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Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants
Open accessAbstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its emerging variants of concern (VOC), such as Delta (B.1.617.2) and Omicron (B.1.1.529), has continued to drive the worldwide pandemic. Therefore, there is a high demand for vaccines with enhanced efficacy, high thermostability, superior design flexibility, and fast manufacturing speed. Here, we report a circular RNA (circRNA) vaccine that encodes the trimeric RBD of SARS-CoV-2 Spike protein. Without the need of nucleotide modification, 5’-capping or 3’-polyadenylation, circRNA could be rapidly produced via in vitro transcription and is highly thermostable whether stored in naked or lipid-nanoparticle (LNP)-encapsulated format. LNP-encapsulated circRNA RBD elicited potent neutralizing antibodies and T cell responses, providing robust protection against Beta (B.1.351) and native viruses in mice and rhesus macaques, respectively. Notably, circRNA vaccine enabled higher and more durable antigen production than 1mΨ-modified mRNA vaccine, eliciting a higher proportion of neutralizing antibodies and stronger Th1-biased immune responses. Importantly, we found that circRNA RBD-Omicron vaccine induced effective neutralizing antibodies against only Omicron but not Delta variant. By contrast, circRNA RBD-Delta could elicit high level of neutralizing antibodies against both Delta and Omicron. Following two doses of either native- or Delta-specific vaccination, circRNA RBD-Delta , but not Omicron or Beta vaccines, could effectively boost the neutralizing antibodies against both Delta and Omicron variants. These results suggest that circRNA RBD-Delta is a favorable choice for vaccination to provide a broad-spectrum protection against the current variants of concern of SARS-CoV-2.
Overview
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TL;DR
A circular RNA vaccine expressing trimeric SARS-CoV-2 RBD elicited neutralizing antibodies and T cell responses in mice and rhesus macaques, with higher and more durable antigen expression than 1mΨ-modified mRNA. The circRNARBD-Delta vaccine showed broad neutralization against Delta and Omicron and was an effective booster, whereas the Omicron-specific vaccine neutralized Omicron but not Delta.
Key findings
- LNP-circRNARBD induced RBD-specific IgG endpoint GMTs of ∼1.9 × 10⁴ (10 μg) and ∼5.7 × 10⁵ (50 μg) in mice, with pseudovirus NT50 ∼4.5 × 10³ and authentic SARS-CoV-2 NT50 ∼7.0 × 10⁴.
- circRNARBD-Delta elicited an NT50 of ∼1.4 × 10⁵ against Delta pseudovirus at 10 μg and maintained Omicron neutralization with NT50 ∼4.7 × 10³; as a third booster after two-dose circRNARBD, it raised Omicron geometric mean NT50 from ∼4 × 10² to ∼3.2 × 10⁴.
- circRNARBD-Omicron induced Omicron-specific IgG GMTs of ∼4.7 × 10⁴ (5 μg) and ∼2.2 × 10⁵ (10 μg), with Omicron NT50s of ∼2.5 × 10³ and ∼8.6 × 10³, but neutralizing activity was hardly detected against native strain or Delta.
- In rhesus macaques, circRNARBD IgG GMTs were ∼2.1 × 10⁴ (20 μg), ∼1.6 × 10⁴ (100 μg), and ∼7 × 10³ (500 μg); authentic virus NT50s were ∼80, ∼120, and ∼50, respectively. Vaccinated macaques showed nearly 1,000-fold reduced lung genomic RNA at 100/500 μg and nearly no detectable subgenomic RNA at all doses, with no severe clinical adverse effects.
Methods
- circRNA vaccines encoded trimeric SARS-CoV-2 RBD with a human tPA signal peptide and T4 fibritin foldon, produced by group I intron autocatalysis or T4 RNA ligase, and encapsulated in LNPs; comparisons used 1mΨ-modified and unmodified mRNA encoding the same RBD sequence.
- Female BALB/c mice (6–8 weeks) were immunized intramuscularly with varying circRNA doses; 2–4-year-old male rhesus macaques received 20, 100, or 500 μg circRNARBD, circRNACtrl, or PBS on days 0 and 21. Mice were challenged with Beta variant; macaques were challenged with native SARS-CoV-2.
- Analyses included ELISA endpoint GMTs, pseudovirus and authentic virus NT50 assays, RT-qPCR viral loads, ELISpot and flow cytometry for T cell cytokines, histopathology, and unpaired or paired two-sided Student’s t tests.
Limitations
- Stated by the paper: small rhesus macaque numbers caused high variation and large error bars; immunogenicity of IVT-produced circRNAs remains a potential concern; safety awaits further NHP and clinical trials; the mRNA comparator encoded trimeric RBD and differed from mRNA-1273 and BNT162b2, which encode full-length spike and use different manufacturing processes.
- Evident from the text: no human clinical data are reported; protection against Omicron and Delta was assessed mainly by neutralization assays, while mouse challenge used Beta and macaque challenge used native SARS-CoV-2.
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77 Own result · 21 Not checked yet · 13 Own method · 12 Own interpretation
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In the paper
“Abundant RBD antigens in the supernatant of both human and murine cells were detected by western blot, indicating the high compatibility of circRNAs (Figure 1B).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD produced functional SARS-CoV-2 RBD antigens
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“The circRNARBD elicited a high level of RBD-specific IgG endpoint geometric mean titers (GMTs), reaching ∼1.9 × 104 for the 10-μg dose and ∼5.7 × 105 for the 50-μg dose (Figure 1I).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > SARS-CoV-2 circRNARBD vaccine induced sustained humoral immune responses with high levels of neutralizing antibodies
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“ELISA showed that the RBD-Beta-specific IgG endpoint GMT was ∼1.6 × 104 at 1 week after the boost (Figure 1L).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > SARS-CoV-2 circRNARBD-Beta vaccine-elicited antibodies showed preferential neutralizing activity against the Beta variant
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“The concentration of RBD antigens produced by circRNARBD reached ∼1,400 ng/mL, 600-fold higher than those produced by its linear precursor RNA (Figure 1D).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD produced functional SARS-CoV-2 RBD antigens
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“and authentic SARS-CoV-2 virus with an NT50 of ∼7.0 × 104 (Figure 1K).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > SARS-CoV-2 circRNARBD vaccine induced sustained humoral immune responses with high levels of neutralizing antibodies
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“The secreted RBD antigens could effectively block SARS-CoV-2 pseudovirus infection (Figure 1E).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD produced functional SARS-CoV-2 RBD antigens
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“Similarly, abundant RBD antigens were detected in the supernatant at a concentration of ∼1,000 ng/mL, which was ∼200-fold higher than those produced by its linear precursor RNA (Figures S2C and S2D).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD produced functional SARS-CoV-2 RBD antigens
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“The purity of circRNARBD was over 90%, calculated via the denaturing gel electrophoresis and the subsequent semi-quantitative analysis (Figures S1G–S1I).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD produced functional SARS-CoV-2 RBD antigens
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“In line with pseudovirus neutralization assay, the sera from immunized mice neutralized the authentic SARS-CoV-2 Beta and native (D614G) strains with NT50 values of 2.6 × 104 (Figure 1O) and 6.0 × 103 (Figure 1P), respectively.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > SARS-CoV-2 circRNARBD-Beta vaccine-elicited antibodies showed preferential neutralizing activity against the Beta variant
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“At 4°C, little reduction in RBD antigens produced by LNP-circRNA could be detected from 1 to 28 days (Figure S3B).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine enabled higher and more durable antigen expression than mRNA vaccine
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In the paper
“Consistent with a recent report (Gu et al., 2020; Chen et al., 2021; Montagutelli et al., 2021), the Beta variant could infect wild-type BALB/c mice and replicate in their lungs (Figure 1Q), likely due to mutations in the spike such as K417N, E484K, and N501Y.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD-Beta vaccine protected mice against infection with the Beta variant
What the sources say
- Not checked yetcites Gu et al., 2020
- Not checked yetcites Chen et al., 2021
- Not checked yetcites Montagutelli et al., 2021
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“We found that the majority of the purified circRNARBD fractions were resistant to exonuclease-RNase R, whereas the nicked RNARBD were almost completely degraded, indicating that purified circRNARBD were mostly in circular format (Figure S1F).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD produced functional SARS-CoV-2 RBD antigens
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“The circRNARBD encapsulation efficiency was greater than 93%, with an average diameter of 100 nm (Figure 1G).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > SARS-CoV-2 circRNARBD vaccine induced sustained humoral immune responses with high levels of neutralizing antibodies
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“The circRNARBD-Beta-elicited antibodies could also neutralize all three pseudoviruses, with the highest activity against its corresponding Beta variant (Figure 1N).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > SARS-CoV-2 circRNARBD-Beta vaccine-elicited antibodies showed preferential neutralizing activity against the Beta variant
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“Pseudovirus neutralization assays revealed that circRNARBD-elicited antibodies could effectively neutralize all three pseudoviruses, with the highest neutralizing activity against the native (D614G) strain (Figure 1M).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > SARS-CoV-2 circRNARBD-Beta vaccine-elicited antibodies showed preferential neutralizing activity against the Beta variant
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“With the help of foldon, the circRNARBD encoded stable homogeneous RBD trimers in the supernatant, which were dissociated into monomers under reducing conditions (Figure 1C).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD produced functional SARS-CoV-2 RBD antigens
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“Importantly, we found that the innate immune responses elicited by LNP-encapsulated circRNARBD were comparable with those by LNP-encapsulated 1mΨ-mRNARBD and significantly lower than those by the transfected RNAs (Figure 3E).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine enabled higher and more durable antigen expression than mRNA vaccine
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“The sera from circRNARBD-Delta-vaccinated mice effectively neutralized the Delta pseudovirus in a dose-dependent manner, with an NT50 of ∼1.4 × 105 for the 10-μg dose (Figure 2C).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD-Delta vaccine induced potent neutralizing antibodies against SARS-CoV-2 Delta
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“The circRNA produced much higher levels of RBD antigens at all time points than both 1mΨ-mRNA and unmodified mRNA, and they were maintained for a longer period (Figure 3 A).”
- Also stated in: § Abstract · plain
“Notably, the circRNA vaccine enabled higher and more durable antigen production than the 1mΨ-modified mRNA vaccine”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine enabled higher and more durable antigen expression than mRNA vaccine
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“The sera from circRNARBD-Delta-immunized mice exhibited the highest neutralizing activity against Delta and the lowest against Beta (Figures 2D and 2E).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD-Delta vaccine induced potent neutralizing antibodies against SARS-CoV-2 Delta
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“Importantly, we found that the circRNARBD-Omicron vaccine induced effective neutralizing antibodies against the Omicron but not the Delta variant.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Abstract
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“The IgG endpoint GMTs reached ∼2.1 × 104 (20-μg dose), ∼1.6 × 104 (100-μg dose), and ∼7 × 103 (500-μg dose) for circRNARBD vaccines, whereas circRNACtrl- or PBS-immunized rhesus macaques failed to induce RBD-specific antibodies (Figure 6B).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine elicited potent neutralizing antibodies and Th1-biased immune responses in rhesus macaques
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“The authentic SARS-CoV-2 neutralization assay showed NT50 values of ∼80 for the 20-μg dose, ∼120 for the 100-μg dose, and ∼50 for the 500-μg dose (Figures 6D and 6E).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine elicited potent neutralizing antibodies and Th1-biased immune responses in rhesus macaques
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“The ELISpot assay showed evident IFN-γ and IL-2 responses but nearly undetectable IL-4 in circRNARBD-immunized rhesus macaques (Figure 6F)”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine elicited potent neutralizing antibodies and Th1-biased immune responses in rhesus macaques
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“circRNARBD-immunized rhesus macaques of all doses were well protected because only very mild pneumonia was observed (Figure 6H).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine protected the rhesus macaques against SARS-CoV-2 infection
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“Here, we report a circular RNA (circRNA) vaccine that elicited potent neutralizing antibodies and T cell responses by expressing the trimeric RBD of the spike protein,”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Abstract
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“CircRNARBD-Delta appeared to be a much better booster than circRNARBD against both Delta and Omicron variants, which elevated the geometric mean NT50 from ∼4 × 102 to ∼3.2 × 104 against the Omicron (Figures 5K and 5L).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > The third booster with the circRNARBD-Delta vaccine markedly elevated the neutralizing antibodies against the current VOCs
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“the circRNARBD-Delta vaccine protected against both Delta and Omicron”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Abstract
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- Rests on an assumption: Neutralizing antibody titers against a SARS-CoV-2 variant in vitro predict protection against that variant in vivo.
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“Both vaccines effectively boosted neutralizing antibodies against both Delta (Figure 5K) and Omicron (Figure 5L).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > The third booster with the circRNARBD-Delta vaccine markedly elevated the neutralizing antibodies against the current VOCs
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“The neutralizing activity against Omicron elicited by each one of the three circRNA vaccines dropped 74-fold (native), 15-fold (Beta), and 44-fold (Delta) in comparison with the neutralizing activity against their corresponding variants (Figure 5 A).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD-Delta vaccine elicited high levels of broad-spectrum neutralizing antibodies against both the Delta and Omicron variants
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“The pseudovirus neutralization assay showed NT50 values of ∼180 for the 20-μg dose, ∼520 for the 100-μg dose, and ∼390 for the 500-μg dose (Figure 6C).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine elicited potent neutralizing antibodies and Th1-biased immune responses in rhesus macaques
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“CircRNARBD vaccines induced evident IL-6 and monocyte chemoattractant protein-1 (MCP-1) (Figures S7 A and S7B), whereas TNF-α, IL-1β, and IFN-α were nearly undetectable (Figures S7C–S7E).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine did not cause clinical signs of illness in rhesus macaques
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“Both the pseudotyped and authentic SARS-CoV-2 neutralization assays showed that the circRNARBD vaccine-immunized rhesus macaque plasma could effectively inhibit the corresponding native strain, whereas the Alpha, Delta, and Beta variants could also be inhibited, but with reduced activity, especially against the Beta variant (Figures 6D and 6E).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNA vaccine elicited potent neutralizing antibodies and Th1-biased immune responses in rhesus macaques
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“Our result argues against this possibility because our Omicron-specific vaccine failed to cross-protect against the Delta variant (Figures 5D–5F) or boost the two-dose Delta vaccine (Figures 5H and 5I).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Discussion
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.
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 comparison with the mRNA vaccine, the circRNA vaccine elicited higher and more durable immunogens, leading to distinct Th1-biased T cell immune responses from the mRNA vaccine (Figures 3 and S3).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > 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
“circRNA vaccine did not cause clinical signs of illness or enhanced pathology in vaccinated NHPs”
- Also stated in: § Limitations of the study · plain
“our study showed that circRNA vaccines did not cause any clinical signs of illness in rhesus macaques, even at high doses (500 μg per rhesus macaque) (Figure 6)”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Discussion
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. The quote only partly states this claim.
- Also stated in: § Limitations of the study · plain
None of the sources cited for this claim have been checked yet.
In the paper
“Omicron carries over 30 mutations on the spike protein, 15 of which are located in the receptor-binding domain (RBD) (Dejnirattisai et al., 2022), resulting in a significant decrease in the effectiveness of prior neutralizing antibodies (Cameroni et al., 2022; Cao et al., 2021; Cele et al., 2022; Liu et al., 2022a; Planas et al., 2022).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Introduction
What the sources say
- Not checked yetcites Dejnirattisai et al., 2022
- Not checked yetcites Cameroni et al., 2022
- Not checked yetcites Cao et al., 2021
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The S protein, S1 subunit, or RBD antigen of SARS-CoV-2 can induce both B cell and T cell responses, generating highly potent neutralizing antibodies against SARS-CoV-2 (Bangaru et al., 2020; Hsieh et al., 2020; Walls et al., 2020).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Introduction
What the sources say
- Not checked yetcites Bangaru et al., 2020
- Not checked yetcites Hsieh et al., 2020
- Not checked yetcites Walls et al., 2020
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Although it has recently been reported that an additional boost with original SARS-CoV-2 vaccines after receiving a prior two-dose vaccination regimen could partly elevate the neutralizing capability, the neutralization of Omicron pseudovirus was 4- to 13-fold lower than that of the wild type (Garcia-Beltran et al., 2022).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Introduction
What the sources say
- Not checked yetcites Garcia-Beltran et al., 2022
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, due to its susceptibility to exonuclease digestion, the current mRNA vaccine still has certain limitations including inherent instability and suboptimal thermostability after LNP encapsulation for in vivo administration (Durymanov and Reineke, 2018; Fenton et al., 2016; Jackson et al., 2020).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Introduction
What the sources say
- Not checked yetcites Durymanov and Reineke, 2018
- Not checked yetcites Fenton et al., 2016
- Not checked yetcites Jackson et al., 2020
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.
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
“Sanger sequencing confirmed the precise circularization of circRNARBD by this approach (Figure S2B).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Results > CircRNARBD produced functional SARS-CoV-2 RBD antigens
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.
None of the sources cited for this claim have been checked yet.
In the paper
“Compared with the linear mRNA, circRNA is highly stable due to its covalently closed ring structure, which protects it from exonuclease-mediated degradation (Enuka et al., 2016; Kristensen et al., 2019; Memczak et al., 2013).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Introduction
What the sources say
- Not checked yetcites Enuka et al., 2016
- Not checked yetcites Kristensen et al., 2019
- Not checked yetcites Memczak et al., 2013
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The S protein mediates viral entry into host cells by binding to its receptor, angiotensin-converting enzyme 2 (ACE2), through the RBD at the C terminus of the S1 subunit.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Introduction
What the sources say
- Not checked yetcites Hoffmann et al., 2020
- Not checked yetcites Shang et al., 2020
- Not checked yetcites Wrapp et al., 2020
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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 summary, circRNA holds the potential to become an effective and safe platform for vaccination against viral infection—including SARS-CoV-2 emerging variants—as well as possibly becoming a therapeutic platform, owing to its specific properties.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Results in mice and rhesus macaques predict immunogenicity, protection, and safety of circRNA vaccines in humans.
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
“By contrast, the circRNARBD-Delta vaccine appeared to produce antigens possessing high immunogenicity and consequently elicit a high level of neutralizing antibodies against Delta (Figures 2 and 3).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Unlike antibodies and protein drugs, circRNAs encode therapeutic antibodies in the cytoplasm, allowing them to target intracellular targets such as TP53 (Sabapathy and Lane, 2018) and KRAS (Mukhopadhyay et al., 2021), bypassing the cytomembrane barrier.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Discussion
What the sources say
- Not checked yetcites Sabapathy and Lane, 2018
- Not checked yetcites Mukhopadhyay et al., 2021
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
“The circRNA-encoded RBD trimers were functional and successfully induced potent neutralizing antibodies and specific T cell responses against SARS-CoV-2 in both mice and rhesus macaques (Figures 2, 4, and 6).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > 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.
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
“All animal experiments with SARS-CoV-2 challenge were conducted under animal biosafety level 3 (ABSL3) facilities at the Institute of Pathogen Biology, Chinese Academy of Medical Sciences.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Experimental model and subject details
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
“All the animal experiments with SARS-CoV-2 challenge were reviewed and approved by the Committee on the Ethics of Animal Experiments of the Institute of Pathogen Biology, Chinese Academy of Medical Sciences.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Experimental model and subject details
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 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
“Our Delta-specific vaccination could cross-protect against all other variants, including Omicron (Figures 2E, 5A, 5B, and 5C), and could also be used as an effective booster following two-dose original SARS-CoV-2 vaccines (Figures 5K and 5L).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Discussion
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.
- Rests on an assumption: Results in mice and rhesus macaques predict immunogenicity, protection, and safety of circRNA vaccines in humans.
- Rests on an assumption: Neutralizing antibody titers are a correlate of protection against SARS-CoV-2 in humans.
None of the sources cited for this claim have been checked yet.
In the paper
“It is worth noting that the mRNA vaccine we used for the comparison study is different from the two widely administered vaccines, mRNA-1273 and BNT162b2, both of which encode the full-length spike antigens and were produced by different manufacturing processes, whereas the mRNA vaccine in this study encoded the trimeric RBD of spike (Corbett et al., 2020a, 2020b; Vogel et al., 2021).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Discussion > Limitations of the study
What the sources say
- Not checked yetcites Corbett et al., 2020a, 2020b
- Not checked yetcites Vogel et al., 2021
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.
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 animal experiments were approved by Peking University Laboratory Animal Center (Beijing) and undertaken in accordance with the National Institute of Health Guide for Care and Use of Laboratory Animals.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Experimental model and subject details
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
“All animal procedures were approved by the Institutional Animal Care and Use Committee of the Institute of Medical Biology, Chinese Academy of Medical Science.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Experimental model and subject details
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
“The 2- to 4-year-old male rhesus macaque experiments were performed in the animal biosafety level 4 (ABSL-4) facility of the National Kunming High-level Biosafety Primate Research Center, Yunnan, China.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Experimental model and subject details
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.
None of the sources cited for this claim have been checked yet.
In the paper
“Given that RBD trimers bind to hACE2 better than their monomeric counterparts and have been shown to enhance the humoral immune response (Bouwman et al., 2021; Routhu et al., 2021; Sahin et al., 2020)”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > Discussion
What the sources say
- Not checked yetcites Bouwman et al., 2021
- Not checked yetcites Routhu et al., 2021
- Not checked yetcites Sahin et al., 2020
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The mouse model for the SARS-CoV-2 Beta variant challenge has previously been characterized (Montagutelli et al., 2021).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Method details
What the sources say
- Not checked yetcites Montagutelli et al., 2021
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
“Amplified SARS-CoV-2 was confirmed via RT–PCR, sequencing and transmission electronic microscopy, and titrated via plaque assay (106 PFU/ml).”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Experimental model and subject details
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
“Dimethyl sulfoxide (DMSO) served as an unstimulating control, and phytohemagglutinin (PHA-P, Sigma) and CELL STIMULATION COCKTAIL (Thermo Fisher) were used as positive controls.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Method details
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
“Dimethyl sulfoxide (DMSO) served as an unstimulating control, and phytohemagglutinin (PHA-P, Sigma) and CELL STIMULATION COCKTAIL (Thermo Fisher) were used as positive controls.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Method details
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
“Histopathological analysis of tissue slides was scored by 3 independent pathologists blinded to the groups of animals.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Method details
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.
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 test for each rhesus macaque was performed in two or three technical repetitions.”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Method details
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Neutralizing antibody titers against a SARS-CoV-2 variant in vitro predict protection against that variant in vivo.
“Among all three, the circRNARBD-Delta vaccine maintained sufficient neutralizing activity against Omicron (Figure 5A), with an NT50 of ∼4.7 × 103,”
“the circRNARBD-Delta vaccine protected against both Delta and Omicron”
The paper relies on this without support.
Results in mice and rhesus macaques predict immunogenicity, protection, and safety of circRNA vaccines in humans.
“In summary, circRNA holds the potential to become an effective and safe platform for vaccination against viral infection—including SARS-CoV-2 emerging variants—as well as possibly becoming a therapeutic platform, owing to its specific properties.”
The paper relies on this without support.
Neutralizing antibody titers are a correlate of protection against SARS-CoV-2 in humans.
“Our Delta-specific vaccination could cross-protect against all other variants, including Omicron (Figures 2E, 5A, 5B, and 5C), and could also be used as an effective booster following two-dose original SARS-CoV-2 vaccines (Figures 5K and 5L).”
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?
In the citing paper
“In addition, circRNA has recently been developed for COVID-19 mRNA vaccines due to its natural high stability.112”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [112]
In the citing paper
“the results revealed that circRNA prepared with sequences of Delta strains resulted in broad-spectrum protection and production of neutralizing antibodies against both Delta and Omicron.”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [227]
In the citing paper
“In addition, vaccination with circRNA prepared with the original SARS-CoV-2 strain sequence followed by a booster dose of the vaccine containing circRNA prepared with Delta sequences conferred good protection against Delta and Omicron.”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [227]
In the citing paper
“Moreover, the vaccine also showed neutralizing activity against the Beta variant (B.1.351).”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [112]
In the citing paper
“After immunizing mice with the obtained vaccine, long-lasting neutralizing antibodies and Th1-biased cellular immune responses were produced.”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [112]
In the citing paper
“Liang and colleagues112 developed a circRNA vaccine against SARS-CoV-2 encoding a trimeric receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, considering that in RBD the signal peptide sequence of human tissue plasminogen activator (tPA) was fused to the N-terminus to ensure antigen secretion, whereas the trimerization motif of bacteriophage T4 fibritin protein (foldon) was fused to”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [112]
In the citing paper
“previous studies have reported that cell transfection efficiency was maintained when circRNA was kept at room temperature for two weeks.112”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [112]
In the citing paper
“However, vaccines produced with circRNA prepared based on Omicron sequences provided a narrower protection, and produced neutralizing antibodies could protect only against Omicron but not against Delta.”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [227]
In the citing paper
“In the preclinical study, the candidate was administered to mice i.m. at two different doses (10 and 50 μg) in a p-b regimen 2 weeks apart, which elicited a high titer of neutralizing antibodies in a dose-dependent manner, with Th1-biased T cell responses.59”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [59]
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
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Key resources table
“| Anti-Mouse TNF-α Monoclonal Antibody, PE/Cyanine7 | BioLegend | Cat#506324; RRID:AB_2256076 | | Anti-Mouse IL-4 Monoclonal Antibody, PE | BioLegend | Cat#504104; RRID:AB_315318 |”
§ Circular RNA vaccines against SARS-CoV-2 and emerging variants > STAR★Methods > Method details
“IL-4 (Biolegend, #506324); TNF-α (Biolegend, #504104)”
Citations
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Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
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Circular RNAs are a large class of animal RNAs with regulatory potency
Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., et al. (2013) · Nature · doi:10.1038/nature11928 · Cited by 7,990
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The biogenesis, biology and characterization of circular RNAs
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mRNA vaccines — a new era in vaccinology
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Cited by
Sorted by citations
Circular RNAs: Characterization, cellular roles, and applications
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RNA-based therapeutics: an overview and prospectus
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Advances in COVID-19 mRNA vaccine development
Fang, E., Liu, X., Li, M., Zhang, Z., Song, L., Zhu, B., Wu, X., Liu, J., Zhao, D., & Li, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00950-y · Cited by 601
The landscape of mRNA nanomedicine
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Self-citationmRNA-based cancer therapeutics
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Metadata
- Authors
- Qu, L., Yi, Z., Shen, Y., Lin, L., Chen, F., Xu, Y., Wu, Z., Tang, H., Zhang, X., Tian, F., Wang, C., Xiao, X., Dong, X., Guo, L., Lu, S., Yang, C., Tang, C., Yang, Y., Yu, W., Wang, J., Zhou, Y., Huang, Q., Yisimayi, A., Cao, Y., Wang, Y., Zhou, Z., Peng, X., Wang, J., Xie, X. S., & Wei, W.
- Affiliations
- Peking University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- National Institutes for Food and Drug Control (CN)
- Corresponding author
- Wei, Wensheng
- ORCID
- Qu, Liang
- Yi, Zongyi
- Shen, Yong
- Lin, Liangru
- Chen, Feng
- Zhang, Xiaoxue
- Tian, Feng
- Wang, Chunhui
- Xiao, Xia
- Guo, Li
- Lu, Shuaiyao
- Yang, Chengyun
- Tang, Cong
- Yang, Yun
- Yu, Wenhai
- Wang, Junbin
- Zhou, Yanan
- Huang, Qing
- Yisimayi, Ayijiang
- Cao, Yunlong
- Wang, Youchun
- Zhou, Zhuo
- Peng, Xiaozhong
- Wang, Jianwei
- Xie, Xiaoliang Sunney
- Wei, Wensheng
- Venue
- Cell
- Publisher
- openRxiv
- Published
- 2021-03-16
- Volume
- 185
- Issue
- 10
- Pages
- 1728-1744.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8971115
- OpenAlex
- W4226027283
- Cited by
- 636
- References
- 107
- Citations by year
- 2026: 107 · 2025: 170 · 2024: 151 · 2023: 129 · 2022: 73 · 2021: 4
- FWCI
- 64.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (2018ZX10301401, 2020YFA0707800, 31870893, 31930016)
- Chinese Academy of Sciences
- Ministry of Science and Technology of the People's Republic of China
- China Postdoctoral Science Foundation
- Tsinghua University
- Peking University
- Beijing Municipal Science and Technology Commission
- National Postdoctoral Program for Innovative Talents
- Institute of Microbiology, Chinese Academy of Sciences
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, COVID-19 vaccines, SARS-CoV-2 variants of concern, Omicron variant, Delta variant, booster vaccination, vaccine protection
- MeSH terms
- RNA, Circular, COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, Animals, Antibodies, Viral, Humans, Macaca mulatta, Vaccines, Synthetic, Mice, Antibodies, Neutralizing
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 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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