFFIT, rabies neutralizing titers, WHO guidance, and the Kansas State University Rabies Laboratory found no passage addressing the cited method. (LLM, conf=0.76)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Meulengracht-Gilbert Syndrome (MGS), a benign genetic disorder which is present in approximately 10% of young men in Bavaria and affects bilirubin processing leading to elevated levels of unconjugated bilirubin in the blood [14], [15], [16].”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
What the sources say
- Not checked — no full text of the sourcecites [14] Sieg A. Arab L. Schlierf G. Stiehl A. Kommerell B. Die Prävalenz des Gilbert-Syndroms in Deutschland Prevalence of Gilbert's syndrome in Germany Dtsch Med Wochenschr 112 1987 1206 1208 3608845 source
- Not checked — no full text of the sourcecites [15] Strassburg C.P. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome) Best Pract Res Clin Gastroenterol 24 2010 555 571 20955959 source
- Partly supportedcites [16] Wagner K.H. Shiels R.G. Lang C.A. Khoei N.S. Bulmer A.C. Diagnostic criteria and contributors to Gilbert’s syndrome Crit Rev Clin Lab Sci 55 2018 129 139 29390925 sourceExperimental — accuracy not yet measured
The ‘Bilirubin biology—An evolutionary perspective’ section describes Gilbert-Meulengracht syndrome as benign, reports a 2–10% prevalence among people of Caucasian ethnicity, and links elevated unconjugated bilirubin to genetic changes affecting its processing. It does not give a prevalence specifically for young men in Bavaria, so the claim’s population-specific figure is not supported by this source. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“This contrasts with recent reports of mRNA-LNP vaccines against the SARS-CoV-2 virus responsible for the COVID-19 pandemic which had similar rates of reactogenicity and in which reactogenicity noticeably increased after a second dose [17], [18].”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
What the sources say
- Partly supportedcites [17] Mulligan M.J. Lyke K.E. Kitchin N. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults Nature 586 2020 589 593 32785213 sourceExperimental — accuracy not yet measured
The Discussion says BNT162b1 had a safety and tolerability profile consistent with earlier mRNA vaccines and that reactogenicity was generally higher after the second dose at the 10 µg and 30 µg levels. The safety results (p. 3) likewise report systemic events in more participants after dose two. The paper does not establish that its reactogenicity rates were similar to those of the vaccine discussed by the citing authors. (LLM, conf=0.83)
- Supportedcites [18] Jackson L.A. Anderson E.J. Rouphael N.G. An mRNA vaccine against SARS-CoV-2 - preliminary report New Engl J Med 383 2020 1920 1931 32663912 PMC7377258 source
The Vaccine Safety results report systemic adverse events after each dose, with higher rates after the second vaccination in all three dose groups. The Discussion likewise says greater reactogenicity followed the second vaccination and describes the safety profile as similar to those reported for other mRNA vaccines. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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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
“There was a high rate of solicited systemic adverse events in this group, with 41 events reported by 9 participants, 32 (78%) of which were described as mild or moderate, but 9 (22%) of which were described as ever in 6 participants.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 9- 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
“There was only one report of any other local reaction—a case of mild redness in one participant—with no reports of injection site swelling or itching.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“No vaccine-related serious adverse events or withdrawals occurred.”
- Also stated in: § Safety · plain
“there have been no vaccine-related SAEs or AESIs throughout the study to date.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Abstract > Results
plain- 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
“One Rabipur participant was hospitalized with appendicitis, which was not considered to be related to the vaccine.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainSingle case- 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 most frequent systemic AEs were headache, fatigue, myalgia and chills, the majority with onset within 24 h of vaccination on Days 1 or 2.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 9- 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 most frequent of these were three cases of lack of appetite (all severe), three cases of night sweats (two severe), two cases of dizziness (one severe), and two cases of tachycardia (one severe).”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 3- 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
“Severe cases of fatigue, chills and myalgia which occurred became moderate or mild within 24 h of onset, except for one case of severe fatigue that lasted for 29 h, and a second case of severe fatigue lasting three days with onset on Day 5 that was related to an acute gastroenteritis-like illness with nausea and vomiting.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plain- 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 majority of unsolicited AEs resolved within 24 h of onset and the only medication used for treatment of such AEs was ibuprofen, used by 4 of 10 (40%) participants.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 10- 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
“Unsolicited adverse events were reported by 9 (90%) of the 10 participants; 7 (70%) of these were considered to be related to vaccination, including 5 (50%) graded as severe.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plaindirectn = 10- 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
“All but one of the participants reported pain at the injection site, which was graded as severe in one case.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 10- 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
“GMTs were 853 U/mL (95% CI: 455–1599), 1581 U/mL (899–2780), and 2409 U/mL (1113–5215) at Day 29 after the first dose in the 1, 2, and 5 μg CV7202 groups, respectively, and these levels did not further increase in one dose groups.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – ELISA RABV-G-specific immunoglobulin antibodies
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
“All participants in the Rabipur group had titers ≥ 0·5 IU/mL by Day 15, 7 days after the second vaccination and this 100% rate was maintained up to Day 57.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – Neutralizing antibodies
plain- 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.
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
“Amongst the 16 participants of the 2 μg CV7202 group there was one (6%) report of severe injection site pain and three (19%) participants reported severe solicited systemic AEs; chills (two), headache (two) and myalgia (one).”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 16- 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
“Systemic AEs mainly consisted of transient mild or moderate headache, fatigue and chills, and any cases that were described as initially severe rapidly moderated and resolved, most within 48–72 h and all within the 7-day reporting period.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
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 third described previous clinically significant elevations which were added to their medical history.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainSingle 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.
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 the 1 μg CV7202 group there were no severe AEs reported, although 4 (25%) of the 16 participants in this group reported moderate AEs.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 16- 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
“Three unsolicited AEs were reported by two participants—one had a single episode of loose stool and another had two episodes of lower back pain—that were considered to be possibly related to the vaccination.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainconditionaln = 2- 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
“All but one of these reports occurred after the first dose, with onset on Days 1 or 2, all had improved to mild or moderate by Day 3 within 48 h and all but one had resolved by Day 4.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 16- 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
“In this small trial CV7202 appeared to be safe, with no vaccine-related SAEs or withdrawals due to AEs.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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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
“When these five participants were interviewed for more detail two reported that episodic jaundice and/or bilirubin elevations had been present ‘since youth’.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 2- 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 GMT did not further increase following a third dose of Rabipur but was maintained at 9·1 IU/mL through to Day 57.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – Neutralizing antibodies
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
“These were present in prevaccination (baseline) samples and post-vaccination samples in no specific pattern and with no particular association with any study vaccine.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 5- 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
“one participant had a split bilirubin typical for MGS and in combination with a history of raised elevations the diagnosis of MGS was marked in the medical history without genetic confirmation.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainSingle 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.
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
“A further incremental increase to 33,373 U/mL (21236–52447) was observed after the third dose and this level was sustained to Day 57.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – ELISA RABV-G-specific immunoglobulin antibodies
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
“Responses were markedly increased following the second dose on Day 29 such that 5 of the 8 (63%) participants who received a second dose of 1 μg and 7 of 8 (83%) participants who received a second dose of 2 μg had titers ≥ 0·5 IU/mL at Day 36.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – Neutralizing antibodies
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
“Three of the five had one or more bilirubin elevations that were marked as clinically significant during the conduct of the study, two of which were present at baseline.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 3- 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
“Following a 5 μg dose of CV7202, VNT levels ≥ 0·5 IU/ml were observed from Day 29 in two of nine (22%) participants and these responses were maintained up to Day 57, the last timepoint assessed (Fig. 3 ).”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – Neutralizing antibodies
plainn = 9- 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
“These were more pronounced in the 2 μg group in which 5 of 16 (31%) had VNT levels ≥ 0·5 IU/ by Day 29, whereas no participants in the 1 μg group displayed an adequate response (0·5 IU/mL) by Day 29 after one dose (Fig. 3).”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – Neutralizing antibodies
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
“The major finding from the laboratory safety assessments was the observation of transient lymphopenia at Day 2, the day after vaccination in 9 of 16 and 14 of 16 in the 1 and 2 μg CV7202 groups, respectively, and 6 of 8 and 8 of 8 in those groups at Day 30, one day after the second dose.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
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. The quote only partly states this claim.
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
“GMTs were higher than 0·5 IU/mL at Day 36 in both groups and were further increased at Days 43 and 57.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – Neutralizing antibodies
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
“Much larger increases were observed after second vaccinations, peaking at 34,186 U/mL (13253–88185) and 20,707 U/mL (5592–76678) at Day 43 in the 1 and 2 μg groups, respectively.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – ELISA RABV-G-specific immunoglobulin antibodies
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
“An IgG response was not detected one week after the first Rabipur vaccination; GMTs were 461 and 464 at Days 1 and 8, respectively, but rapidly increased to 12,460 U/mL (95% CI: 6575–23611) at Day 15, 7 days after the second dose.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – ELISA RABV-G-specific immunoglobulin antibodies
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
“An anomaly which was not considered to be vaccine-related was the observation of asymptomatic, isolated elevated bilirubin levels in several young male participants recruited at the Munich site which were not temporally associated with vaccination.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainn = 5- 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
“Following observations of high reactogenicity when using the 5 μg dose of CV7202 we found 1 and 2 μg dosages were better tolerated, with no safety concerns and two doses elicited immune responses in terms of neutralizing activity and IgG antibodies that were comparable with three doses of licensed rabies vaccine.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
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
“In a second suspected MGS participant split bilirubin was requested at a visit when total bilirubin was normal and there were no further elevations observed. Because of a childhood history of intermittent icterus on further questioning, suspected MGS was marked in their medical history.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainSingle 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.
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
“There were also transient increases in IgM antibodies but not IgA after second doses of Rabipur and CV7202 (data not shown), but direct comparison of the kinetics of these responses is complicated by the different vaccination schedules—1 and 8 days for licensed vaccine and 1 and 29 days for CV7202—and no second 5 μg dose.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
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
“Importantly, we showed that all recipients, despite the low amount of mRNA included in the vaccine, had functional antibody responses after two 1 or 2 μg doses of CV7202, with GMTs of both rabies-specific neutralizing and RABV-G-specific IgG antibodies that were not significantly lower than those observed after three doses of licensed rabies vaccine.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
boosted- 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.
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
“The study protocol was approved by the respective Ethical Committees of the two institutions and registered on ClinicalTrials.gov (NCT03713086).”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Methods
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. It may state two separate claims as one.
In the paper
“had VNTs ≥ 0·5 IU/mL, considered an adequate response by the WHO.”
- Also stated in: § Virus-neutralizing antibodies · plain
“with a titer ≥ 0·5 IU/mL considered an adequate response to vaccination [11].”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Abstract > Results
What the sources say
- Not checked — no full text of the sourcecites [11] WHO. Rabies vaccines WHO position paper. Wkly Epidemiol Rec 2007; 82:425–36. 18064757
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.
- Also stated in: § Virus-neutralizing antibodies · plain
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
“One participant from the Rabipur control group was lost to follow up after Day 1, and one participant in the 5 μg CV7202 group withdrew consent at Day 15 for personal reasons.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results
plainn = 2- 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.
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
“In this exploratory phase 1 trial we only used descriptive statistics, with no confirmatory statistical inference planned or performed.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Methods > ELISA for RABV-G-specific immunoglobulins
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. It may state two separate claims as one.
In the paper
“All solicited and unsolicited AEs were graded according to severity, using mild, moderate or severe as categories using the FDA toxicity grading scale [10].”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Methods > Study design and participants
What the sources say
- Not checked — no full text of the sourcecites [10] CDC. Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials (September 2007) Available at: https://www.fda.gov/media/73679/download Accessed 28 February 2020. 37532612 source
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.
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
“Trial procedures were done in accordance with International Conference on Harmonization (ICH) and Good Clinical Practice guidelines, and applicable regulatory requirements.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Methods
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. 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
“The remaining 51 participants completed study procedures through to the Day 57 visit.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results
plainn = 51- 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 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
“This was not observed in the 5 μg group as the first blood sampling in this group was conducted on Day 3, rather than Day 2, when lymphopenia was no longer present.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
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
“Two 1 μg or 2 μg doses of CV7202 were well tolerated and elicited rabies neutralizing antibody responses that met WHO criteria in all recipients”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Abstract > Conclusions
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 the third participant with clinically significant elevation of bilirubin results of the split bilirubin analysis was not typical for MGS, but the participant had a recent symptomatic acute CMV illness. Considering the pattern of bilirubin elevations, overall clinical picture and prevalence in Munich, per exclusionem MGS is still suspected in this participant who has been referred to their GP”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
plainSingle case- 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
“Having previously demonstrated the concept of mRNA vaccination in humans using rabies glycoprotein as antigen we have now confirmed the preclinical observations that lipid encapsulation also protects the mRNA molecule in humans and enhances the generation of protective immune responses after two doses in a similar manner to the inactivated control vaccine.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
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
“Our initial studies of the mRNA technology using rabies mRNA, CV7201, found that there was potential for a human mRNA rabies vaccine, but the mode of delivery of the molecule was critical to elicit an adequate immune response due to its known instability in physiological conditions [8].”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
What the sources say
- Not checked — no full text of the sourcecites [8] Alberer M. Gnad-Vogt U. Hong H.S. Mehr K.T. Backert L. Finak G. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial Lancet 390 2017 1511 1520 28754494 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.
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 already mentioned, using rabies as a model antigen presents several advantages in this early development program, but the principles being investigated can be applied to other viral pathogens.”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Discussion
plain- 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. It may state two separate claims as one.
The paper relies on this without support.
The virtually 100% fatality outcome of rabies disease means that volunteers in phase 1 trials, providing they have no history of rabies vaccination, will represent an immunologically naïve population.
“Furthermore, the virtually 100% fatality outcome of rabies disease means that volunteers in phase 1 trials, providing they have no history of rabies vaccination, will represent an immunologically naïve population.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Both CVnCoV and CV2CoV are based on RNActive technology4–7 and consist of non-chemically modified sequence-engineered mRNA without pseudouridine6–12.”
From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [12]
Experimental — accuracy not yet measuredIn the citing paper
“Phase I results suggest that two 1 µg doses yield high neutralizing titres, strong adaptive immune responses, and were well tolerated190.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [190]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“| Diarrhea | 2 (10) | 1 (10) | 1 (10) | 0 |”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
Reported 10 · recomputed 20
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
“| Fatigue | 7 (70) | 1 (10) | 3 (30) | 3 (30) |”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Safety
“| Fatigue | 8 (80) | 6 (38) | 4 (50) | 9 (56) | 5 (63) | 5 (45) | 5 (50) | 1 (10) |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“7 of 8 (83%) participants who received a second dose of 2 μg had titers ≥ 0·5 IU/mL at Day 36”
§ Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial > Results > Immunogenicity – Neutralizing antibodies
Reported 83 · recomputed 87.5
Citations
Cites
mRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667 · cited 1×
“Several mRNA vaccine candidates using this approach have been reported to be in development [22,23].”
BackgroundThe effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak
Chinazzi, M., Davis, J. T., Ajelli, M., Gioannini, C., Litvinova, M., Merler, S., Pastore y Piontti, A., Mu, K., Rossi, L., Sun, K., et al. (2020) · Science · doi:10.1126/science.aba9757 · Cited by 3,694 · cited 1×
“There are increasing risks of spread of novel pathogens through human vectors with international travel as evidenced by the 2020 Covid-19 pandemic [2], or animal vectors with climate change illustrated by the increasingly wide range of dengue, chikungunya and Zika virus endemicity [3–5].”
BackgroundAn mRNA Vaccine against SARS-CoV-2 — Preliminary Report
Jackson, L. A., Anderson, E. J., Rouphael, N. G., Roberts, P. C., Makhene, M., Coler, R. N., McCullough, M. P., Chappell, J. D., Denison, M. R., Stevens, L. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2022483 · Cited by 3,237 · cited 3×
“This contrasts with recent reports of mRNA-LNP vaccines against the SARS-CoV-2 virus responsible for the COVID-19 pandemic which had similar rates of reactogenicity and in which reactogenicity noticeably increased after a second dose [17,18].”
BackgroundResultMulligan, M. J., Lyke, K. E., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Neuzil, K., Raabe, V., Bailey, R., Swanson, K. A., et al. (2020) · doi:10.1101/2020.06.30.20142570 · Cited by 1,569 · cited 2×
“This contrasts with recent reports of mRNA-LNP vaccines against the SARS-CoV-2 virus responsible for the COVID-19 pandemic which had similar rates of reactogenicity and in which reactogenicity noticeably increased after a second dose [17,18].”
BackgroundResultThe current and future global distribution and population at risk of dengue
Messina, J. P., Brady, O. J., Golding, N., Kraemer, M. U. G., Wint, W., Ray, S. E., Pigott, D. M., Shearer, F. M., Johnson, K. B., Earl, L., et al. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0476-8 · Cited by 1,490
Chikungunya Virus and the Global Spread of a Mosquito-Borne Disease
Weaver, S. C., & Lecuit, M. (2015) · New England Journal of Medicine · doi:10.1056/nejmra1406035 · Cited by 988
mRNA vaccine delivery using lipid nanoparticles
Reichmuth, A. M., Oberli, M. A., Jaklenec, A., Langer, R., & Blankschtein, D. (2016) · Therapeutic Delivery · doi:10.4155/tde-2016-0006 · Cited by 624 · cited 9×
“Several mRNA vaccine candidates using this approach have been reported to be in development [22,23].”
BackgroundInfluentialAlberer, M., Gnad-Vogt, U., Hong, H. S., Mehr, K. T., Backert, L., Finak, G., Gottardo, R., Bica, M. A., Garofano, A., Koch, S. D., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)31665-3 · Cited by 530 · cited 2×
“We demonstrated the proof-of-concept of mRNA for human vaccines in the first-ever human clinical trial of RABV-G mRNA using an initial formulation (CV7201) with the cationic protein protamine [8].”
MethodResultSelf-citationThe promise of mRNA vaccines: a biotech and industrial perspective
Jackson, N. A. C., Kester, K. E., Casimiro, D., Gurunathan, S., & DeRosa, F. (2020) · npj Vaccines · doi:10.1038/s41541-020-0159-8 · Cited by 498
Petersen, E., Wilson, M. E., Touch, S., McCloskey, B., Mwaba, P., Bates, M., Dar, O. A., Mattes, F. M., Kidd, M., Ippolito, G., et al. (2016) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2016.02.001 · Cited by 362
Cited by
Sorted by citations
Items 201–204 of 204
Advances and Challenges in Nanodelivery Systems for RNA Vaccines
Li, H., Zhao, Y., Yang, J., Guo, J., Cai, H., & Tong, A. (2026) · ACS Nano · doi:10.1021/acsnano.6c10327 · Cited by 2
Liu, Y., Guo, X., Hu, Q., Gan, C., Nie, S., Xiang, J., Liu, Y., Zou, J., Wu, X., Li, C., et al. (2026) · Materials Today Bio · doi:10.1016/j.mtbio.2026.103568 · Cited by 3
Tian, C., Nie, J., Chen, Y., Dong, C., Ji, M., Liu, Y., Nie, J., Zhang, X., Sun, J., Gang, J., et al. (2026) · Materials & Design · doi:10.1016/j.matdes.2026.116854 · Cited by 1
Li, X., Hu, P., Chen, Y., et al. (2026) · Journal of Clinical Microbiology · doi:10.1128/jcm.00877-26
Metadata
- Authors
- Aldrich, C., Leroux–Roels, I., Huang, K. B., Bica, M. A., Loeliger, E., Schoenborn-Kellenberger, O., Walz, L., Leroux-Roels, G., von Sonnenburg, F., & Oostvogels, L.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- CureVac (Germany) (DE)
- Ghent University Hospital (BE)
- Corresponding author
- Oostvogels, Lidia
- Venue
- Vaccine
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 39
- Issue
- 8
- Pages
- 1310-1318
- ISSN
- 0264-410X (ISSN-L)
- PMC
- PMC7825876
- OpenAlex
- W3123863498
- Semantic Scholar
- 167dca1d8f3120bca1016be833118620c6addb05
- Cited by
- 204
- References
- 25
- Citations by year
- 2026: 18 · 2025: 35 · 2024: 43 · 2023: 41 · 2022: 44 · 2021: 22
- FWCI
- 18.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Vaccine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › Rabies epidemiology and control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- rabies vaccine, mRNA vaccines, lipid nanoparticles, rabies virus glycoprotein, low-dose vaccination, vaccine safety, reactogenicity, neutralizing antibodies, IgG, dose-dependent immune response, rabies prevention, route of administration, immunogenicity
- MeSH terms
- Immunogenicity, Vaccine, Antibodies, Viral, Belgium, Germany, Humans, Lipids, Rabies Vaccines, RNA, Messenger, Nanoparticles
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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