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Cited by 123SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesVaccine Coverage and Hesitancy

Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial

Open access
Oda, Yoshiaki, Kumagai, Yuji, Kanai, Manabu, Iwama, Yasuhiro, Okura, Iori, Minamida, Takeshi, Yagi, Yukihiro, Kurosawa, Toru +3 more·2024·The Lancet Infectious Diseases
DOI 10.1016/s1473-3099(23)00650-3
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Abstract

Background Licensed mRNA COVID-19 vaccines require booster doses to sustain SARS-CoV-2-specific responses, creating the need for novel, broadly immunogenic vaccines. We aimed to compare the immunogenicity, safety, and tolerability of ARCT-154-a self-amplifying mRNA vaccine against SARS-CoV-2 D614G variant-with the BNT162b2 (Comirnaty; Pfizer-BioNTech) mRNA vaccine when administered as a fourth-dose booster. Methods This double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial, conducted at 11 outpatient clinical sites in Japan, enrolled healthy adults aged at least 18 years who had previously been immunised with two doses of an mRNA COVID-19 vaccine (BNT162b2 or mRNA-1273 [Spikevax; Moderna]) followed by a third dose of BNT162b2 at least 3 months before enrolment. Participants were randomly assigned, in a 1:1 ratio using an Interactive Response Technology system with a block size of four, and with stratification by age (18-64 years or ≥65 years) and by interval since last COVID-19 vaccination (<5 months or ≥5 months), to receive either ARCT-154 or BNT162b2 as a fourth-dose booster via deltoid intramuscular injection. Participants and investigators assessing outcomes were masked to group assignment. The primary objective, measured in per-protocol set 1 (consisting of participants with no evidence of previous SARS-CoV-2 infection who received their intended injection according to protocol), was to show that the immune response 28 days after the ARCT-154 vaccine was non-inferior to that of the BNT162b2 vaccine, measured in terms of both pseudovirus neutralising antibody geometric mean titre (GMT) ratios and seroresponse rates against the wild-type Wuhan-Hu-1 strain of SARS-CoV-2. Non-inferiority was declared when the lower limit of the 95% CI of the ARCT-154 to BNT162b2 GMT ratio exceeded 0·67, and when the lower limit for the difference in seroresponse rates exceeded -10%. Key secondary endpoints included the immune response against the omicron BA.4/5 subvariant, which was assessed for non-inferiority and superiority in per-protocol set 1. Safety was assessed in the full analysis set. This study was registered on the Japan Registry for Clinical Trials, jRCT 2071220080, and is ongoing. Findings Between Dec 13, 2022, and Feb 25, 2023, we enrolled and randomly assigned 828 participants to receive ARCT-154 (n=420) or BNT162b2 (n=408) vaccines as a fourth-dose booster. In per-protocol set 1, the GMTs of surrogate neutralising antibodies induced against the Wuhan-Hu-1 SARS-CoV-2 strain in the ARCT-154 group (5641 [95% CI 4321-7363]) were non-inferior to those in the BNT162b2 group (3934 [2993-5169]) when measured at 28 days after boosting, with a GMT ratio of 1·43 (95% CI 1·26-1·63). Seroresponse rates were 65·2% (95% CI 60·2-69·9) in the ARCT-154 group versus 51·6% (46·4-56·8) in the BNT162b2 group, a difference of 13·6% (95% CI 6·8-20·5). GMTs against the omicron BA.4/5 variant on day 29 were 2551 (1687-3859) in the ARCT-154 group and 1958 (1281-2993) in the BNT162b2 group-a GMT ratio of 1·30 (1·07-1·58)-with seroresponse rates of 69·9% (65·0-74·4) and 58·0% (52·8-63·1). Both boosters were equally well tolerated. No treatment-related deaths were reported, nor were there severe or serious adverse events considered to be causally associated related to study vaccination. One serious adverse event, a foot deformity reported in a participant in the BNT162b2 group, was observed but determined not to have a causal relationship to the study vaccination. One severe adverse event, a case of abnormal hepatic function in the ARCT-154 group, was considered to be related to study vaccine. Adverse events of special interest for detection of myocarditis and pericarditis included chest pain (one case in the ARCT-154 group and three cases in the BNT162b2 group) and shortness of breath (two cases in the BNT162b2 group), all of which were considered to have a reasonable possibility of being related to vaccination. Local reactions were reported by 398 (95%) of 420 participants receiving the ARCT-154 vaccine and 395 (97%) of 408 participants receiving the BNT162b2 vaccine, and solicited systemic adverse events by 276 (66%) of those receiving the ARCT-154 vaccine and 255 (63%) of those receiving the BNT162b2 vaccine. Adverse events were mainly mild in severity, occurring and resolving within 3-4 days after vaccination. Interpretation In adults who had previously received three doses of an mRNA COVID-19 vaccine, immune responses 28 days after an ARCT-154 booster dose were non-inferior to those observed after a BNT162b2 booster dose for the Wuhan-Hu-1 strain of SARS-CoV-2 and superior for the Omicron BA.4/5 variant. Increased immune responses at 28 days might provide increased likelihood of protection against these strains during this period and could also result in longer duration of protection. Further studies will assess the immunogenicity induced against more recent SARS-CoV-2 variants. Funding Japanese Ministry of Health, Labour, and Welfare. Translation For the Japanese translation of the abstract see Supplementary Materials section.

AI snapshot

Written from the paper’s full text.

TL;DR

In adults who had previously received three mRNA COVID-19 vaccine doses, a fourth-dose ARCT-154 self-amplifying RNA booster was non-inferior to BNT162b2 for Wuhan-Hu-1 neutralising antibody GMT and seroresponse at day 29, and superior for the omicron BA.4/5 subvariant. Safety through day 29 showed no treatment-related deaths and mainly mild adverse events.

Key findings

  • Against Wuhan-Hu-1 in per-protocol set 1, day-29 GMTs were 5641 (95% CI 4321–7363) after ARCT-154 versus 3934 (2993–5169) after BNT162b2, with a GMT ratio of 1.43 (95% CI 1.26–1.63); seroresponse rates were 65.2% (60.2–69.9) versus 51.6% (46.4–56.8), a difference of 13.6% (6.8–20.5).
  • Against omicron BA.4/5, day-29 GMTs were 2551 (1687–3859) after ARCT-154 versus 1958 (1281–2993) after BNT162b2, with a GMT ratio of 1.30 (1.07–1.58); seroresponse rates were 69.9% (65.0–74.4) versus 58.0% (52.8–63.1), a difference of 11.6% (4.9–18.3), meeting superiority criteria.
  • Solicited local reactions were reported by 398 (95%) of 420 ARCT-154 recipients and 395 (97%) of 408 BNT162b2 recipients; solicited systemic adverse events by 276 (66%) and 255 (63%), respectively. Adverse events were mainly mild and resolved within 3–4 days.
  • No treatment-related deaths occurred. One severe adverse event, abnormal hepatic function in the ARCT-154 group, was considered related to study vaccine; one serious adverse event, foot deformity in the BNT162b2 group, was judged unrelated. No myocarditis or pericarditis was detected among participants reporting chest pain or shortness of breath.

Methods

  • Double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial at 11 outpatient clinical sites in Japan; 828 adults aged ≥18 years who had received three documented mRNA COVID-19 vaccine doses, with the third dose being BNT162b2 at least 3 months before enrolment, were randomly assigned 1:1 to ARCT-154 (n=420) or BNT162b2 (n=408) as a fourth-dose booster.
  • Randomisation used an Interactive Response Technology system with block size four, stratified by age (18–64 or ≥65 years) and interval since last COVID-19 vaccination (<5 or ≥5 months); participants and outcome assessors were masked.
  • Primary immunogenicity analysis was in per-protocol set 1 (385 ARCT-154, 374 BNT162b2), requiring no evidence of previous SARS-CoV-2 infection and receipt of intended injection per protocol; non-inferiority required the lower 95% CI of the ARCT-154 to BNT162b2 GMT ratio to exceed 0.67 and the lower 95% CI for seroresponse-rate difference to exceed −10%. GMTs were analysed by ANCOVA and seroresponse differences by the Miettinen-Nurminen method; safety was assessed in the full analysis set.

Limitations

  • The paper states low numbers of older participants limited analysis of responses in older people; only 19 participants were aged ≥65 years, and small subgroup numbers prevented statistical demonstration of non-inferiority in some groups.
  • The paper states immunogenicity and safety were monitored only up to day 29; durability at 3, 6, and 12 months and cellular immunity are still being assessed, and protective responses against currently dominant variants such as omicron XBB subvariants EG.5.1 and BA.2.86 and future variants still need evaluation.
  • The paper notes observed seroconversion rates were low (65% ARCT-154, 52% BNT162b2), probably because high baseline immunity made a four-fold increase harder to achieve; the text also makes evident that no independent data monitoring committee was used.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s1473-3099(23)00650-3

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

12 of 17 cited sources checked · 3 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Immune responses to mRNA COVID-19 vaccines wane in the months immediately following administration.

    “These vaccines are effective, but the immune response wanes in the months immediately following administration.8,9”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] Andrews, 2022, Covid-19 vaccine effectiveness against the omicron (B.1.1.529) variant, N Engl J Med source

      The Discussion says antibodies wane with time since vaccination, which supports waning in one component of the immune response. But it also says cellular immunity probably continues to limit severe disease; the Results measure declining vaccine effectiveness, not a decline in the immune response as a whole. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [9] Andrejko, 2023, Waning of 2-dose BNT162b2 and mRNA-1273 vaccine effectiveness against symptomatic SARS-CoV-2 infection accounting for depletion-of-susceptibles bias, Am J Epidemiol source

      The Discussion (page not available in our copy) reports waning protection against symptomatic SARS-CoV-2 infection over the months after two doses of BNT162b2 or mRNA-1273. That supports declining vaccine effectiveness, but the study does not measure immune responses directly, so it does not establish that those responses themselves wane. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    mRNA COVID-19 vaccines have been associated with cases of myocarditis in young adults.

    “As mRNA COVID-19 vaccines have been associated with cases of myocarditis in young adults, 19 we monitored for chest pain and shortness of breath in the 7 days after vaccination as indicators of myocarditis and pericarditis.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Alami, 2023, Risk of myocarditis and pericarditis in mRNA COVID-19-vaccinated and unvaccinated populations: a systematic review and meta-analysis, BMJ Open source
  • Premisecitation

    Data from the major phase 1/2/3/3b study of ARCT-154 (NCT05012943) showed a vaccine safety profile similar to that of saline placebo.

    “This finding is consistent with data from the major phase 1/2/3/3b study of ARCT-154 (NCT05012943), which showed a vaccine safety profile similar to that of the saline placebo.18”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Nguyen, 2023, Safety and immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine, Res Sq source

      The Introduction identifies a pooled phase 1/2/3a/3b study of ARCT-154, but reports its immunogenicity and efficacy, not its safety relative to placebo. A search for saline placebo, safety profile, and adverse events found no passage in our copy stating the claimed comparison. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
  • Findingown data

    One severe adverse event, abnormal hepatic function in an ARCT-154 recipient, was considered related to study vaccine.

    “One severe adverse event, a case of abnormal hepatic function in the ARCT-154 group, was considered to be related to study vaccine.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The ratio of surrogate neutralising antibody GMTs at day 29 after ARCT-154 versus BNT162b2 was 1.43 (95% CI 1.26-1.63).

    “The first primary immunogenicity endpoint, the ratio of surrogate neutralising antibody GMTs at day 29 after ARCT-154 and after BNT162b2, was 1•43 (95% CI 1•26-1•63).”
    Quote in the paperSubstantial claim
  • May combine two claims. 48
  • Classified as probably not a substantial claim. 16
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    For some COVID-19 vaccines, heterologous boosting improves the magnitude and breadth of the immune response compared with homologous boosters; however, for mRNA vaccines, a homologous mRNA booster is usually superior to a heterologous non-mRNA booster.

    “For some COVID-19 vaccines, heterologous boosting has been shown to improve both the magnitude and the breadth of the immune response when compared with homologous boosters; 7,21,22 however, this has not been the case for mRNA vaccines, for which the response to a homologous mRNA booster is usually superior to the response to a heterologous non-mRNA booster.[10][11][12]”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [7] Au, 2022, Effectiveness of heterologous and homologous COVID-19 vaccine regimens: living systematic review with network meta-analysis, BMJ source

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

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [21] Munro, 2022, Lancet Infect Dis source

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

      Experimental — accuracy not yet measured
    • cites [22] Naito, 2022, Reactogenicity and immunogenicity of BNT162b2 or mRNA-1273 COVID-19 booster vaccinations after two doses of BNT162b2 among healthcare workers in Japan: a prospective observational study, Expert Rev Vaccines source
    • cites [10][11][12]

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

  • May combine two claims.

    Premisecitation

    The primary phase 1/2/3a/3b study (NCT05012943) demonstrated absolute efficacy of ARCT-154 as a primary vaccination regimen in Vietnamese adults: 56.6% against any COVID-19 and 95.3% against severe COVID-19.

    “This study follows the primary phase 1/2/3a/3b study (NCT05012943), which demonstrated the safety of ARCT-154 compared with placebo and from which absolute efficacies were calculated as 56•6% (95% CI 48•7-63•3) against any COVID-19 and 95•3% (80•5-98•9) against severe COVID-19 when used as a primary vaccination regimen in Vietnamese adults.18”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Nguyen, 2023, Safety and immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine, Res Sq source

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

    Premisecitation

    ARCT-154 is an saRNA vaccine encoding the spike protein of the SARS-CoV-2 B.1 lineage with the D614G mutation.

    “One such formulation, ARCT-154, encodes the spike protein of the B.1 lineage with the D614G (Asp614Gly) mutation, one of the earliest detected variants of SARS-CoV-2.17”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] Korber, 2020, Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus, Cell source

      The Results section (“The D614G Variant”; page unavailable) documents D614G in early SARS-CoV-2 sequences, supporting its description as an early variant. Our copy does not identify the B.1 lineage or discuss ARCT-154, so it cannot support the claim about that vaccine’s formulation or encoded spike. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The waning of neutralising antibodies induced by mRNA vaccines has been associated with increased susceptibility to infection with the omicron variant of SARS-CoV-2.

    “The waning of neutralising antibodies induced by mRNA vaccines has been associated with increased susceptibility to infection with the omicron (B.1.1.529)variant of SARS-CoV-2.23”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Gilboa, 2022, Durability of immune response after COVID-19 booster vaccination and association with COVID-19 omicron infection, JAMA Netw Open source

      The Results (Association Between IgG Antibody Levels and Susceptibility to Omicron Infection) report faster neutralizing-antibody decline among infected than uninfected participants aged 65 or older. The Discussion likewise limits the observed association between waning and Omicron transmission to at least that age group. The citing sentence leaves out this population qualifier and presents the association more generally. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A systematic meta-analysis found that the effectiveness of mRNA vaccines against the omicron variant wanes to less than 20% within 6 months of primary immunisation and to less than 30% within 9 months of a booster dose.

    “A systematic meta-analysis found that the effectiveness of mRNA vaccines against the omicron variant wanes to less than 20% within 6 months of primary immunisation and to less than 30% within 9 months of a booster dose.24”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Menegale, 2023, Evaluation of waning SARS-CoV-2 vaccine-induced immunity: a systematic review and meta-analysis, JAMA Netw Open source

      The Abstract Findings (page not available) report effectiveness below 20% at six months after a primary course and below 30% at nine months after a booster. However, the Results describe these as pooled estimates across different vaccine products, not estimates specifically for mRNA vaccines. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a small phase 1 trial reported in 2023, another saRNA vaccine elicited neutralising antibodies and T-cell responses against SARS-CoV-2 D614G strain and beta, delta, and omicron variants in older adults (≥60 years) previously immunised with ChAdOx1 nCoV-19 vaccine, and the boost persisted for at least 6 months.

    “However, in a small phase 1 trial reported in 2023, another saRNA vaccine elicited neutralising antibodies and T-cell responses against SARS-CoV-2 D614G strain and beta, delta, and omicron variants in older adults (aged ≥60 years) who had previously been immunised with the adenovirus-vectored ChAdOx1 nCoV-19 vaccine.25 Furthermore, this boost in immunity was shown to persist for at least 6 months.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Palmer, 2023, GRT-R910: a self-amplifying mRNA SARS-CoV-2 vaccine boosts immunity for ≥6 months in previously-vaccinated older adults, Nat Commun 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.

    Findingcitation

    Both ARCT-154 and BNT162b2 were well tolerated with mainly mild-to-moderate solicited adverse events, similar to those reported in previous studies of mRNA vaccine boosters.

    “Both ARCT-154 and BNT162b2 were well tolerated with mainly mild-tomoderate solicited adverse events, similar to those reported in previous studies of mRNA vaccine boosters.21,22”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [21] Munro, 2022, Lancet Infect Dis source
    • cites [22] Naito, 2022, Reactogenicity and immunogenicity of BNT162b2 or mRNA-1273 COVID-19 booster vaccinations after two doses of BNT162b2 among healthcare workers in Japan: a prospective observational study, Expert Rev Vaccines source

  • May combine two claims.

    Findingown data

    No reports of solicited local reactions or systemic adverse events described as grade 4 or life-threatening were received.

    “No reports of solicited local reactions or of systemic adverse events described as grade 4 or lifethreatening were received.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adverse events of special interest for myocarditis and pericarditis included chest pain (one case ARCT-154, three BNT162b2) and shortness of breath (two BNT162b2), all considered to have a reasonable possibility of being related to vaccination.

    “Adverse events of special interest for detection of myocarditis and pericarditis included chest pain (one case in the ARCT-154 group and three cases in the BNT162b2 group) and shortness of breath (two cases in the BNT162b2 group), all of which were considered to have a reasonable possibility of being related to vaccination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Baseline immunity against the Wuhan-Hu-1 strain of SARS-CoV-2 was evident in both the ARCT-154 and BNT162b2 groups, with similar baseline GMTs in per-protocol set 1.

    “Background immunity against the Wuhan-Hu-1 strain of SARS-CoV-2 was evident in both the ARCT-154 and the BNT162b2 groups, with similar baseline GMTs in both groups in per-protocol set 1 (figure 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Seroresponse rates against Wuhan-Hu-1 at day 29 were 65.2% (95% CI 60.2-69.9) in ARCT-154 and 51.6% (46.4-56.8) in BNT162b2, a difference of 13.6% (95% CI 6.8-20.5).

    “Seroresponse rates were 65•2% (95% CI 60•2-69•9) in the ARCT-154 group versus 51•6% (46•4-56•8) in the BNT162b2 group, a difference of 13•6% (95% CI 6•8-20•5).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The pre-specified non-inferiority margins (GMT ratio 0.67 and seroresponse rate difference -10%) are clinically acceptable.

  • May combine two claims.

    Findingown data

    Up to day 29, no deaths, adverse events of special interest, or medically significant adverse events were reported.

    “Up to day 29, the interim cut-off presented in this analysis, no deaths, adverse events of special interest, or medically significant adverse events were reported (table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Seroresponse rates against Wuhan-Hu-1 on day 29 were 65.2% in the ARCT-154 group and 51.6% in the BNT162b2 group, a difference of 13.6% (95% CI 6.8-20.5).

    “Seroresponse rates against the Wuhan-Hu-1 strain of SARS-CoV-2 on day 29 were 65•2% (95% CI 60•2-69•9) in the ARCT-154 group and 51•6% (46•4-56•8) in the BNT162b2 group, a difference of 13•6% (95% CI 6•8-20•5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two ARCT-154 recipients reported chest pain (one related, one unrelated), and four BNT162b2 recipients reported five symptoms of interest (three chest pain and two shortness of breath, all considered related).

    “Two recipients of the ARCT-154 vaccine reported chest pain (table 2): one within 1 day of vaccination, which the respective investigator considered to be related to the vaccine, and the other 6 days after vaccination, which was considered unrelated.Four recipients of the BNT162b2 vaccine reported five symptoms of interest: three cases of chest pain occurring within 1-3 days of vaccination and two”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In per-protocol set 1, the GMTs of surrogate neutralising antibodies against Wuhan-Hu-1 at 28 days after boosting were 5641 (95% CI 4321-7363) in ARCT-154 and 3934 (2993-5169) in BNT162b2, with a GMT ratio of 1.43 (95% CI 1.26-1.63).

    “In per-protocol set 1, the GMTs of surrogate neutralising antibodies induced against the Wuhan-Hu-1 SARS-CoV-2 strain in the ARCT-154 group (5641 [95% CI 4321-7363]) were non-inferior to those in the BNT162b2 group (3934 [2993-5169]) when measured at 28 days after boosting, with a GMT ratio of 1•43 (95% CI 1•26-1•63).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The pre-specified non-inferiority margins (GMT ratio 0.67 and seroresponse rate difference -10%) are clinically acceptable.

  • May combine two claims.

    Findingown data

    The majority of unsolicited adverse events were mild or moderate, but seven were severe: one in the ARCT-154 group (abnormal hepatic function, related) and six in the BNT162b2 group (three nasopharyngitis and one each of pyrexia, ankle fracture, and foot deformity, none related).

    “The majority of the reported unsolicited adverse events were mild or moderate, but seven were described as severe (grade 3): one in the ARCT-154 group (a case of abnormal hepatic function, assessed as related to the investigative vaccine by the investigators) and six in the BNT162b2 group (three cases of nasopharyngitis and one case each of pyrexia, ankle fracture, and foot deformity, none of”
    Quote in the paperNot a substantial claim

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

    Findingown data

    759 individuals were included in per-protocol set 1.

    “759 individuals were included in per-protocol set 1”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In participants previously immunised with three doses of BNT162b2, GMTs against omicron BA.4/5 were 2088 after ARCT-154 versus 1479 after BNT162b2, a GMT ratio of 1.41 (1.13-1.77).

    “after three doses of BNT162b2, the GMTs against omicron BA.4/5 were 2088 (95% CI 1271-3429; n=306) after ARCT-154 and 1479 (884-2473; n=298) after a fourth dose of BNT162b2, a GMT ratio of 1•41 (1•13-1•77).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At day 29, ARCT-154 increased surrogate neutralising antibody GMTs against Wuhan-Hu-1 from 813 to 5641, with a geometric mean fold rise of 6.7.

    “At day 29, both groups displayed marked increases in surrogate neutralising antibody GMTs, from 813 (95% CI 716-924) to 5641 (4321-7363) after ARCT-154, a geometric mean fold rise of 6•7 (95% CI 6•0-7•5)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Non-inferiority of the responses against Wuhan-Hu-1 and omicron BA.4/5 after ARCT-154 compared with BNT162b2 was also indicated when groups were separated by age, gender, or interval since the last booster, although small numbers in some groups prevented a statistical demonstration of non-inferiority.

    “Non-inferiority of the responses against Wuhan-Hu-1 and omicron BA.4/5 after ARCT-154, compared with the responses after BNT162b2, were also indicated when the groups were further separated according to age category (<65 years vs ≥65 years), gender (male vs female), or interval since the last COVID-19 booster vaccine before the study vaccine was administered (<5 months vs ≥5 months; appendix 2 pp”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Seroresponse rates against omicron BA.4/5 on day 29 were 69.9% (65.0-74.4) in ARCT-154 and 58.0% (52.8-63.1) in BNT162b2.

    “GMTs against the omicron BA.4/5 variant on day 29 were 2551 (1687-3859) in the ARCT-154 group and 1958 (1281-2993) in the BNT162b2 group-a GMT ratio of 1•30 (1•07-1•58)-with seroresponse rates of 69•9% (65•0-74•4) and 58•0% (52•8-63•1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No treatment-related deaths were reported, and no severe or serious adverse events considered causally associated with study vaccination occurred.

    “No treatment-related deaths were reported, nor were there severe or serious adverse events considered to be causally associated related to study vaccination.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The GMT ratio for omicron BA.4/5 was 1.30 (95% CI 1.07-1.58), and the lower limit of the 95% CI exceeded the non-inferiority criterion of 0.67.

    “The GMT ratio was 1•30 (95% CI 1•07-1•58), in which the lower limit of the 95% CI exceeded the non-inferiority criterion of 0•67”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In participants previously immunised with two doses of mRNA-1273 and one dose of BNT162b2, GMTs against omicron BA.4/5 were 4012 after ARCT-154 versus 3836 after BNT162b2, a GMT ratio of 1.05 (0.713-1.54).

    “In those previously immunised with two doses of mRNA-1273 and one dose of BNT162b2, GMTs were 4012 (1933-8329; n=78) after ARCT-154 and 3836 (1884-7809; n=298) after BNT162b as fourth doses, a GMT ratio of 1•05 (0•713-1•54).”
    Quote in the paperSubstantial claim

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

    Findingown data

    The mean age of participants in the full analysis set was 45.7 years (SD 11.8, range 18-77), of whom 485 (59%) were female and 340 (41%) were male.

    “The mean age of participants in the full analysis set was 45•7 years (SD 11•8, range 18-77), of whom 485 (59%) were female and 340 (41%) were male.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    One serious adverse event, a foot deformity in a BNT162b2 recipient, was observed but determined not to have a causal relationship to study vaccination.

    “One serious adverse event, a foot deformity reported in a participant in the BNT162b2 group, was observed but determined not to have a causal relationship to the study vaccination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Solicited systemic adverse events were mainly mild and transient, starting and resolving within 1-3 days after vaccination.

    “As with the local reactions, solicited systemic adverse events were mainly mild and transient, starting and resolving within 1-3 days after vaccination (figure 3; appendix 2 p 12).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Adverse events were mainly mild in severity, occurring and resolving within 3-4 days after vaccination.

    “Adverse events were mainly mild in severity, occurring and resolving within 3-4 days after vaccination.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Most participants (658 [80%] of 825) had received BNT162b2 exclusively for all three doses; 166 (20%) had received two doses of mRNA-1273 before a third-dose booster of BNT162b2, and one (<1%) received one dose of mRNA-1273 before two doses of BNT162b2.

    “Most participants (658 [80%] of 825) had received the BNT162b2 vaccine exclusively for all three doses; 166 (20%) had received two doses of mRNA-1273 before receiving a third-dose booster of BNT162b2, and one (<1%) received one dose of mRNA-1273 before two doses of BNT162b2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    GMTs against omicron BA.4/5 on day 29 were 2551 (1687-3859) in ARCT-154 and 1958 (1281-2993) in BNT162b2, a GMT ratio of 1.30 (1.07-1.58).

    “GMTs against the omicron BA.4/5 variant on day 29 were 2551 (1687-3859) in the ARCT-154 group and 1958 (1281-2993) in the BNT162b2 group-a GMT ratio of 1•30 (1•07-1•58)-with seroresponse rates of 69•9% (65•0-74•4) and 58•0% (52•8-63•1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    817 (99%) of 825 participants still had neutralising antibodies against the Wuhan-Hu-1 strain of SARS-CoV-2 before receiving the study vaccine, while 654 (79%) had neutralising antibodies against the omicron BA.4/5 subvariant.

    “817 (99%) of 825 still had neutralising antibodies against the Wuhan-Hu-1 strain of SARS-CoV-2 before they received the study vaccine, while 654 (79%) had neutralising antibodies against the omicron BA.4/5 subvariant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most reported local reactions were transient, starting within 1-2 days of vaccination and resolving by day 4, and were mild or moderate in severity.

    “Most reported local reactions were transient, starting within 1 day or 2 days of vaccination and resolving by day 4 (appendix 2 p 11), and were described as mild or moderate in severity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    GMTs against omicron BA.4/5 increased from 275 to 2551 in the ARCT-154 group (GMFR 8.0) and from 292 to 1958 in the BNT162b2 group (GMFR 5.7).

    “GMTs increased from 275 (95% CI 227-335) on day 1 to 2551 (1687-3859) on day 29 in the ARCT-154 group (geometric mean fold rise of 8•0 [95% CI 7•0-9•1]), and from 292 (236-360) on day 1 to 1958 (1281-2993) on day 29 in the BNT162b2 group (5•7 [5•0-6•4]).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    One serious adverse event, a foot deformity, occurred in a participant in the BNT162b2 group and was not considered causally related to vaccination.

    “One serious adverse event, reported in a participant in the BNT162b2 group, was described as a foot deformity, and the investigators did not consider it to have any causal relationship to the study vaccination.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Similar immune responses were observed across subgroups, including men and women and older individuals (≥65 years), although low numbers in some groups mean caution should be exercised in interpretation.

    “Similar immune responses were observed across subgroups, including in men and women and in older individuals (≥65 years), although the low numbers of participants in some groups (eg, only 19 participants were aged ≥65 years) mean that caution should be exercised in the interpretation of these data (appendix 2 pp 5-7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Six participants (two ARCT-154 and four BNT162b2) reported chest pain and/or shortness of breath; one ARCT-154 case and all four BNT162b2 cases were considered related, but myocarditis and pericarditis were excluded after evaluation.

    “Six participants, two who received the ARCT-154 vaccine and four who received the BNT162b2 vaccine, reported one or both symptoms.Although one case in the ARCT-154 group and all four cases in the BNT162b2 group were considered to be related to the study vaccines, myocarditis and pericarditis were excluded after evaluation by the investigators or a cardiologist.”
    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 conductown data

    This trial was a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial conducted at 11 outpatient clinical sites in Japan.

    “This double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial was conducted at 11 out patient clinical sites in Japan (appendix 2 p 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Self-amplifying RNA vaccines require lower doses to enhance antigen expression than conventional mRNA-based vaccines and could improve the efficacy and duration of protection.

    “Preclinical studies suggest that saRNA vaccines, which are not restricted to COVID-19, require lower doses to enhance antigen expression than conventional mRNA-based vaccines and could improve the efficacy and duration of protection.[14][15][16]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14][15][16]

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

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Participants were randomly assigned 1:1 using an Interactive Response Technology system with block size four, stratified by age (18-64 or ≥65 years) and interval since last COVID-19 vaccination (<5 or ≥5 months).

    “At enrolment, participants were randomly assigned (1:1) using an Interactive Response Technology system with a block size of four, stratified by age (18-64 years or ≥65 years) and the interval since last COVID-19 vaccination (<5 months or ≥5 months), to receive either the ARCT-154 or the BNT162b2 vaccine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Administering a homologous booster dose extends the duration of response but does not broaden it against antigenic drift.

    “Administering a booster dose of the same vaccine type, known as homologous boosting, extends the duration of response but does not broaden it against the antigenic drift that occurs as new variants emerge.[10][11][12]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10][11][12]

      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

    Randomisation lists were generated by external unmasked statisticians who had no further role in endpoint analyses.

    “Randomisation lists were generated by external unmasked statisticians who had no further role in endpoint analyses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The study was registered on the Japan Registry for Clinical Trials, jRCT 2071220080.

    “This study was registered on the Japan Registry for Clinical Trials, jRCT 2071220080, and is ongoing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The sample size was justified: assuming a GMT ratio of 1.0 with SD 0.40 and seroresponse rate of 85%, 270 participants per group were required for 90% power to detect non-inferiority (GMT margin 0.67, seroresponse margin -10%, one-sided 2.5%), and with 10% dropout and 20% seropositive exclusion, 780 participants were needed.

    “For the immunogenicity evaluations, the ratio of the neutralising antibody GMTs against the Wuhan-Hu-1 SARS-CoV-2 strain measured 28 days after booster vaccination between the two groups was assumed to be 1•0 with a standard deviation of 0•40, and the seroresponse rate of each group was assumed to be 85%.To obtain a statistical power of 90% to detect the non-inferiority of ARCT-154 compared with B”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    There was no independent data monitoring committee.

    “There was no independent data monitoring committee.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Both the ARCT-154 and BNT162b2 vaccines were reasonably well tolerated in this population, with no reports of deaths, serious adverse events, or medically significant adverse events causally associated with vaccination.

    “Furthermore, both the ARCT-154 and BNT162b2 vaccines were reasonably well tolerated in this population, with no reports of deaths, serious adverse events, or medically significant adverse events that were causally associated with vaccination.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Participants and investigators assessing outcomes were masked to group assignment.

    “Participants and investigators assessing outcomes were masked to group assignment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The lower limit of the 95% CI for the seroresponse difference exceeded the predefined margin of -10%, so the primary objective of non-inferiority of the immune response to ARCT-154 compared with BNT162b2 was met in terms of GMTs and seroresponse rates.

    “Because the lower limit of the 95% CI exceeded the predefined margin of -10%, the primary objective-the non-inferiority of the immune response to ARCT-154 compared with the response to BNT162b2was also met, both in terms of GMTs and seroresponse rates.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Only data up to day 29 are reported here; safety monitoring up to 12 months is ongoing.

    “Only data up to day 29 are reported here; safety monitoring up to 12 months is ongoing.”
    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 conductown data

    The study protocol was approved by the institutional review boards of all participating sites, and the study was conducted according to the Declaration of Helsinki and Good Clinical Practice.

    “The study protocol (appendix 2) was approved by the institutional review boards of all participating sites.The study was conducted according to the ethical principles of the Declaration of Helsinki and Good Clinical Practice.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

    “The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Occurrences of chest pain and shortness of breath between days 1 and 7 were specifically monitored as indicators of potential myocarditis and pericarditis.

    “Occurrences of the symptoms of interest, chest pain and shortness of breath, between days 1 and 7 were specifically monitored as indicators of potential myocarditis and pericarditis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    A 5 μg booster dose of ARCT-154 is safe, is well tolerated, and induces a robust immune response to the Wuhan-Hu-1 strain of SARS-CoV-2 that is non-inferior to the response induced by a homologous 30 μg booster dose of BNT162b2.

    “We show that a 5 μg booster dose of ARCT-154 is safe, is well tolerated, and induces a robust immune response to the Wuhan-Hu-1 strain of SARS-CoV-2 that is non-inferior to the response induced by a homologous 30 μg booster dose of the BNT162b2 mRNA vaccine.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The pre-specified non-inferiority margins (GMT ratio 0.67 and seroresponse rate difference -10%) are clinically acceptable.

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

    Study design and conductnone given

    Vaccines were prepared in opacified syringes and administered by study staff who were unmasked to the randomisation code and had no further role in the study.

    “Vaccines were prepared in opacified syringes and administered by study staff who were unmasked to the randomisation code supplied by the study sponsor and who had no further role in the study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The criteria for superiority of the ARCT-154 response over the BNT162b2 response for omicron BA.4/5 were met because the lower limit of the 95% CI for the GMT ratio was greater than 1.0 and the same lower limit for the difference in seroresponse rate was greater than 0%.

    “Notably, as the lower limit of the 95% CI for the GMT ratio was greater than 1•0, and the same lower limit for the difference in seroresponse rate was greater than 0%, the criteria for superiority of the ARCT-154 response over the BNT162b2 response were met.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The low numbers of older participants limit analysis of the response in older people, and further assessment will be required in this population.

    “Our study has some limitations, notably the low numbers of older participants, which limits analysis of the response in older people and a further assessment will be required in this population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The observed seroconversion rates were low (65% for ARCT-154 and 52% for BNT162b2), probably because the high level of immunity at baseline following previous immunisations made a four-fold increase more difficult to achieve.

    “Although antibody titres were high after boosting in this study, the observed seroconversion rates were low: 65% for ARCT-154 and 52% for BNT162b2.These seroconversion rates were probably due to the high level of immunity at baseline following previous immunisations, making a four-fold increase more difficult to achieve.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The saRNA platform appears to induce non-inferior, and for the omicron BA.4/5 subvariant superior, heterologous responses compared with homologous boosting with an mRNA vaccine.

    “Nevertheless, this saRNA platform appears to induce non-inferior, and for the omicron BA.4/5 subvariant, superior, heterologous responses compared with homologous boosting with an mRNA vaccine-a characteristic that is highly desirable in a period of continued viral evolution.”
    Quote in the paperSubstantial claim
57 of 57

  • The paper relies on this without support.

    The pre-specified non-inferiority margins (GMT ratio 0.67 and seroresponse rate difference -10%) are clinically acceptable.

    “Non-inferiority was declared when the lower limit of the 95% CI of the ARCT-154 to BNT162b2 GMT ratio exceeded 0•67, and when the lower limit for the difference in seroresponse rates exceeded -10%.”

  • The paper relies on this without support.

    Neutralising antibody titres and seroresponse rates are valid correlates of protection against SARS-CoV-2 infection and disease.

    “Increased immune responses at 28 days might provide increased likelihood of protection against these strains during this period and could also result in longer duration of protection.”
2 of 2

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.

  • Abstract denies vaccine-related severe adverse events

    Major

    The abstract says no severe adverse events were considered causally associated with vaccination, but immediately reports a severe event considered related to the ARCT-154 vaccine.

  • Omicron subgroup count exceeds the number with that vaccination history

    Minor

    The omicron analysis lists 298 BNT162b2 recipients previously given two mRNA-1273 doses, whereas the baseline table lists only 79 such recipients in the entire BNT162b2 group.

2 of 2

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Authors
Oda, Y., Kumagai, Y., Kanai, M., Iwama, Y., Okura, I., Minamida, T., Yagi, Y., Kurosawa, T., Greener, B., Zhang, Y., & Walson, J. L.
Affiliations
  • Meiji Seika Pharma Co., Ltd. (Japan) (JP)
  • Kitasato Institute Hospital (JP)
  • Arcturus Therapeutics (United States) (US)
Corresponding author
Walson, Judd L
ORCID
Venue
The Lancet Infectious Diseases
Publisher
Elsevier BV
Published
2024-04
Volume
24
Issue
4
Pages
351-360
ISSN
1473-3099 (ISSN-L)
DOI
10.1016/s1473-3099(23)00650-3
OpenAlex
W4389990639
Cited by
123
References
27
Citations by year
2026: 32 · 2025: 58 · 2024: 31 · 2023: 1 · 2013: 1
FWCI
23.33
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Infectious Diseases (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Labour Health and Welfare Organization
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Social Sciences › Health › Vaccine Coverage and Hesitancy
Keywords
self-amplifying RNA vaccine, COVID-19 booster vaccination, BNT162b2, mRNA vaccines, SARS-CoV-2, immunogenicity, vaccine safety, neutralizing antibodies, non-inferiority, mRNA-1273
MeSH terms
Immunogenicity, Vaccine, COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, BNT162 Vaccine, Adolescent, Adult, Aged, Antibodies, Viral, Double-Blind Method, Humans, Middle Aged, RNA, Young Adult

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

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