Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.

Name: Kaimen Rigor review — BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.
Item: BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.
Rating: 59
Author: Alpha1

Schmidt AC, Fairlie L, Hellström E, Luabeya Kany Kany A, Middelkoop K, Naidoo K, Nair G, Gela A, Nemes E, Scriba TJ, Cinar A, Frahm N, Mogg R, Kaufman D, Dunne MW, Hatherill M, BCG REVAX Study Team

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Kaimen Rigor review — 1★ (Critical), 0 critical, 6 high issues for “BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 10, 2026

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BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.

Schmidt AC, Fairlie L, Hellström E, Luabeya Kany Kany A, Middelkoop K, Naidoo K, Nair G, Gela A, Nemes E, Scriba TJ, Cinar A, Frahm N, Mogg R, Kaufman D, Dunne MW, Hatherill M, BCG REVAX Study Team

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DOI

10.1056/NEJMoa2412381

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.

Schmidt AC, Fairlie L, Hellström E, Luabeya Kany Kany A, Middelkoop K, Naidoo K, Nair G, Gela A, Nemes E, Scriba TJ, Cinar A, Frahm N, Mogg R, Kaufman D, Dunne MW, Hatherill M, BCG REVAX Study Team

Paper source

BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 10, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

1 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×6−3★
ReportingData & code availability not met−0.5★
ReportingBiological variables partially met−0.25★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.29.0Source: full text

Biggest issues

01Data and code not shared
highDisclosurereviewer-assessedFull detail
No data availability statement, repository deposit, or code sharing is provided. The trial is registered on ClinicalTrials.gov, but the paper does not state where data can be accessed.
02Internal contradictions in the reported numbers
mediumArithmeticreviewer-assessedFull detail
The Discussion states the initial QFT conversion rate was 6.5-6.9% per person-year, but Table 1 reports incidence rates of 0.0069 and 0.0065 with person time in months; converting those rates to per-year gives approximately 7.8-8.3% per person-year, inconsistent with the text.
“The overall initial QFT conversion rate in this trial (6.5-6.9% per person-year) was lower than the 9.9% per person-year reported for the earlier trial.”
Table 1Find in source
03Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT02075203 was first submitted to ClinicalTrials.gov on 2014-02-17, after the registered study start date of 2014-02. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT02075203
reviewer’s wording

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 103AuthenticityData authenticity concerns 404DisclosureReporting gaps 05AvailabilityNone found 106CopyeditCopyediting

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This is a rigorously designed and reported randomized phase 2b trial whose null primary result (BCG revaccination did not prevent sustained Mtb infection) is transparently reported and recomputes consistently. The main weaknesses are reporting and consistency gaps: no data availability statement, unnamed ethics committee and no explicit consent statement, unreported sex distribution and weight, unconfirmed proportional-hazards assumption, and several concrete internal numerical contradictions (BCG n=918 vs 919; 1836 vs 1835; incidence-rate units). These are fixable reporting/consistency issues rather than threats to the primary null conclusion.

Three independent reviewer runs were reconciled; reviewers converged on five dimensions and diverged on biological variables (fail vs warn), statistical analysis (warn vs pass), and reporting transparency (pass vs warn), here resolved toward warn by weighing the verifiable evidence. The statistics verification recomputed only 1 reported test (limited coverage; the remaining tests are unverified, not confirmed); citation checks found no retracted or unlocatable references; all 3 reproducibility links were live.

Numerical inconsistencies

1 finding · worst medium

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.

Overstated conclusions

1 finding · worst low

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Conclusions only partially backed by the presented evidenceAssessed

7 major claims checked against the paper's own evidence: all adequately supported.

Data authenticity concerns

1 finding · worst medium

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Other integrity concernAssessed

6 integrity concerns flagged (0 high).

Reporting gaps

4 findings · worst high

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Data and code not sharedAssessed
Biological variables underreported (sex, age, strain)Assessed
Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed

Eight Dimensions4 pass · 3 warn · 1 fail

The introduction cites the prior phase 2 trial that showed a VE of 45% for sustained Mtb infection, and discusses the need for confirmation in a larger, more diverse population. It also addresses the limitations of the earlier trial, including small sample size and secondary endpoint. The current trial's objectives and hypotheses follow logically from the cited evidence.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study clearly establishes its scientific foundation by citing prior work (NCT02075203) and providing a logical rationale for the confirmatory trial, while acknowledging limitations of the earlier study.

Evidence

paraphrase[Abstract, Introduction (paragraphs 3-4)]

“A prior phase 2 trial assessed the efficacy of the investigational H4:IC31 vaccine and Bacille Calmette-Guérin (BCG) vaccine versus placebo for protection against Mtb infection...”

paraphrase[Introduction (paragraph 4)]

“However, because no more than 5-10% of Mtb-infected individuals progress to TB, VE for prevention of sustained Mtb infection may not predict VE for prevention of disease...”

paraphrase[Introduction (paragraph 5)]

“we set out to: a) confirm that BCG revaccination confers prevention of sustained Mtb infection in a larger population with expanded age range and geographical area; and b) identify candidate correlates of protection...”

PASSReviewer 2· 90% conf

The premise is well established from a prior phase 2 trial, with a clear rationale and acknowledgment of the surrogate-endpoint limitation.

Evidence

paraphrase[Abstract, Background]

“In a prior phase 2 trial ( NCT02075203 ), BCG revaccination failed to provide protection from primary Mycobacterium tuberculosis ( Mtb ) infection but prevented sustained Mtb infection (secondary endpoint), defined as initial interferon gamma release assay (IGRA) conversion followed by two additional positive IGRA results 3 and 6 months post initial conversion, with a vaccine efficacy [VE] of 45% (95% CI 6% to 68%).”

paraphrase[Introduction]

“However, because no more than 5-10% of Mtb -infected individuals progress to TB, VE for prevention of sustained Mtb infection may not predict VE for prevention of disease (POD) if the protective immune response leading to prevention of sustained Mtb infection is only induced in the majority of individuals who would not have progressed to disease without vaccination.”

IntroductionFind in source

PASSReviewer 3· 90% conf

The study is well grounded in a prior phase 2 trial, with a clear rationale and an explicit description of how the current design addresses limitations of prior work.

Evidence

paraphrase[Introduction]

“BCG revaccination failed to provide protection from primary Mtb infection, assessed by initial QFT conversion. However, significant vaccine efficacy (VE) was observed for the secondary endpoint, prevention of sustained Mtb infection (POSI; VE 45%, 95% CI 6% to 68%).”

“In the absence of a licensed vaccine for the prevention of TB in adolescents and adults, we set out to: a) confirm that BCG revaccination confers prevention of sustained Mtb infection in a larger population with expanded age range and geographical area; and b) identify candidate correlates of protection for this trial endpoint”

IntroductionFind in source

“the sample size per treatment arm was approximately 3 times larger; the age range increased to include 10- and 11-year-olds; and the geographical footprint expanded”

DiscussionFind in source

Randomization method and unit are reported, as is the observer-blind design with the caveat of inadvertent unblinding. The power calculation is explicit (90% power, one-sided alpha 2.5%, 118 events). Inclusion criteria are summarized and the mITT population and missing completely at random assumption are defined. The clinical-trial-specific not-applicable items (biological-replicate distinction, wet-lab controls, independent replication) are appropriately marked.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The study design is well-reported with randomization, power analysis, inclusion/exclusion criteria, and placebo control, but blinding was observer-blind and unblinding occurred due to injection site lesions.

Evidence

paraphrase[Methods, Trial Design and Objectives]

“Randomization was stratified by age, sex, trial site, and school cluster (Worcester site only). Randomization to BCG or placebo was assigned using a validated Interactive Voice/Web Response System.”

paraphrase[Methods, Statistical analysis]

“The trial was designed to provide 90% power with a 1-sided alpha of 2.5% for the primary endpoint analysis. Assuming a true VE of 45%, at least 118 sustained QFT conversion events were required...”

paraphrase[Methods, Trial Design and Objectives]

“The trial was observer-blind until the primary endpoint analyses were completed. Inadvertent unblinding occurred due to recognizable lesion formed at the BCG injection site.”

PASSReviewer 2· 80% conf

Core design elements for a randomized trial are adequately reported, including randomization, blinding, power calculation, and definition of the mITT population.

Evidence

“Randomization to BCG or placebo was assigned using a validated Interactive Voice/Web Response System. The trial was observer-blinded until the primary endpoint analyses were completed. Inadvertent unblinding occurred due to recognizable lesion formed at the BCG injection site.”

MethodsFind in source

paraphrase[Methods, Statistical analysis]

“The modified intention-to-treat (mITT) population included all participants who received the trial treatment and were QFT negative at the D71 visit, or at the first trial visit post D71 for which a QFT result was available.”

Statistical analysisFind in source

PASSReviewer 3· 95% conf

The trial design is rigorous: randomization via a validated IVRS with stratification, observer blinding described, an explicit power calculation, and clear analysis populations and missing-data assumptions.

Evidence

“Randomization to BCG or placebo was assigned using a validated Interactive Voice/Web Response System.”

MethodsFind in source

“The trial was observer-blinded until the primary endpoint analyses were completed. Inadvertent unblinding occurred due to recognizable lesion formed at the BCG injection site.”

MethodsFind in source

Statistical analysisFind in source

The text gives median age, HIV/QFT-negative status, and the proportion self-identifying as Black African. Sex is referenced only as a randomization/stratification variable and is not reported as a baseline count or percentage. Weight is not reported, and the baseline table is referenced but not shown in the provided text.

Sub-criteria

demographicsADEQUATE

sex reportedINADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 80% conf

The study fails to adequately report several biological variables: sex distribution is not explicitly provided in the text, weight is not reported, and demographics are limited to race only.

Evidence

“The median age was 13 years (range, 10-18) and most participants (1464 [79.8%]) self-identified as Black African.”

ResultsFind in source

absence[Results, Baseline characteristics and disposition]

Sex distribution is not explicitly reported in the text

“most participants (1464 [79.8%]) self-identified as Black African.”

ResultsFind in source

WARNReviewer 2· 60% conf

Age and race/ethnicity are reported, but explicit sex distribution and weight/comorbidity data are not presented in the text.

Evidence

“The median age was 13 years (range, 10-18) and most participants (1464 [79.8%]) self-identified as Black African.”

ResultsFind in source

“Randomization was stratified by age, sex, trial site, and school cluster (Worcester site only).”

MethodsFind in source

absence[Methods, Participants]

Weight and comorbidity details are not provided.

WARNReviewer 3· 70% conf

Age, health status, and race/ethnicity are reported, and sex is mentioned as a stratification variable, but sex distribution, weight, and detailed comorbidity information are not provided in the text.

Evidence

“Randomization was stratified by age, sex, trial site, and school cluster (Worcester site only).”

MethodsFind in source

“The median age was 13 years (range, 10-18) and most participants (1464 [79.8%]) self-identified as Black African.”

ResultsFind in source

“Demographics and baseline characteristics were comparable between the two groups ().”

ResultsFind in source

The paper says 'the trial was conducted in accordance with ... the IRB/IEC' but does not name the specific ethics committee that approved the study, nor does it provide a protocol number. Informed consent is only mentioned in a figure label ('informed consent form') but no description of the consent process is provided. Regulatory compliance with ICH GCP and SAHPRA is stated. For a human trial, these are important missing details.

Sub-criteria

iacuc statementN/A

informed consentNOT REPORTED

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The paper states compliance with regulatory standards and mentions IRB/IEC, but does not name a specific ethics committee or provide a protocol number, and informed consent is not explicitly described.

Evidence

“The trial was conducted in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, SAHPRA (South African Health Products Regulatory Authority) Regulations, the IRB/IEC, and other applicable country and local requirements.”

MethodsFind in source

paraphrase[Methods, Trial oversight; Figure 1A]

“Informed consent is only mentioned as 'ICF' in Figure 1A, with no description of the consent process in the text.”

paraphrase[Methods, Trial oversight]

WARNReviewer 2· 70% conf

Regulatory compliance is stated by name, but no named IRB/IEC approval with protocol number or explicit informed-consent statement is present in the text.

Evidence

MethodsFind in source

“ICF, informed consent form; PC, post conversion; QFT, QuantiFERON-TB Test”

Figure 1Find in source

absence[Methods]

No explicit statement of written informed consent or parental permission is found.

WARNReviewer 3· 85% conf

Regulatory compliance is stated, but no named IRB/IEC approval with protocol number is given, and informed consent is only implied by an acronym in a figure legend.

Evidence

MethodsFind in source

“ICF, informed consent form”

Figure 1Find in source

absence[Full text]

No explicit informed-consent statement or ethics-approval number is provided.

The BCG vaccine (BCG Danish 1331, AJ Vaccines, Copenhagen, Denmark) is identified with manufacturer and source. The placebo is not described in detail. No statistical software (e.g., SAS, R) is mentioned; only MedDRA version 26.0 is noted for coding AEs. For a clinical trial, the investigational product is adequately identified, but the absence of software identification is a minor gap.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The investigational product (BCG vaccine) is well identified, but statistical software is not named, and placebo formulation is not described.

Evidence

“BCG (BCG Danish 1331 vaccine, AJ Vaccines, Copenhagen, Denmark)”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software is not named

absence[Methods, Trial Design and Objectives]

Placebo is not described

WARNReviewer 2· 70% conf

The investigational product and assay are well identified, but antibodies for the immunogenicity assay and statistical software are not reported.

Evidence

“BCG (BCG Danish 1331 vaccine, AJ Vaccines, Copenhagen, Denmark)”

MethodsFind in source

“Immunogenicity was evaluated as the frequency of BCG-specific CD4 or CD8 T cells expressing one or more of the following cytokines: IFN-γ, tumor necrosis factor (TNF), interleukin (IL)-2, IL-17 and/or IL-22, by whole blood intracellular cytokine staining (WB-ICS) assay.”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software is not identified.

WARNReviewer 3· 75% conf

The investigational BCG product is well identified, but the antibodies used in the immunogenicity assay and the statistical software are not identified.

Evidence

“BCG (BCG Danish 1331 vaccine, AJ Vaccines, Copenhagen, Denmark)”

MethodsFind in source

“by whole blood intracellular cytokine staining (WB-ICS) assay”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software is not identified.

The primary analysis used a stratified log-rank test and stratified Cox model; HR, VE, and 95% CIs are reported, and P=0.58 is exact. Per-group n, CIs, and cumulative event curves are presented. The main omissions—statistical software and proportional-hazards diagnostics—do not undermine the primary results.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedINADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

Statistical tests are named and effect sizes with CIs are reported, but assumptions of the Cox model are not verified, statistical software is not identified, and there is a minor numerical inconsistency in the total randomized count.

Evidence

paraphrase[Methods, Statistical analysis]

“The primary efficacy endpoint was analyzed using a log-rank test, stratified by sex and age group... Hazard ratio (HR) and 95% CIs were estimated from a stratified Cox proportional hazards model.”

paraphrase[Results, Efficacy; Table 1]

“one-sided P=0.58; VE point estimate of −3.8% (95% CI −48.3% to 27.4%)”

paraphrase[Abstract, Results]

“A total of 1836 participants were enrolled; 918 participants received BCG and 917 received placebo. (later: A total of 1836 were randomized 1:1 to BCG (n=919) or placebo (n=917).)”

PASSReviewer 2· 75% conf

Statistical tests, exact p-value, effect sizes with CIs, and data presentation are sound; no arithmetic impossibilities were found, but statistical software is not identified.

Evidence

“The primary efficacy endpoint was analyzed using a log-rank test, stratified by sex and age group (10-11 years old, 12-14 years old, and >14 years old) to evaluate differences in distributions of event times between the BCG revaccination and placebo groups.”

Statistical analysisFind in source

“The observed HR was 1.038 (95% CI 0.73 to1.48), for a VE point estimate of −3.8% (95% CI −48.3% to 27.4%).”

AbstractFind in source

absence[Methods, Statistical analysis]

Statistical software is not identified.

PASSReviewer 3· 85% conf

Statistical tests and effect estimates are clearly reported with CIs and exact P for the primary endpoint; arithmetic spot-checks of counts and percentages were consistent.

Evidence

Statistical analysisFind in source

“The observed HR was 1.038 (95% CI 0.73 to1.48), for a VE point estimate of −3.8% (95% CI −48.3% to 27.4%).”

AbstractFind in source

“one-sided P=0.58”

ResultsFind in source

The paper mentions the ClinicalTrials.gov identifier NCT04152161 but does not include a data availability statement. There is no mention of data repository deposit, accession numbers, or code sharing. For a clinical trial, a data availability statement is expected, even if it refers to managed access. The absence of any such statement is a significant omission.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 95% conf

No data availability statement, repository deposit, or code sharing is provided. The trial is registered on ClinicalTrials.gov, but the paper does not state where data can be accessed.

Evidence

absence[Entire paper]

No data availability statement

absence[Entire paper]

No repository deposit mentioned

absence[Entire paper]

No code sharing mentioned

FAILReviewer 2· 80% conf

No data availability statement, repository deposition, accession numbers, or code sharing route is reported in the manuscript text.

Evidence

absence[Manuscript (full text)]

No data availability statement is present in the text.

“Supported by Bill & Melinda Gates Foundation; ClinicalTrials.gov (http://clinicaltrials.gov/) Identifier NCT04152161”

ConclusionFind in source

FAILReviewer 3· 90% conf

No data availability statement is present, and no repository, accession numbers, or code-sharing mechanism is reported.

Evidence

absence[Full text]

No data availability statement is present.

“Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.”

FundingFind in source

Methods are sufficiently detailed for replication. The trial is registered with a number. All outcomes (primary, secondary, exploratory) are reported, including negative results. Limitations are discussed in the Discussion. Conclusions are proportional to the evidence. However, no explicit conflicts-of-interest statement is provided, and while a CONSORT diagram is included, the paper does not state that it follows CONSORT reporting guidelines. Funding is acknowledged.

Sub-criteria

funding coiNOT REPORTED

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The manuscript is well-structured, methods are detailed, the trial is registered, and null results are reported. However, a conflicts-of-interest statement is absent and the use of CONSORT is not explicitly acknowledged.

Evidence

paraphrase[Abstract, Methods]

“ClinicalTrials.gov Identifier NCT04152161”

“The VE point estimate for the primary endpoint was −0.038 (95% CI, −0.483 to 0.274)”

ResultsFind in source

absence[End of manuscript]

No conflicts-of-interest statement

PASSReviewer 2· 80% conf

The trial is registered, the null primary result is transparently reported, limitations are discussed, and conclusions are proportional; the main gaps are no explicit CONSORT checklist statement and no explicit conflicts-of-interest declaration.

Evidence

“ClinicalTrials.gov (http://clinicaltrials.gov/) Identifier NCT04152161”

ConclusionFind in source

“Other limitations include that enrollment was paused for four months due to COVID-19 pandemic restrictions, and schools were closed for several additional months , which may have contributed to a lower incidence rate.”

DiscussionFind in source

absence[Manuscript (full text)]

No explicit conflicts-of-interest statement is present.

WARNReviewer 3· 80% conf

Trial registration, transparent null-result reporting, limitations, and proportional conclusions are present, but methods are incomplete in the text, no reporting guideline is mentioned, and a conflicts-of-interest statement is missing.

Evidence

“ClinicalTrials.gov (http://clinicaltrials.gov/) Identifier NCT04152161”

AbstractFind in source

DiscussionFind in source

“Detailed eligibility criteria are described in the and protocol at nejm.org (http://nejm.org/) .”

MethodsFind in source

Registered (2 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 15 references by DOI: 9 verified — 6 no DOI (shown, not verified).

3 data/code links checked; 3 live.

Copyediting

1 finding · worst low

Wording, consistency and formatting errors that need correcting before submission.

Wording or formatting errors that need correctingAssessed

11 copyedit issues flagged (2 major): mostly consistency, clarity, typo.

Kaimen Rigor Action ItemsFinal pass before journal submission

As a published work, the paper is methodologically robust at its core — the primary null result is credible, the reported test recomputes consistently, and the trial was pre-registered — so an informed reader should not doubt the central conclusion. However, the verifiable internal contradictions in participant counts (n=918 vs 919; 1836 vs 1835) and the incidence-rate units (Discussion 6.5-6.9% vs Table 1 ~7.8-8.3% per person-year), together with the absent data availability statement and unnamed ethics committee, warrant a formal correction/erratum and an independent re-check of the disposition data before the paper is relied upon for pooling or meta-analysis.

1.
HIGHdata code
Add a Data Availability statement describing the managed-access route for de-identified participant data (e.g., a named data-access committee or controlled-access platform) with request conditions and timeframe.
The paper contains no data availability statement, repository deposit, or code-sharing route, which is a required element for a data-driven clinical trial.
2.
HIGHrigor
Reconcile the BCG group count (n=918 in the abstract/safety tables vs n=919 in Figure 1) and the enrollment/follow-up sums (1836 enrolled but 918+917=1835; 1752+83=1835) across the abstract, Results, and Figure 1.
These are verifiable impossible-number contradictions in participant disposition that undermine the integrity of the CONSORT accounting.
3.
HIGHrigor
Reconcile the Discussion's '6.5-6.9% per person-year' initial QFT conversion rate with Table 1's person-month-based incidence rates (which imply ~7.8-8.3% per person-year); correct the text or the table units.
The text and table report inconsistent incidence rates for the same quantity, a concrete internal contradiction an informed reader can verify.
4.
HIGHethics
Name the specific IRB/research ethics committee(s) that approved the protocol and include the protocol/approval number; add an explicit statement that written informed consent/assent was obtained from participants and parents/guardians.
The Trial oversight section cites ICH GCP/SAHPRA/IRB-IEC but names no approving committee and gives no consent statement, a required reporting element for a human trial.
5.
HIGHreporting
Report the sex distribution (n, %) and weight or BMI in the baseline characteristics table; the text currently reports only age and race, with sex appearing only as a stratification variable.
Sex and weight are relevant baseline biological variables whose absence prevents assessment of group comparability.
6.
HIGHcopyedit
Fix the garbled methods sentence in the Participants section — 'Detailed eligibility criteria are described in the and protocol at nejm.org' — to refer clearly to the protocol and Supplementary Appendix.
This truncated sentence is a major clarity defect in the Methods that would read as an error in print.
7.
MEDIUMreporting
Identify the antibodies (clone, fluorophore, vendor, dilution/RRID) and flow-cytometry analysis software (e.g., FlowJo version) used in the whole-blood ICS immunogenicity assay, in Methods or the Supplement.
The WB-ICS assay is described without antibody details, preventing replication of the immunogenicity endpoint.
8.
MEDIUMstatistics
Identify the statistical software and version (e.g., SAS 9.4, R) used for all analyses in the Statistical Analysis section.
No statistical software is named, a routine reporting requirement for reproducibility.
9.
MEDIUMstatistics
State how the proportional-hazards assumption was assessed for the stratified Cox model (e.g., Schoenfeld residuals) or explicitly note that it was not tested.
The primary analysis uses a Cox model, but the PH assumption is not discussed, leaving the primary model's validity unverified.
10.
MEDIUMreporting
Add a statement that the trial is reported per CONSORT 2010 and cite the completed checklist.
No reporting guideline is acknowledged despite the RCT design and CONSORT flow diagram.
11.
MEDIUMreporting
Add a conflicts-of-interest declaration for all authors.
Funding is acknowledged but no COI statement is present, a standard transparency requirement.
12.
MEDIUMcopyedit
Reconcile the 'double-blind' terminology in the abstract with the 'observer-blind' description in Methods, and explain whether participants were blinded given the acknowledged unblinding from injection-site lesions.
The abstract and Methods describe the blinding inconsistently, which could mislead readers about the blinding level.
13.
LOWcopyedit
Fix the missing spaces ('A total of1836') and the grammar ('CI were' → 'CIs were').
Minor typos that a copyedit should catch before publication.
14.
LOWcopyedit
Replace the 'Supplementary Material Supp' placeholder at the end of the manuscript with a proper references list or delete it.
Placeholder text would be published as-is otherwise.
15.
LOWother
Acknowledge that the underpinning prior trial (NCT02075203) was retrospectively registered (submitted 2014-02-17 after the registered 2014-02 start) and note this when weighing the confirmatory rationale.
Retrospective registration of the prior trial means its protocol and outcomes were not on the public record before it ran, which an informed reader should weigh.

Full text (30,048 chars)Analyzed: Aug 10, 2026

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BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection.

Schmidt AC, Fairlie L, Hellström E, Luabeya Kany Kany A, Middelkoop K, Naidoo K, Nair G, Gela A, Nemes E, Scriba TJ, Cinar A, Frahm N, Mogg R, Kaufman D, Dunne MW, Hatherill M, BCG REVAX Study Team

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DOI

10.1056/NEJMoa2412381

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Issued Aug 10, 2026Engine 7.29.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

1 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×6−3★
ReportingData & code availability not met−0.5★
ReportingBiological variables partially met−0.25★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.29.0Source: full text

Biggest issues

01Data and code not shared
highDisclosurereviewer-assessedFull detail
No data availability statement, repository deposit, or code sharing is provided. The trial is registered on ClinicalTrials.gov, but the paper does not state where data can be accessed.
02Internal contradictions in the reported numbers
mediumArithmeticreviewer-assessedFull detail
The Discussion states the initial QFT conversion rate was 6.5-6.9% per person-year, but Table 1 reports incidence rates of 0.0069 and 0.0065 with person time in months; converting those rates to per-year gives approximately 7.8-8.3% per person-year, inconsistent with the text.
“The overall initial QFT conversion rate in this trial (6.5-6.9% per person-year) was lower than the 9.9% per person-year reported for the earlier trial.”
Table 1Find in source
03Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT02075203 was first submitted to ClinicalTrials.gov on 2014-02-17, after the registered study start date of 2014-02. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT02075203
reviewer’s wording

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 103AuthenticityData authenticity concerns 404DisclosureReporting gaps 05AvailabilityNone found 106CopyeditCopyediting

Numerical inconsistencies

1 finding · worst medium

Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.

Overstated conclusions

1 finding · worst low

Conclusions only partially backed by the presented evidenceAssessed

7 major claims checked against the paper's own evidence: all adequately supported.

Data authenticity concerns

1 finding · worst medium

Other integrity concernAssessed

6 integrity concerns flagged (0 high).

Reporting gaps

4 findings · worst high

Data and code not sharedAssessed
Biological variables underreported (sex, age, strain)Assessed
Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed

Eight Dimensions4 pass · 3 warn · 1 fail

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

paraphrase[Abstract, Introduction (paragraphs 3-4)]

“A prior phase 2 trial assessed the efficacy of the investigational H4:IC31 vaccine and Bacille Calmette-Guérin (BCG) vaccine versus placebo for protection against Mtb infection...”

paraphrase[Introduction (paragraph 4)]

“However, because no more than 5-10% of Mtb-infected individuals progress to TB, VE for prevention of sustained Mtb infection may not predict VE for prevention of disease...”

paraphrase[Introduction (paragraph 5)]

PASSReviewer 2· 90% conf

The premise is well established from a prior phase 2 trial, with a clear rationale and acknowledgment of the surrogate-endpoint limitation.

Evidence

paraphrase[Abstract, Background]

paraphrase[Introduction]

IntroductionFind in source

PASSReviewer 3· 90% conf

The study is well grounded in a prior phase 2 trial, with a clear rationale and an explicit description of how the current design addresses limitations of prior work.

Evidence

paraphrase[Introduction]

IntroductionFind in source

“the sample size per treatment arm was approximately 3 times larger; the age range increased to include 10- and 11-year-olds; and the geographical footprint expanded”

DiscussionFind in source

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Evidence

paraphrase[Methods, Trial Design and Objectives]

paraphrase[Methods, Statistical analysis]

paraphrase[Methods, Trial Design and Objectives]

“The trial was observer-blind until the primary endpoint analyses were completed. Inadvertent unblinding occurred due to recognizable lesion formed at the BCG injection site.”

PASSReviewer 2· 80% conf

Core design elements for a randomized trial are adequately reported, including randomization, blinding, power calculation, and definition of the mITT population.

Evidence

MethodsFind in source

paraphrase[Methods, Statistical analysis]

Statistical analysisFind in source

PASSReviewer 3· 95% conf

Evidence

“Randomization to BCG or placebo was assigned using a validated Interactive Voice/Web Response System.”

MethodsFind in source

“The trial was observer-blinded until the primary endpoint analyses were completed. Inadvertent unblinding occurred due to recognizable lesion formed at the BCG injection site.”

MethodsFind in source

Statistical analysisFind in source

Sub-criteria

demographicsADEQUATE

sex reportedINADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 80% conf

The study fails to adequately report several biological variables: sex distribution is not explicitly provided in the text, weight is not reported, and demographics are limited to race only.

Evidence

“The median age was 13 years (range, 10-18) and most participants (1464 [79.8%]) self-identified as Black African.”

ResultsFind in source

absence[Results, Baseline characteristics and disposition]

Sex distribution is not explicitly reported in the text

“most participants (1464 [79.8%]) self-identified as Black African.”

ResultsFind in source

WARNReviewer 2· 60% conf

Age and race/ethnicity are reported, but explicit sex distribution and weight/comorbidity data are not presented in the text.

Evidence

“The median age was 13 years (range, 10-18) and most participants (1464 [79.8%]) self-identified as Black African.”

ResultsFind in source

“Randomization was stratified by age, sex, trial site, and school cluster (Worcester site only).”

MethodsFind in source

absence[Methods, Participants]

Weight and comorbidity details are not provided.

WARNReviewer 3· 70% conf

Evidence

“Randomization was stratified by age, sex, trial site, and school cluster (Worcester site only).”

MethodsFind in source

“The median age was 13 years (range, 10-18) and most participants (1464 [79.8%]) self-identified as Black African.”

ResultsFind in source

“Demographics and baseline characteristics were comparable between the two groups ().”

ResultsFind in source

Sub-criteria

iacuc statementN/A

informed consentNOT REPORTED

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Evidence

MethodsFind in source

paraphrase[Methods, Trial oversight; Figure 1A]

“Informed consent is only mentioned as 'ICF' in Figure 1A, with no description of the consent process in the text.”

paraphrase[Methods, Trial oversight]

WARNReviewer 2· 70% conf

Regulatory compliance is stated by name, but no named IRB/IEC approval with protocol number or explicit informed-consent statement is present in the text.

Evidence

MethodsFind in source

“ICF, informed consent form; PC, post conversion; QFT, QuantiFERON-TB Test”

Figure 1Find in source

absence[Methods]

No explicit statement of written informed consent or parental permission is found.

WARNReviewer 3· 85% conf

Regulatory compliance is stated, but no named IRB/IEC approval with protocol number is given, and informed consent is only implied by an acronym in a figure legend.

Evidence

MethodsFind in source

“ICF, informed consent form”

Figure 1Find in source

absence[Full text]

No explicit informed-consent statement or ethics-approval number is provided.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The investigational product (BCG vaccine) is well identified, but statistical software is not named, and placebo formulation is not described.

Evidence

“BCG (BCG Danish 1331 vaccine, AJ Vaccines, Copenhagen, Denmark)”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software is not named

absence[Methods, Trial Design and Objectives]

Placebo is not described

WARNReviewer 2· 70% conf

The investigational product and assay are well identified, but antibodies for the immunogenicity assay and statistical software are not reported.

Evidence

“BCG (BCG Danish 1331 vaccine, AJ Vaccines, Copenhagen, Denmark)”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software is not identified.

WARNReviewer 3· 75% conf

The investigational BCG product is well identified, but the antibodies used in the immunogenicity assay and the statistical software are not identified.

Evidence

“BCG (BCG Danish 1331 vaccine, AJ Vaccines, Copenhagen, Denmark)”

MethodsFind in source

“by whole blood intracellular cytokine staining (WB-ICS) assay”

MethodsFind in source

absence[Methods, Statistical analysis]

Statistical software is not identified.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedINADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

Evidence

paraphrase[Methods, Statistical analysis]

paraphrase[Results, Efficacy; Table 1]

“one-sided P=0.58; VE point estimate of −3.8% (95% CI −48.3% to 27.4%)”

paraphrase[Abstract, Results]

“A total of 1836 participants were enrolled; 918 participants received BCG and 917 received placebo. (later: A total of 1836 were randomized 1:1 to BCG (n=919) or placebo (n=917).)”

PASSReviewer 2· 75% conf

Statistical tests, exact p-value, effect sizes with CIs, and data presentation are sound; no arithmetic impossibilities were found, but statistical software is not identified.

Evidence

Statistical analysisFind in source

“The observed HR was 1.038 (95% CI 0.73 to1.48), for a VE point estimate of −3.8% (95% CI −48.3% to 27.4%).”

AbstractFind in source

absence[Methods, Statistical analysis]

Statistical software is not identified.

PASSReviewer 3· 85% conf

Statistical tests and effect estimates are clearly reported with CIs and exact P for the primary endpoint; arithmetic spot-checks of counts and percentages were consistent.

Evidence

Statistical analysisFind in source

“The observed HR was 1.038 (95% CI 0.73 to1.48), for a VE point estimate of −3.8% (95% CI −48.3% to 27.4%).”

AbstractFind in source

“one-sided P=0.58”

ResultsFind in source

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 95% conf

No data availability statement, repository deposit, or code sharing is provided. The trial is registered on ClinicalTrials.gov, but the paper does not state where data can be accessed.

Evidence

absence[Entire paper]

No data availability statement

absence[Entire paper]

No repository deposit mentioned

absence[Entire paper]

No code sharing mentioned

FAILReviewer 2· 80% conf

No data availability statement, repository deposition, accession numbers, or code sharing route is reported in the manuscript text.

Evidence

absence[Manuscript (full text)]

No data availability statement is present in the text.

“Supported by Bill & Melinda Gates Foundation; ClinicalTrials.gov (http://clinicaltrials.gov/) Identifier NCT04152161”

ConclusionFind in source

FAILReviewer 3· 90% conf

No data availability statement is present, and no repository, accession numbers, or code-sharing mechanism is reported.

Evidence

absence[Full text]

No data availability statement is present.

FundingFind in source

Sub-criteria

funding coiNOT REPORTED

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Evidence

paraphrase[Abstract, Methods]

“ClinicalTrials.gov Identifier NCT04152161”

“The VE point estimate for the primary endpoint was −0.038 (95% CI, −0.483 to 0.274)”

ResultsFind in source

absence[End of manuscript]

No conflicts-of-interest statement

PASSReviewer 2· 80% conf

Evidence

“ClinicalTrials.gov (http://clinicaltrials.gov/) Identifier NCT04152161”

ConclusionFind in source

DiscussionFind in source

absence[Manuscript (full text)]

No explicit conflicts-of-interest statement is present.

WARNReviewer 3· 80% conf

Evidence

“ClinicalTrials.gov (http://clinicaltrials.gov/) Identifier NCT04152161”

AbstractFind in source

DiscussionFind in source

“Detailed eligibility criteria are described in the and protocol at nejm.org (http://nejm.org/) .”

MethodsFind in source

Registered (2 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 15 references by DOI: 9 verified — 6 no DOI (shown, not verified).

3 data/code links checked; 3 live.

Copyediting

1 finding · worst low

Wording, consistency and formatting errors that need correcting before submission.

Wording or formatting errors that need correctingAssessed

11 copyedit issues flagged (2 major): mostly consistency, clarity, typo.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
Add a Data Availability statement describing the managed-access route for de-identified participant data (e.g., a named data-access committee or controlled-access platform) with request conditions and timeframe.
The paper contains no data availability statement, repository deposit, or code-sharing route, which is a required element for a data-driven clinical trial.
2.
HIGHrigor
Reconcile the BCG group count (n=918 in the abstract/safety tables vs n=919 in Figure 1) and the enrollment/follow-up sums (1836 enrolled but 918+917=1835; 1752+83=1835) across the abstract, Results, and Figure 1.
These are verifiable impossible-number contradictions in participant disposition that undermine the integrity of the CONSORT accounting.
3.
HIGHrigor
Reconcile the Discussion's '6.5-6.9% per person-year' initial QFT conversion rate with Table 1's person-month-based incidence rates (which imply ~7.8-8.3% per person-year); correct the text or the table units.
The text and table report inconsistent incidence rates for the same quantity, a concrete internal contradiction an informed reader can verify.
4.
HIGHethics
Name the specific IRB/research ethics committee(s) that approved the protocol and include the protocol/approval number; add an explicit statement that written informed consent/assent was obtained from participants and parents/guardians.
The Trial oversight section cites ICH GCP/SAHPRA/IRB-IEC but names no approving committee and gives no consent statement, a required reporting element for a human trial.
5.
HIGHreporting
Report the sex distribution (n, %) and weight or BMI in the baseline characteristics table; the text currently reports only age and race, with sex appearing only as a stratification variable.
Sex and weight are relevant baseline biological variables whose absence prevents assessment of group comparability.
6.
HIGHcopyedit
Fix the garbled methods sentence in the Participants section — 'Detailed eligibility criteria are described in the and protocol at nejm.org' — to refer clearly to the protocol and Supplementary Appendix.
This truncated sentence is a major clarity defect in the Methods that would read as an error in print.
7.
MEDIUMreporting
Identify the antibodies (clone, fluorophore, vendor, dilution/RRID) and flow-cytometry analysis software (e.g., FlowJo version) used in the whole-blood ICS immunogenicity assay, in Methods or the Supplement.
The WB-ICS assay is described without antibody details, preventing replication of the immunogenicity endpoint.
8.
MEDIUMstatistics
Identify the statistical software and version (e.g., SAS 9.4, R) used for all analyses in the Statistical Analysis section.
No statistical software is named, a routine reporting requirement for reproducibility.
9.
MEDIUMstatistics
State how the proportional-hazards assumption was assessed for the stratified Cox model (e.g., Schoenfeld residuals) or explicitly note that it was not tested.
The primary analysis uses a Cox model, but the PH assumption is not discussed, leaving the primary model's validity unverified.
10.
MEDIUMreporting
Add a statement that the trial is reported per CONSORT 2010 and cite the completed checklist.
No reporting guideline is acknowledged despite the RCT design and CONSORT flow diagram.
11.
MEDIUMreporting
Add a conflicts-of-interest declaration for all authors.
Funding is acknowledged but no COI statement is present, a standard transparency requirement.
12.
MEDIUMcopyedit
Reconcile the 'double-blind' terminology in the abstract with the 'observer-blind' description in Methods, and explain whether participants were blinded given the acknowledged unblinding from injection-site lesions.
The abstract and Methods describe the blinding inconsistently, which could mislead readers about the blinding level.
13.
LOWcopyedit
Fix the missing spaces ('A total of1836') and the grammar ('CI were' → 'CIs were').
Minor typos that a copyedit should catch before publication.
14.
LOWcopyedit
Replace the 'Supplementary Material Supp' placeholder at the end of the manuscript with a proper references list or delete it.
Placeholder text would be published as-is otherwise.
15.
LOWother
Acknowledge that the underpinning prior trial (NCT02075203) was retrospectively registered (submitted 2014-02-17 after the registered 2014-02 start) and note this when weighing the confirmatory rationale.
Retrospective registration of the prior trial means its protocol and outcomes were not on the public record before it ran, which an informed reader should weigh.

Full text (30,048 chars)Analyzed: Aug 10, 2026