Rigor Reviewed

Rigor-Reviewed Manuscript

Feasibility, safety, and impact of the RTS,S/AS01(E) malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.

Name: Adcurare Rigor Record — Feasibility, safety, and impact of the RTS,S/AS01(E) malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.
Item: Feasibility, safety, and impact of the RTS,S/AS01(E) malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.
Rating: 96
Author: Adcurare

Asante KP, Mathanga DP, Milligan P, Akech S, Oduro A, Mwapasa V, Moore KA, Kwambai TK, Hamel MJ, Gyan T, Westercamp N, Kapito-Tembo A, Njuguna P, Ansong D, Kariuki S, Mvalo T, Snell P, Schellenberg D, Welega P, Otieno L, Chimala A, Afari EA, Bejon P, Maleta K, Agbenyega T, Snow RW, Zulu M, Chinkhumba J, Samuels AM, Malaria Vaccine Programme Evaluation Partners

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Adcurare Rigor Review — 4.25★ (Strong), 0 critical, 3 high issues for “Feasibility, safety, and impact of the RTS,S/AS01(E) malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.6.0Source: full text

Problems surfaced2 types

Data/code availability incomplete
Internal contradictions in the reported numbers

This Adcurare Rigor Review uses AI 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.

The paper presents a well-designed cluster-randomized evaluation of the RTS,S malaria vaccine implementation with clear scientific premise, robust design, thorough reporting of biological variables and ethics, and transparent reporting of limitations. The main weakness is data and code availability: the data availability statement uses future tense without a DOI and no analysis code is shared, which limits reproducibility.

All eight dimensions were applicable to this human interventional study. Species/strain/source and housing conditions were not applicable; blinding was not applicable for this open-label implementation study. The three reviewers largely agreed, with minor divergence on data code availability (pass vs. warn) and checklist sub-criteria coding. The statistics verification component checked 4 out of many tests and found all consistent; the remaining analyses are unverified. No retracted or fabricated references were detected. The copyedit pass identified 8 minor issues.

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

Recomputed 4 tests: 4 consistent, 0 inconsistent, 4 via agent-written checks.

1 integrity concern flagged (0 high).

Reporting

Eight Dimensions7 pass · 1 warn

The introduction and 'Research in context' section thoroughly cite the phase 3 trial and earlier studies, outlining the known safety signals (meningitis, cerebral malaria, and a sex-specific mortality difference) and gaps in evidence for real-world implementation. The rationale linking these gaps to the study objectives is explicit, and limitations of prior research (e.g., uncertainty about the fourth dose's value) are acknowledged.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper clearly establishes the scientific premise, citing prior trials and highlighting specific safety signals that the evaluation was designed to address.

Evidence

direct quote[Introduction, paragraph 3 and Research in context]

“With respect to safety, the focus was on three signals seen in the phase 3 trial, none of which were temporally associated with vaccination: an excess of meningitis and cerebral malaria cases in recipients of RTS,S, and an interaction between sex and vaccine group with respect to effects on mortality”

direct quote[Introduction, paragraph 2 and Methods, paragraph 1]

“The pilot was designed to assess: the feasibility of implementing four doses of the vaccine in a schedule beyond regular contacts of the Expanded Program on Immunization (EPI); the vaccine's safety; and the impact of vaccine introduction on mortality and on the incidence of hospital admission with severe malaria.”

direct quote[Research in context]

“It appeared that the fourth vaccine dose was necessary to reduce a child's overall risk of severe malaria over the 4 years of the trial, although there was uncertainty regarding this conclusion.”

PASSReviewer 2· 95% conf

The paper thoroughly establishes the scientific premise by citing prior trials, acknowledging their limitations, and providing a clear rationale for the pilot evaluation.

Evidence

direct quote[Introduction, paragraphs 2-4]

“In 2015, the European Medicines Agency reviewed data from a multicentre phase 3 trial of the RTS,S/AS01 E malaria vaccine (henceforth RTS,S) and earlier studies, and gave a positive scientific opinion under Article 58”

direct quote[Introduction, paragraph 3]

direct quote[Introduction, paragraph 2]

PASSReviewer 3· 95% conf

The study clearly establishes its scientific foundation, citing prior work, providing a logical rationale, and addressing limitations of the phase 3 trial.

Evidence

direct quote[Introduction, paragraph 1-3]

“In 2015, the European Medicines Agency reviewed data from a multicentre phase 3 trial of the RTS,S/AS01 E malaria vaccine... and gave a positive scientific opinion under Article 58”

direct quote[Introduction, paragraph 3]

paraphrase[Methods, paragraph 1 and Discussion]

“The evaluation was designed to resolve specific safety signals and assess impact under routine programmatic conditions, addressing gaps from the phase 3 trial.”

Randomization was performed with an independent statistician using constrained methods to balance implementation and comparison areas on key covariates. The randomization unit (clusters defined by EPI) is clearly stated. Inclusion/exclusion criteria are defined via age eligibility and vaccination schedule. A power analysis was conducted for safety and impact outcomes, estimating required events and timing of analyses. Replicate distinction is not relevant here (human trial, not bench science), and blinding is not applicable because this is an open-label implementation study with a rationale. Outlier handling is addressed through pre-specified statistical methods and sensitivity analyses. Appropriate controls (comparison areas) and independent oversight (DSMB) are described.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsN/A

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is robust: cluster randomization with constraints, pre-specified eligibility and analysis plan, and powered for key safety and impact outcomes.

Evidence

direct quote[Methods, Randomisation]

“Constrained randomisation in each country was used to balance implementing and comparator areas with respect to the number of infants surviving to 12 months, malaria parasite prevalence ... EPI coverage ... and number of hospitals, health centres, and dispensaries.”

direct quote[Methods, Statistical methods]

“We estimated the number of events required for 90% power to detect a difference between implementation and comparison areas, for each safety outcome, if the safety signal occurred at the level observed in the phase 3 trial, after allowing for dilution of effects due to incomplete RTS,S coverage and contamination.”

direct quote[Methods, Statistical methods]

“Eligibility was defined according to the child's age at admission or death (determined by date of birth or recalled age), the date of vaccine introduction, and the country-specific schedule.”

PASSReviewer 2· 95% conf

The design is a cluster-randomised evaluation with constrained randomisation, pre-specified outcomes, power analysis, and clear definitions of eligibility, though blinding was not applicable and replication is ongoing.

Evidence

direct quote[Methods, Randomisation]

“An independent statistician assisted the EPI to randomly assign clusters to introduce RTS,S in 2019 (implementing areas) or to delay introduction (comparator areas); Constrained randomisation in each country was used to balance implementing and comparator areas”

direct quote[Methods, Statistical methods]

“We estimated the number of events required for 90% power to detect a difference between implementation and comparison areas, for each safety outcome”

direct quote[Methods, Statistical methods]

“Evaluation continues to assess the impact of four doses of RTS,S.”

PASSReviewer 3· 92% conf

The cluster-randomised design is robust, with adequate reporting of randomisation methods, pre-specified eligibility criteria, and power analysis. Blinding of participants was not feasible due to the nature of the intervention, but the analysis methods are appropriate.

Evidence

direct quote[Methods, Randomisation]

“Constrained randomisation in each country was used to balance implementing and comparator areas with respect to the number of infants surviving to 12 months, malaria parasite prevalence”

paraphrase[Methods, Statistical methods]

“The paper describes a priori power calculations for each safety outcome and for severe malaria, accounting for dilution due to incomplete coverage and contamination, concluding that 24 months of data would be sufficient.”

direct quote[Methods, Statistical methods]

“Eligibility was defined according to the child's age at admission or death (determined by date of birth or recalled age), the date of vaccine introduction, and the country-specific schedule”

The paper reports sex for all participants and presents sex-stratified analyses for the key safety outcome (mortality). Age is reported as the primary eligibility criterion (children aged 5-59 months). Health status is implicitly assessed through malaria prevalence data and verbal autopsies. Species/strain/source and housing conditions are N/A for human studies. Demographics such as socioeconomic status, LLIN use, and malaria prevalence are extensively reported and used in subgroup analyses.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables relevant to a human trial (age, sex, health status) are well reported; species/strain and housing conditions are not applicable.

Evidence

direct quote[Methods, Statistical methods; Results, paragraph 6]

“The female-to-male mortality ratio in vaccine-eligible age groups was compared between implementation and comparison areas similarly, using data in non-eligible boys and girls as auxiliary variables.”

paraphrase[Methods, Statistical methods; Results]

“Age eligibility is determined by birth date and vaccination schedule; mortality and hospital admissions are primary outcomes.”

direct quote[Table; Results, paragraph 1-2]

“The prevalence of P falciparum according to rapid diagnostic tests in children aged 5–48 months was 21% (Ghana), 26% (Kenya), and 28% (Malawi) in implementation areas”

PASSReviewer 2· 95% conf

Key biological variables (age, sex, health status) are well reported for the human subjects, and baseline characteristics are comprehensively described.

Evidence

direct quote[Results, paragraph 4]

“The mortality ratio was 0·95 (0·85–1·07) in girls and 0·91 (0·80–1·04) in boys (); the relative mortality ratio (girls:boys) was 1·03 (0·88–1·21, p=0·71).”

direct quote[Methods, Statistical methods]

“Eligibility was defined according to the child's age at admission or death (determined by date of birth or recalled age), the date of vaccine introduction, and the country-specific schedule”

direct quote[Results, Table 1]

“Table Characteristics of the evaluation areas before RTS,S introduction Ghana | Kenya | Malawi”

PASSReviewer 3· 98% conf

The study reports key biological variables for human subjects: sex, age, and demographics including malaria prevalence and bednet use. Sex and age are well-reported and used in stratified analyses.

Evidence

direct quote[Results, paragraph 7]

“2386 from implementation areas (1220 girls and 1166 boys) and 2362 from comparison areas (1265 girls and 1097 boys)”

direct quote[Methods, Statistical methods]

“Children just above the eligible age limit (by up to 2 months) were excluded.”

direct quote[Table 1, Figure 1]

“Malaria prevalence (age 5–48 months): 21% (Ghana), 26% (Kenya), 28% (Malawi) in implementation areas.”

The paper states that consent was obtained following approval by the institutional review boards of evaluation partners' institutions and WHO. The trial is registered on ClinicalTrials.gov (NCT03806465) as an observational study. For sentinel surveillance in Kenya, parental consent was obtained for CSF storage. Regulatory compliance is implied through the oversight of national health authorities and WHO. An independent data safety monitoring board provided oversight.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethics approval, informed consent, and regulatory compliance are explicitly stated and adequate for this multi-country human trial.

Evidence

direct quote[Methods, final paragraph]

“Consent of a parent or guardian was sought for data collection following approval by the institutional review boards of the evaluation partners’ institutions and WHO.”

direct quote[Methods, final paragraph]

“The evaluation is registered on ClinicalTrials.gov (http://ClinicalTrials.gov) (NCT03806465) as an observational study.”

direct quote[Methods, final paragraph]

“An independent data safety monitoring board and the Malaria Vaccine Implementation Programme Advisory Group provided oversight.”

PASSReviewer 2· 95% conf

The paper reports approval from institutional review boards and informed consent procedures, with a clinical trial registration, meeting standards for human subjects research.

Evidence

direct quote[Methods, Ethical considerations]

“Consent of a parent or guardian was sought for data collection following approval by the institutional review boards of the evaluation partners’ institutions and WHO”

direct quote[Methods, Ethical considerations]

“Sentinel surveillance in Kenya used an established routine system and parental consent was only obtained for CSF storage.”

direct quote[Methods, Ethical considerations]

“The evaluation is registered on ClinicalTrials.gov (http://ClinicalTrials.gov) ( NCT03806465 ) as an observational study.”

PASSReviewer 3· 93% conf

The study reports ethical approval from multiple institutional review boards, informed consent procedures that varied by country, and compliance with regulatory standards. The ethical framework is appropriately described for a large-scale public health evaluation.

Evidence

direct quote[Methods, Statistical methods (final paragraph)]

“Consent of a parent or guardian was sought for data collection following approval by the institutional review boards of the evaluation partners’ institutions and WHO”

direct quote[Methods, Statistical methods]

“Sentinel surveillance in Kenya used an established routine system and parental consent was only obtained for CSF storage.”

direct quote[Methods, Statistical methods]

“The evaluation is registered on ClinicalTrials.gov (NCT03806465) as an observational study. An independent data safety monitoring board and the Malaria Vaccine Implementation Programme Advisory Group provided oversight.”

The RTS,S/AS01E vaccine is named with its schedule and manufacturer details. Diagnostic reagents (e.g., RDTs, lumbar puncture kits) are mentioned but not catalogued in exhaustive detail, which is adequate for a field trial. Software for verbal autopsy (InterVA) and statistical analysis (Stata version 15) are identified. Custom code is not described but the analysis plan is published. Antibodies, cell lines, and mycoplasma testing are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The investigational product (RTS,S vaccine) is clearly identified; key software and diagnostic reagents are reported adequately.

Evidence

direct quote[Introduction; Methods, Vaccine introduction]

“The RTS,S/AS01 E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019”

direct quote[Methods, Statistical methods; Methods, Mortality surveillance]

“Stata, version 15, was used for the analyses.”

paraphrase[Methods, Sentinel hospital surveillance]

“Laboratory reagents and lumbar puncture kits were provided, but no specific catalog numbers are given.”

PASSReviewer 2· 95% conf

The investigational product (RTS,S/AS01 vaccine) is identified by name and manufacturer, and key software (Stata) is identified with version, meeting standards for a clinical trial of a drug/biologic.

Evidence

direct quote[Abstract, Methods]

“feasibility, safety, and impact of the RTS,S/AS01 E malaria vaccine when implemented through national immunisation programmes”

direct quote[Methods, Statistical methods]

“Stata, version 15, was used for the analyses.”

PASSReviewer 3· 91% conf

The study identifies the key investigational product (RTS,S/AS01E vaccine) with manufacturer and schedule, and identifies software (Stata 15). Other resources (antibodies, cell lines, etc.) are not applicable.

Evidence

direct quote[Methods, Vaccine introduction]

“Doses were scheduled at age 6, 7, 9, and 24 months in Ghana and Kenya, and age 5, 6, 7, and 22 months in Malawi”

direct quote[Methods, Statistical methods]

“Stata, version 15, was used for the analyses.”

The primary analysis uses a ratio-of-ratios (IRR) approach described in a referenced methodology paper. Exact p-values and 95% CIs are reported for all main outcomes. Effect sizes (IRRs, mortality ratios) are presented with CIs. Software (Stata 15) is identified. Data presentation includes forest plots, tables with CIs, and individual data points are not expected in a cluster-randomized trial of this scale. Assumptions verification is not explicitly detailed for each test, but the careful study design and pre-specified analysis plan provide adequate justification. Mathematical plausibility is not verified here due to large Ns and continuous data.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Statistical tests are named, exact p-values and confidence intervals are reported, effect sizes are given, and data presentation is clear.

Evidence

direct quote[Methods, Statistical methods]

“IRRs were estimated as a double ratio of event counts, comparing the ratio of events between eligible and non-eligible age groups in RTS,S implementation areas with that in comparison areas.”

direct quote[Results, paragraph 6]

“the relative mortality ratio (girls:boys) was 1·03 (0·88–1·21, p=0·71)”

direct quote[Methods, Statistical methods]

“Stata, version 15, was used for the analyses.”

PASSReviewer 2· 95% conf

Statistical tests are named, exact p-values and confidence intervals are reported for key outcomes, effect sizes with CIs are presented, software is identified, and data presentation includes per-group n and defined error bars.

Evidence

direct quote[Methods, Statistical methods; Results]

“We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes)...”

direct quote[Results, paragraph 4]

“the relative mortality ratio (girls:boys) was 1·03 (0·88–1·21, p=0·71)”

direct quote[Methods, Statistical methods]

“Stata, version 15, was used for the analyses.”

PASSReviewer 3· 95% conf

Statistical tests are named (IRR from a double-ratio estimator), exact p-values are reported with 95% CIs, software is identified, and data presentation is clear with individual-level counts and forest plots. Assumptions behind the ratio-estimator method are described.

Evidence

direct quote[Methods, Statistical methods]

“IRRs were estimated as a double ratio of event counts, comparing the ratio of events between eligible and non-eligible age groups in RTS,S implementation areas with that in comparison areas”

direct quote[Results, paragraph 7]

“the relative mortality ratio (girls:boys) was 1·03 (0·88–1·21, p=0·71)”

direct quote[Methods, Statistical methods]

“Stata, version 15, was used for the analyses.”

The paper states: 'Anonymised data will be made available through Harvard Dataverse. Requests for access will be reviewed by a data access committee.' This is reported_and_adequate for data_availability_statement because it names a repository and a managed-access process. However, no accession numbers or repository links are provided in the paper. Custom code is not mentioned as shared. Since the study generated large-scale clinical data, repository_deposit and code_sharing are not fully met, leading to a 'warn' status.

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositINADEQUATE

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

A data availability statement is present, but it is vague ('available on reasonable request'), and code is not publicly shared, which is a gap for transparency.

Evidence

direct quote[Data sharing section (at end of Discussion)]

“Anonymised data will be made available through Harvard Dataverse. Requests for access will be reviewed by a data access committee.”

absence[Data sharing section]

No specific repository accession numbers or DOI are provided in the paper.

absence[Entire text]

Custom code is not mentioned as shared.

PASSReviewer 2· 90% conf

A data availability statement is present and describes a concrete access route (Harvard Dataverse with a data access committee), which is adequate for individual patient data.

Evidence

direct quote[Data sharing section]

“Anonymised data will be made available through Harvard Dataverse. Requests for access will be reviewed by a data access committee.”

WARNReviewer 3· 89% conf

There is a data availability statement, but it is vague ('available through Harvard Dataverse with requests reviewed by a data access committee' without specifying the timeframe or platform details). No code sharing is mentioned.

Evidence

direct quote[Data sharing]

“Anonymised data will be made available through Harvard Dataverse. Requests for access will be reviewed by a data access committee.”

absence[Data sharing]

No code sharing statement is present.

Methods are comprehensive, including randomization, surveillance, and statistical analysis. The trial is registered at ClinicalTrials.gov (NCT03806465). Limitations are explicitly discussed (e.g., contamination, dilution, diagnostic imperfections, under-reporting of deaths). Conclusions are proportional: the paper states reductions in severe malaria and mortality but does not overstate causal claims, acknowledging that these are associations from an open-label implementation study. Funding sources and conflicts of interest are stated. A reporting guideline is not explicitly referenced (e.g., CONSORT for cluster trials), but the study was pre-specified with a published analysis plan.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper is transparent: methods are sufficiently detailed, the trial is registered, limitations are discussed, and conclusions are proportional to the evidence.

Evidence

direct quote[Methods, final paragraph]

“The evaluation is registered on ClinicalTrials.gov (http://ClinicalTrials.gov) (NCT03806465) as an observational study.”

direct quote[Discussion, paragraph 8]

“Despite efforts to strengthen clinical investigation, diagnostic performance was imperfect and events could have been missed or misclassified. It is also likely that deaths have been under-reported through the mortality surveillance system.”

direct quote[Abstract and Discussion]

“RTS,S introduction was associated with a 32% reduction (95% CI 5–51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0–18%) in all-cause mortality (excluding injury).”

PASSReviewer 2· 95% conf

Methods are described in detail, the study is registered, all outcomes are reported transparently with negative results, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

direct quote[Methods, Ethical considerations]

“The evaluation is registered on ClinicalTrials.gov (http://ClinicalTrials.gov) ( NCT03806465 ) as an observational study.”

direct quote[Discussion, paragraph 5]

“Several factors could have diluted estimates of safety signals.”

direct quote[Abstract, Funding]

“Funding Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.”

PASSReviewer 3· 95% conf

The manuscript is well-structured, methods are detailed enough for replication, the study is registered on ClinicalTrials.gov, limitations are discussed, conclusions are proportional to evidence, and funding/competing interests are transparently reported.

Evidence

paraphrase[Methods, multiple paragraphs]

“The methods describe in detail the cluster randomisation, sentinel hospital surveillance, mortality surveillance, vaccine schedules, and the double-ratio analysis approach.”

direct quote[Methods, Statistical methods (final paragraph)]

“The evaluation is registered on ClinicalTrials.gov (NCT03806465) as an observational study.”

direct quote[Discussion, paragraphs 7-8]

“Despite efforts to strengthen clinical investigation, diagnostic performance was imperfect and events could have been missed or misclassified.”

8 copyedit issues flagged: mostly consistency, clarity, typo.

Checked 21 references: 10 verified — 11 not checked.

Reproducibility

7 data/code links checked; 7 live.

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Adcurare Rigor Action ItemsFinal pass before journal submission

The paper is substantially ready for submission after addressing a handful of minor-to-moderate pre-submission actions. The most consequential gap is data and code availability: the authors should add a DOI for the Harvard Dataverse deposit and share analysis code (e.g., Stata .do files) to meet reproducibility standards. Adding a CONSORT flowchart and a reporting guideline statement would strengthen reporting transparency. The 8 copyedit issues are minor and quick to fix. No critical validity threats were identified.

1.
HIGHdata code
Add a Data Availability section with the permanent DOI or other persistent identifier for the dataset deposited in Harvard Dataverse, rather than stating data 'will be made available'.
A future-tense statement without a DOI is insufficient for immediate reproducibility; readers and reviewers need a direct link to the deposited data.
2.
HIGHdata code
Include a Code Availability statement and share the custom Stata analysis scripts (e.g., .do files) in a public repository (GitHub, Zenodo) with a persistent identifier.
No analysis code is shared; without it, the double-ratio estimation method cannot be independently reproduced, weakening transparency.
3.
HIGHreporting
Add a sentence to the Methods stating that the study was reported in accordance with the CONSORT cluster-randomized trial extension, and include the completed checklist as supplementary material.
Adherence to a recognized reporting guideline is expected for cluster-randomized trials; its absence is a gap in transparency.
4.
MEDIUMreporting
Add a brief statement in the Methods acknowledging that blinding of participants and health workers was not feasible for this implementation study and discussing the potential for bias.
The open-label design is implied but an explicit acknowledgement would strengthen methodological completeness.
5.
MEDIUMreporting
Clarify the discrepancy between the number of children admitted to sentinel hospitals (31,072) and the number residing in defined areas with consent (29,356) by explicitly stating the 1,716 exclusions in the Results or a footnote.
The integrity component flagged this as a mild internal contradiction; providing a simple explanation resolves it.
6.
MEDIUMstatistics
Add a supplementary table or brief paragraph describing how statistical assumptions of the double-ratio method were verified (e.g., sensitivity analyses assessing balance of covariates over time).
The reviewers noted that assumptions verification is minimally discussed; a brief statement would preempt reviewer questions.
7.
MEDIUMreporting
Replace 'RTS,S/AS01E' with 'RTS,S/AS01 E' (with a space) consistently throughout the manuscript to match the correct nomenclature.
The copyedit pass noted inconsistent formatting of the vaccine name; uniformity improves professional presentation.
8.
MEDIUMreporting
Add a CONSORT-style flow diagram showing the numbers of clusters and individuals in each arm from randomization through analysis for both the sentinel hospital and mortality surveillance cohorts.
A flow diagram is standard for cluster-randomized trials and provides a quick overview of attrition and exclusions.
9.
LOWcopyedit
Fix the tense agreement in the Methods, Mortality surveillance section: change 'complete a verbal autopsy' to 'completed a verbal autopsy'.
This minor grammatical error was flagged by the copyedit pass; correcting it improves readability.
10.
LOWcopyedit
Rephrase the sentence about lumbar punctures in the Results: change 'of which 2138 (83.2%) had a white cell count recorded' to 'of these children, 2138 (83.2%) had a white cell count recorded' for clarity.
The copyedit pass noted that the original construction could be ambiguous; the suggested rephrasing improves clarity.
11.
LOWreporting
Clarify in the Abstract that 'the three primary doses' refers to doses 1-3, given that a fourth dose is also part of the schedule.
The copyedit pass noted potential confusion; a brief clarification (e.g., 'the first three doses') resolves it.
12.
LOWother
Consider adding a note that verbal autopsy (InterVA) version is specified to ensure reproducibility of cause-of-death assignment.
While not critical, providing the InterVA version would strengthen reproducibility of the verbal autopsy component.

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Feasibility, safety, and impact of the RTS,S/AS01(E) malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.

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DOI

10.1016/S0140-6736(24)00004-7

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Issued Jul 7, 2026Engine 7.6.0

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