An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

In the paper

“The S glycoprotein mediates host cell attachment and is required for viral entry3; it is the primary vaccine target for many candidate SARS-CoV-2 vaccines.4-7”

What the sources say

• Partly supported

  Section 2, “Spike Protein” (page unavailable), says coronavirus spike proteins have an S1 domain responsible for receptor binding and an S2 domain responsible for fusion, supporting the attachment-and-entry mechanism. The paper does not address SARS-CoV-2 specifically, so it does not directly establish the claim for that virus. The vaccine-target statement is attributed to other citations, not this source. (LLM, conf=0.85)

  cites [3] Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 2012; 4: 1011- 1033. 22816037 PMC3397359 sourceExperimental — accuracy not yet measured

In the paper

“Those studies showed that solicited systemic adverse events tended to be more frequent and more severe with higher doses and after the second vaccination.”

What the sources say

• Partly supported

  The H10N8 Results (§3.2.1; page unavailable) report that fever increased with dose and was more frequent after the second dose in the 100-mg group. The H7N9 Results (§3.2.2; page unavailable) report that 11 of 12 severe solicited events occurred in the highest-dose group, but explicitly state that, except for fever in that group, solicited-event frequency did not increase after the second vaccination. The source therefore supports a dose-related pattern and limited post-second-dose increases, not a general increase in the frequency and severity of systemic events after the second vaccination. (LLM, conf=0.88)

  cites [11] Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 2019; 37: 3326- 3334. 31079849 sourceExperimental — accuracy not yet measured
• Partly supported

  The results (p. 3) say systemic events increased with dose level and were reported by more participants after the second dose; the Discussion also describes generally higher reactogenicity after dose two. Our copy does not establish that solicited systemic events tended to be more severe with higher doses and after the second vaccination. Participants in the 100 µg group did not receive a second dose. (LLM, conf=0.84)

  cites [6] Mulligan MJ, Lyke KE, Kitchin N, et al. Phase 1/2 study to describe the safety and immunogenicity of a COVID-19 RNA vaccine candidate (BNT162b1) in adults 18 to 55 years of age: interim report. July 1, 2020 (https://www.medrxiv.org/content/10.1101/2020.06.30.20142570v1). preprint. sourceExperimental — accuracy not yet measured

In the paper

“The rapid and robust immunogenicity profile of the mRNA-1273 vaccine most likely results from an innovative structure-based vaccine antigen design,23 coupled with a potent lipid-nanoparticle delivery system, and the use of modified nucleotides that avoid early intracellular activation of interferon-associated genes.”

What the sources say

• Partly supported

  The section on stabilizing class I fusion proteins reports that structure-guided, prefusion-stabilized coronavirus spike antigens improved immune responses in mice. That supports the antigen-design rationale for citation 23, but the paper does not establish that this design caused mRNA-1273’s rapid and robust immunogenicity. The citation is attached to antigen design, not to the sentence’s separate claims about lipid-nanoparticle delivery or modified nucleotides. (LLM, conf=0.86)

  cites [23] Graham BS, Gilman MSA, McLellan JS. Structure-based vaccine antigen design. Annu Rev Med 2019; 70: 91- 104. 30691364 PMC6936610 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion report that lipid nanoparticles and modified nucleosides contribute to potent immune responses from the mRNA vaccine platform studied. They do not study mRNA-1273 or attribute its immunogenicity to structure-based antigen design, and they do not establish the claimed avoidance of early interferon-associated gene activation. (LLM, conf=0.88)

  cites [24] Pardi N, Hogan MJ, Naradikian MS, et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 2018; 215: 1571- 1588. 29739835 PMC5987916 sourceExperimental — accuracy not yet measured

In the paper

“The S glycoprotein mediates host cell attachment and is required for viral entry3; it is the primary vaccine target for many candidate SARS-CoV-2 vaccines.4-7”

What the sources say

• ?Not checked — no full text of the sourcecites [4] Callaway E. The race for coronavirus vaccines: a graphical guide. Nature 2020; 580: 576- 577. 32346146 source
• Supported

  The Discussion (page not specified) says that the full-length spike glycoprotein was chosen for most viral-vectored, mRNA, and DNA COVID-19 vaccines in development. This supports the attributed claim that it was a primary target for many candidate vaccines. (LLM, conf=0.93)

  cites [5] Zhu F-C, Li Y-H, Guan X-H, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 2020; 395: 1845- 1854. 32450106 PMC7255193 source
• Partly supported

  The Main section describes the spike protein’s receptor-binding domain as a key target of neutralizing antibodies, and the Methods identify it as the antigen encoded by BNT162b1 (page numbers not provided). This supports spike-derived antigen as a target for this candidate, but the paper does not establish that it is the primary target for many SARS-CoV-2 vaccine candidates. (LLM, conf=0.85)

  cites [6] Mulligan MJ, Lyke KE, Kitchin N, et al. Phase 1/2 study to describe the safety and immunogenicity of a COVID-19 RNA vaccine candidate (BNT162b1) in adults 18 to 55 years of age: interim report. July 1, 2020 (https://www.medrxiv.org/content/10.1101/2020.06.30.20142570v1). preprint. sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion says the authors chose SARS-CoV-2 S protein as the antigen target for their vaccine candidate, and the Results describe constructs encoding it. Our copy does not establish that S is the primary target for many SARS-CoV-2 vaccine candidates, so the broader claim is not fully supported. (LLM, conf=0.84)

  cites [7] Smith TRF, Patel A, Ramos S, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun 2020; 11: 2601- 2601. 32433465 PMC7239918 sourceExperimental — accuracy not yet measured

In the paper

“This descriptive safety profile is similar to that described in a report of two trials of avian influenza mRNA vaccines (influenza A/H10N8 and influenza A/H7N9) that were manufactured by Moderna with the use of an earlier lipid nanoparticle capsule formulation11 and is consistent with an interim report of a phase 1–2 evaluation of a Covid-19 mRNA vaccine encoding the S receptor-binding domain.6”

What the sources say

• Supported

  The Introduction identifies two phase 1 trials of LNP-formulated H10N8 and H7N9 mRNA vaccines. The Results (sections 3.2.1 and 3.2.2) describe their adverse-event profiles, providing the safety report cited for the comparison. The separate claim about a Covid-19 vaccine is attached to citation 6, not this source. (LLM, conf=0.90)

  cites [11] Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 2019; 37: 3326- 3334. 31079849 source
• Supported

  The Main section identifies BNT162b1 as an RNA vaccine encoding the SARS-CoV-2 spike receptor-binding domain. The Abstract describes this interim study and its safety findings, while the Discussion reports its tolerability and safety profile. The avian-influenza comparison is attached to a different citation, not this source. (LLM, conf=0.93)

  cites [6] Mulligan MJ, Lyke KE, Kitchin N, et al. Phase 1/2 study to describe the safety and immunogenicity of a COVID-19 RNA vaccine candidate (BNT162b1) in adults 18 to 55 years of age: interim report. July 1, 2020 (https://www.medrxiv.org/content/10.1101/2020.06.30.20142570v1). preprint. source

In the paper

“Though correlates of protection from SARS-CoV-2 infection have not yet been determined, measurement of serum neutralizing activity has been shown to be a mechanistic correlate of protection for other respiratory viruses, such as influenza14 and respiratory syncytial virus,15 and is generally accepted as a functional biomarker of the in vivo humoral response.16”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [14] Verschoor CP, Singh P, Russell ML, et al. Microneutralization assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children. PLoS One 2015; 10(6): e0131531- e0131531. 26107625 PMC4479562 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [15] Kulkarni PS, Hurwitz JL, Simões EAF, Piedra PA. Establishing correlates of protection for vaccine development: considerations for the respiratory syncytial virus vaccine field. Viral Immunol 2018; 31: 195- 203. 29336703 PMC5863081 source
• Partly supported

  Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [16] Okba NMA, Müller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease patients. Emerging Infect Dis 2020; 26: 1478- 1488. 32267220 PMC7323511 sourceExperimental — accuracy not yet measured

In the paper

“However, interpretation of the significance of those comparisons must account for the variability in Covid-19 convalescent antibody titers according to factors such as patient age, disease severity, and time since disease onset and for the number of samples in the panel.12,13”

What the sources say

• Partly supported

  The Results (Dynamic Changes in Neutralizing Antibodies Against SARS-CoV-2; page unavailable) show that titers varied among patients and changed with time since symptom onset. The Discussion notes a small sample size but says the study could not establish correlations between titer dynamics and clinical characteristics. This source therefore does not establish age or disease severity as factors in titer variability, or specifically assess how the number of samples in a comparison panel affects interpretation. (LLM, conf=0.86)

  cites [12] Wang X, Guo X, Xin Q, et al. Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and convalescent patients. Clin Infect Dis 2020 June 4 (Epub ahead of print). 32497196 PMC7314147 sourceExperimental — accuracy not yet measured
• Partly supported

  The age-group results (p. 7) show that neutralizing-antibody titers vary with patient age, and the kinetics results (p. 6) show that titers change after disease onset. The paper reports a cohort of 175 recovered patients (Figure 3, p. 12), but does not say how panel size affects comparisons; it also excluded severe and critical patients (Discussion, p. 9), so it does not establish variation by disease severity. (LLM, conf=0.86)

  cites [13] Wu F, Wang A, Liu M, et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. April 20, 2020 (https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v2). preprint. sourceExperimental — accuracy not yet measured

In the paper

“These features of the mRNA composition and formulation have been associated with prolonged protein expression, induction of antigen-specific T-follicular helper cells, and activation of germinal center B cells.24”

What the sources say

• Supported

  The Introduction states that modified nucleosides are essential for high and sustained protein production from mRNA-LNPs, associated with potent Tfh and B cell responses. The antigen-specific Tfh results and Discussion further document Tfh induction and GC B cell activation. Page numbers are not provided in the supplied passages. (LLM, conf=0.93)

  cites [24] Pardi N, Hogan MJ, Naradikian MS, et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 2018; 215: 1571- 1588. 29739835 PMC5987916 source

In the paper

“Studies of mRNA-1273 in mice show that the structurally defined spike antigen induces robust neutralizing activity and that the gene-based delivery promotes Th1-biased responses, including CD8 T cells that protect against virus replication in lung and nose without evidence of immunopathology.32”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [32] Corbett KS, Edwards D, Leist SR, et al. SARS-CoV-2 mRNA vaccine development enabled by prototype pathogen preparedness. June 11, 2020 (https://www.biorxiv.org/content/10.1101/2020.06.11.145920v1). preprint. PMC7581537 32756549 sourceExperimental — accuracy not yet measured

In the paper

“We found strong correlations between the binding and neutralization assays and between the live virus and pseudovirus neutralization assays.”

In the paper

“The two-dose vaccine series was generally without serious toxicity; systemic adverse events after the first vaccination, when reported, were all graded mild or moderate.”

In the paper

“Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.”

• Also stated in: § Vaccine Safety · plain

  “Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events.”

In the paper

“Dose-dependent responses to the first and second vaccinations were evident.”

In the paper

“Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common.”

In the paper

“After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever; one of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe.”

In the paper

“At day 43, wild-type virus–neutralizing activity capable of reducing SARS-CoV-2 infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D).”

In the paper

“After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50]: Figure 2C, Fig. S8, and Table 2; 80% inhibitory dilution [ID80]: Fig. S2 and Table S6).”

In the paper

“Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A).”

In the paper

“For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens.”

In the paper

“The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43; the higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43).”

In the paper

“No serious adverse events were noted, and no prespecified trial halting rules were met.”

In the paper

“Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events.”

In the paper

“After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group; all were mild or moderate in severity (Figure 1 and Table S2).”

In the paper

“These findings support further development of this vaccine.”

• Also stated in: § Discussion · plain

  “These safety and immunogenicity findings support advancement of the mRNA-1273 vaccine to later-stage clinical trials.”

In the paper

“The mRNA-1273 vaccine was immunogenic, inducing robust binding antibody responses to both full-length S-2P and receptor-binding domain in all participants after the first vaccination in a time- and dose-dependent fashion.”

In the paper

“Thus, presentation of the naturally folded prefusion conformation of the S glycoprotein to the immune system from an mRNA template enables efficient within-host antigen production and promotes both high-quality and high-magnitude antibody responses to SARS-CoV-2.”

In the paper

“For this report of the interim analysis, results were available only for the 25-μg and 100-μg dose groups.”

In the paper

“These events were associated either with macrophage-tropic coronaviruses susceptible to antibody-dependent enhancement of replication or with vaccine antigens that induced antibodies with poor neutralizing activity and Th2-biased responses.31”

What the sources say

• ?Not checked — no full text of the sourcecites [31] Graham BS. Rapid COVID-19 vaccine development. Science 2020; 368: 945- 946. 32385100 source

In the paper

“The protocol, available with the full text of this article at NEJM.org, permitted interim analyses to inform decisions regarding vaccine strategy and public health; this interim analysis reports findings through day 57.”

In the paper

“Adverse events were graded according to a standard toxicity grading scale (Table S1 in the Supplementary Appendix).9”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [9] Food and Drug Administration. Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials: guidance for industry. September 2007 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical). 37532612

In the paper

“The authors had full access to the data reports, which were prepared from the raw data by the statistical and data coordinating center, and vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol.”

In the paper

“Because of the time-intensive nature of the PRNT assay, for this report of the interim analysis, results were available only for the day 1 and day 43 time points in the 25-μg and 100-μg dose groups.”

In the paper

“The trial was conducted under an Investigational New Drug application submitted to the Food and Drug Administration.”

In the paper

“Participants were not screened for SARS-CoV-2 infection by serology or polymerase chain reaction before enrollment.”

In the paper

“All participants provided written informed consent before enrollment.”

In the paper

“The trial was reviewed and approved by the Advarra institutional review board, which functioned as a single board and was overseen by an independent safety monitoring committee.”

In the paper

“Of the three doses evaluated, the 100-μg dose elicits high neutralization responses and Th1-skewed CD4 T cell responses, coupled with a reactogenicity profile that is more favorable than that of the higher dose.”