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Cited by 3,237SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesSARS-CoV-2 detection and testing

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

Open access
Jackson, Lisa A., Anderson, Evan J., Rouphael, Nadine G., Roberts, Paul C., Makhene, Mamodikoe, Coler, Rhea N., McCullough, Michele P., Chappell, James D. +25 more·2020·New England Journal of Medicine
DOI 10.1056/nejmoa2022483PMC PMC7377258
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Abstract

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. METHODS: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. RESULTS: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. 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. CONCLUSIONS: The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).

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Registry

Crossref · 10.1056/nejmoa2022483

Cites

33 of 35 references verified1 citation errors · 1 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 35 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    S-2P conformational stability translates into greater immunogenicity, based on preservation of neutralization-sensitive epitopes and improved protein expression.

    “Moreover, S-2P conformational stability translates into greater immunogenicity,27-29 based on preservation of neutralization-sensitive epitopes at the apex of the prefusion molecule, as shown for respiratory syncytial virus F glycoprotein,30 and improved protein expression,27 which is particularly advantageous for gene-based antigen delivery.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [27] Pallesen J, Wang N, Corbett KS, et al. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A 2017; 114: E7348- E7357. 28807998 PMC5584442 source
    • cites [28] Wrapp D, De Vlieger D, Corbett KS, et al. Structural basis for potent neutralization of betacoronaviruses by single-domain camelid antibodies. Cell 2020; 181(5): 1004.e15- 1015.e15. 32375025 PMC7199733 source

      The Introduction and Discussion report that immunization with prefusion-stabilized SARS-CoV-1 and MERS-CoV spikes elicited neutralizing antibodies. They do not compare S-2P immunogenicity with an unstabilized spike or show that S-2P stability improved protein expression; the expression yield reported in the Discussion is for the engineered VHH-72-Fc antibody, not S-2P. No page numbers are available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [29] Wang N, Rosen O, Wang L, et al. Structural definition of a neutralization-sensitive epitope on the MERS-CoV S1-NTD. Cell Rep 2019; 28(13): 3395.e6- 3405.e6. 31553909 PMC6935267 source

      The Methods describe S-2P as a stabilized MERS-CoV spike protein, and the Discussion says the S1-NTD is immunogenic. Neither passage reports that S-2P’s conformational stability increases immunogenicity; a search for an S-2P immunogenicity comparison and improved expression found no such result in our copy. The citing sentence attaches the preservation-of-epitopes and expression explanations to other citations. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [30] Crank MC, Ruckwardt TJ, Chen M, et al. A proof of concept for structure-based vaccine design targeting RSV in humans. Science 2019; 365: 505- 509. 31371616 source
  • Premisecitation

    Humoral and cell-mediated immune responses have been associated with vaccine-induced protection against challenge or subsequent rechallenge after SARS-CoV-2 infection in a rhesus macaque model.

    “Humoral and cell-mediated immune responses have been associated with vaccine-induced protection against challenge18 or subsequent rechallenge after SARS-CoV-2 infection in a rhesus macaque model.19”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [18] van Doremalen N, Lambe T, Spencer A, et al. ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. May 13, 2020 (https://www.biorxiv.org/content/10.1101/2020.05.13.093195v1). preprint. 33469217 source
    • cites [19] Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science 2020 May 20 (Epub ahead of print). 32434946 PMC7243369 source
  • Premisecitation

    Stabilizing coronavirus spike proteins by substituting two prolines at the top of heptad repeat 1 prevents structural rearrangements of the fusion (S2) subunit.

    “Stabilizing coronavirus spike proteins by substituting two prolines at the top of heptad repeat 1 prevents structural rearrangements of the fusion (S2) subunit.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [25] Kirchdoerfer RN, Cottrell CA, Wang N, et al. Pre-fusion structure of a human coronavirus spike protein. Nature 2016; 531: 118- 121. 26935699 PMC4860016 source

      The Main section describes HR1 rearranging during S2-mediated fusion and suggests that the pre-fusion structure could guide engineering of stabilized spike proteins. It does not report substituting two prolines at the top of HR1 or show that this substitution prevents S2 rearrangements. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [26] Kirchdoerfer RN, Wang N, Pallesen J, et al. Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis. Sci Rep 2018; 8: 15701- 15701. 30356097 PMC6200764 source

      The Methods describe two proline substitutions, and the Results report that the stabilized SARS-CoV spike retains its prefusion conformation without large changes in S2 after receptor binding. But the Results also observe a subtle rearrangement in the S2 central helix and say only that the mutations may block further propagation. The claim’s unqualified statement that they prevent S2 rearrangements overstates the evidence; page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [27] Pallesen J, Wang N, Corbett KS, et al. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A 2017; 114: E7348- E7357. 28807998 PMC5584442 source

      The Results (p. 3) describe two proline substitutions near HR1 that retain the prefusion shape of MERS-CoV spike, with similar effects in two other betacoronavirus spikes. The Discussion (p. 5) says proline substitution can disfavor refolding of the HR1–central-helix linker and impair or abolish fusion; it does not establish that the substitutions prevent all structural rearrangements of S2. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    In rhesus macaques given DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike protein, post-vaccination neutralizing antibody titers were correlated with protection against SARS-CoV-2 challenge.

    “In rhesus macaques given DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike protein, post-vaccination neutralizing antibody titers were correlated with protection against SARS-CoV-2 challenge.17”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Yu J, Tostanoski LH, Peter L, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 2020 May 20 (Epub ahead of print). 32434945 PMC7243363 source
  • Premisecitation

    Natural history studies suggest that SARS-CoV and MERS-CoV infections, particularly mild illnesses, may not generate long-lived antibody responses.

    “This longitudinal assessment is relevant given that natural history studies suggest that SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus) infections, particularly mild illnesses, may not generate long-lived antibody responses.20-22”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [20] Choe PG, Perera RAPM, Park WB, et al. MERS-CoV antibody responses 1 year after symptom onset, South Korea, 2015. Emerg Infect Dis 2017; 23: 1079- 1084. 28585916 PMC5512479 source
    • cites [21] Cao W-C, Liu W, Zhang P-H, Zhang F, Richardus JH. Disappearance of antibodies to SARS-associated coronavirus after recovery. N Engl J Med 2007; 357: 1162- 1163. 17855683 source
    • cites [22] Wu L-P, Wang N-C, Chang Y-H, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis 2007; 13: 1562- 1564. 18258008 PMC2851497 source

      The Study and Conclusions (pages not provided) support the SARS-CoV portion: antibody levels declined substantially by the third year after illness. This paper does not assess MERS-CoV or compare mild with more severe illness, so it does not support those parts of the cited sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 13
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    The SARS-CoV-2 S glycoprotein mediates host cell attachment and is required for viral entry.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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 source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

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

    “Those studies showed that solicited systemic adverse events tended to be more frequent and more severe with higher doses and after the second vaccination.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • 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

      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)

      Experimental — accuracy not yet measured
    • 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

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    The rapid and robust immunogenicity profile of mRNA-1273 most likely results from structure-based vaccine antigen design, lipid-nanoparticle delivery, and modified nucleotides that avoid early intracellular activation of interferon-associated genes.

    “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.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [23] Graham BS, Gilman MSA, McLellan JS. Structure-based vaccine antigen design. Annu Rev Med 2019; 70: 91- 104. 30691364 PMC6936610 source

      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)

      Experimental — accuracy not yet measured
    • 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

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The S glycoprotein is the primary vaccine target for many candidate SARS-CoV-2 vaccines.

    “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”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [4] Callaway E. The race for coronavirus vaccines: a graphical guide. Nature 2020; 580: 576- 577. 32346146 source
    • 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
    • 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

      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)

      Experimental — accuracy not yet measured
    • 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 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    The descriptive safety profile of mRNA-1273 is similar to that of avian influenza mRNA vaccines and consistent with an interim report of a Covid-19 mRNA vaccine encoding the S receptor-binding domain.

    “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”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • 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
    • 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

  • May combine two claims.

    Premisecitation

    Measurement of serum neutralizing activity has been shown to be a mechanistic correlate of protection for other respiratory viruses, such as influenza and respiratory syncytial virus, and is generally accepted as a functional biomarker of the in vivo humoral response.

    “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”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • 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 source

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

      Experimental — accuracy not yet measured
    • cites [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
    • 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 source

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

      Experimental — accuracy not yet measured
    • Rests on an assumption: Correlates of protection from SARS-CoV-2 infection have not yet been determined.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Interpretation of the significance of comparisons to convalescent serum must account for variability in Covid-19 convalescent antibody titers according to patient age, disease severity, time since disease onset, and the number of samples in the panel.

    “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”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • 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 source

      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)

      Experimental — accuracy not yet measured
    • 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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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

  • May combine two claims.

    Premisecitation

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

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • 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 source

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

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Strong correlations were found between the binding and neutralization assays and between the live virus and pseudovirus neutralization assays.

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

  • May combine two claims.

    Findingown data

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Systemic adverse events were more common after the second vaccination, particularly with the highest dose.

    “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.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

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

    “Dose-dependent responses to the first and second vaccinations were evident.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

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

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

  • May combine two claims.

    Findingown data

    After the second vaccination, fever was reported by 0 participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group; one event in the 250-μg group was graded severe.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At day 43, PRNT80 was detected in all participants, with geometric mean PRNT80 responses of 339.7 in the 25-μg group and 654.3 in the 100-μg group.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Binding antibody IgG GMTs to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

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

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The lowest PsVNA responses were in the 25-μg dose group (geometric mean ID50, 112.3 at day 43); the higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 and 332.2, respectively, at day 43).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

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

    “No serious adverse events were noted, and no prespecified trial halting rules were met.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After the second vaccination, solicited systemic adverse events 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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    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.

    “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).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    These findings support further development of the mRNA-1273 vaccine.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    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 high-quality and high-magnitude antibody responses to SARS-CoV-2.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For this interim analysis, T-cell results were available only for the 25-μg and 100-μg dose groups.

    “For this report of the interim analysis, results were available only for the 25-μg and 100-μg dose groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Graham BS. Rapid COVID-19 vaccine development. Science 2020; 368: 945- 946. 32385100 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    This interim analysis reports findings through day 57.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Adverse events were graded according to a standard toxicity grading scale.

    “Adverse events were graded according to a standard toxicity grading scale (Table S1 in the Supplementary Appendix).9”
    Quote in the paperNot a substantial claim0 of 1 sources 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

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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The authors had full access to the data reports and vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    For this interim analysis, PRNT results were available only for the day 1 and day 43 time points in the 25-μg and 100-μg dose groups.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

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

    “The trial was conducted under an Investigational New Drug application submitted to the Food and Drug Administration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

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

    “Participants were not screened for SARS-CoV-2 infection by serology or polymerase chain reaction before enrollment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All participants provided written informed consent before enrollment.

    “All participants provided written informed consent before enrollment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    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 more favorable than that of the higher dose.

    “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.”
    Quote in the paperSubstantial claim
37 of 37

  • The paper relies on this without support.

    Correlates of protection from SARS-CoV-2 infection have not yet been determined.

    “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”

  • The paper relies on this without support.

    The convalescent serum specimens used as a comparator are representative of immune responses after SARS-CoV-2 infection.

    “For comparison of the participants’ immune responses with those induced by SARS-CoV-2 infection, 41 convalescent serum specimens were also tested.”
2 of 2

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 incidence of grade 3 fever of the two spike protein-based mRNA vaccines, mRNA-1273 and BNT162b2, also varied between the phase 1 and 3 trials.

    “Additionally, the incidence of grade 3 fever of the two spike protein-based mRNA vaccines, mRNA-127319, 20 and BNT162b2,17, 21 also varied between the phase 1 and 3 trials.”

    From Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial (2022) · cites this paper as [19]

    The Results > Vaccine Safety section reports one severe fever event after the second mRNA-1273 dose in this phase 1 trial. The Discussion says a phase 3 trial was anticipated, so this paper does not establish how grade 3 fever incidence varied between phase 1 and phase 3. It also does not report BNT162b2 trial results. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • S-2P differs from the spike protein in the reference SARS-CoV-2 genome (NC_045512) by two amino acids, i.e., amino acids KV at sites 986 and 987 were replaced by PP.

    “Both mRNA encodes the same S-2P protein [5,6] which differ from the spike protein in the reference SARS-CoV-2 genome (NC_045512) by two amino acids, i.e., amino acids KV at sites 986 and 987 were replaced by PP to stabilize the resulting spike protein in the prefusion state to train the host immune system to recognize the virus before its entry into the host cell [7,8].”

    From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [6]

    The Methods (Vaccine; page not provided) state that S-2P has two proline substitutions at positions 986 and 987, stabilizing the spike protein in its prefusion conformation. Our copy does not identify the original amino acids as KV or specify the reference genome accession NC_045512. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The reactogenicity associated with immunization with mRNA-1273 in this trial is similar to that in the phase 1 data reported previously.

    “The reactogenicity associated with immunization with mRNA-1273 in this trial is similar to that in the phase 1 data reported previously. 1,4”

    From Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine (2021) · cites this paper as [1]

  • The mRNA-1273 vaccine demonstrated protection in animal-challenge experiments and encouraging safety and immunogenicity in early-stage human testing.

    “The mRNA-1273 vaccine demonstrated protection in animal-challenge experiments 15 and encouraging safety and immunogenicity in early-stage human testing. 1,4”

    From Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine (2021) · cites this paper as [1]

  • Several studies have reported more frequent and severe solicited systemic adverse events following the second vaccination than we found.

    “Meanwhile, several studies17, 18, 19 have reported more frequent and severe solicited systemic adverse events following the second vaccination than we found.”

    From Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial (2022) · cites this paper as [19]

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Authors
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., Pruijssers, A. J., McDermott, A., Flach, B., Doria-Rose, N. A., Corbett, K. S., Morabito, K. M., O’Dell, S., Schmidt, S. D., Swanson, P. A., Padilla, M., Mascola, J. R., Neuzil, K. M., Bennett, H., Sun, W., Peters, E., Makowski, M., Albert, J., Cross, K., Buchanan, W., Pikaart-Tautges, R., Ledgerwood, J. E., Graham, B. S., & Beigel, J. H.
Affiliations
  • Kaiser Permanente Washington Health Research Institute (US)
  • From Kaiser Permanente Washington Health Research Institute (L.A.J.) and the Center for Global Infectious Disease Research (CGIDR), Seattle Children’s Research Institute (R.N.C.) — both in Seattle; the Department of Medicine, Center for Childhood Infections and Vaccines (CCIV) of Children’s Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta (E.J.A., E.P.), and Hope Clinic, Department of Medicine, Emory University School of Medicine, Decatur (N.G.R., M.P.M.) — both in...
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2020-11-12
Volume
383
Issue
20
Pages
1920-1931
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2022483
PMC
PMC7377258
OpenAlex
W3043722389
Semantic Scholar
7551d80ae7ea66f37f25aca464c7e7400adddc9c
Cited by
3,237
References
34
Citations by year
2026: 111 · 2025: 172 · 2024: 222 · 2023: 399 · 2022: 712 · 2021: 1230 · 2020: 378 · 2019: 1 · 2018: 1 · 2013: 3
FWCI
82.04
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institute of Allergy and Infectious Diseases (HHSN272201500002C, UM1AI148373, UM1AI148576, UM1AI148684)
  • National Center for Advancing Translational Sciences (UL1 TR002243)
  • Dolly Parton COVID-19 Research Fund
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
Keywords
mRNA-1273, SARS-CoV-2, COVID-19 vaccines, mRNA vaccines, dose escalation, antibody response, neutralizing antibodies, vaccine safety, adverse events
MeSH terms
Betacoronavirus, COVID-19, SARS-CoV-2, COVID-19 Vaccines, 2019-nCoV Vaccine mRNA-1273, Adult, Antibodies, Viral, Antibody Formation, Female, Humans, Immunization, Secondary, Male, Pneumonia, Viral, RNA, Messenger, T-Lymphocytes, Viral Vaccines, Coronavirus Infections, Young Adult, Antibodies, Neutralizing, Pandemics, Spike Glycoprotein, Coronavirus

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-14.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-14.

Cited sources are checked by 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.

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