Heterologous two-dose Ebola vaccine regimen in pregnant women in Rwanda: a randomized controlled phase 3 trial.
Nyombayire J, Ingabire R, Mazzei A, Sharkey T, Umuhoza C, Mukamuyango J, Allen S, Tichacek A, Parker R, Wall KM, Katwere M, Keshinro B, Gaddah A, Wang Y, Forcheh CA, McLean C, Oriol-Mathieu V, Luhn K, Robinson C, Karita E
- DOI
- 10.1038/s41591-025-03932-z
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-22
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/72647b92-2a2c-401f-abcd-e0826bc082fd is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- No reported statistical tests were found to recompute.
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.
The paper is a well-conducted and transparently reported phase 3 randomized trial of an Ebola vaccine regimen in pregnant women. All eight rigor dimensions are adequately addressed, with clear ethical approvals, detailed methods, and appropriate statistical reporting. Minor copyediting issues and a few reporting clarifications (e.g., denominator for primary outcomes) are the only concerns.
Both reviewers independently scored all eight dimensions and agreed on 'pass' for each; the only minor divergence was on the power analysis sub-criterion (Reviewer 2 rated it 'reported but inadequate'), which does not change the overall dimension status. The statistics verification component checked 0 tests (none were machine-verifiable), so no statistical claims are independently confirmed beyond the reviewers' plausibility checks. The citation check found no retracted or unresolved references.
Numerical inconsistencies
1 finding · worst lowValues 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
- lowinternal contradictionThe abstract states '2,013 were randomized' but the results section says '2,013 were enrolled and randomized (group A, n = 993; group B, n = 1,020)', which sums to 2,013, so no contradiction. However, the FAS for group A is 992 (one less than randomized), which is explained by one woman not receiving dose 1.
“Among 3,484 women screened, 2,013 were randomized, and 2,012 women and 1,945 infants born alive were descriptively analyzed.”
AbstractFind in source - lowinternal contradictionThe number of women with adverse maternal/fetal outcomes in group A is reported as 51 of 977, but the FAS for group A is 992. The denominator 977 is not explained in the text; it may be due to exclusions for missing outcomes, but this is not explicitly stated.
“Adverse maternal/fetal outcomes of interest were reported in 51 of 977 (5.2%; 95% CI = 3.9–6.8%) women in group A”
ResultsFind in source
Overstated conclusions
None foundConclusions 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.
Checked — nothing surfaced.
4 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2The Ad26.ZEBOV, MVA-BN-Filo vaccine regimen is safe in pregnant women, with no unexpected safety issues.The paper reports comparable frequencies of adverse outcomes between groups and no unexpected safety signals, supporting the claim.Evidence: Table 2 and Table 3 show similar frequencies of adverse maternal/fetal and neonatal/infant outcomes between groups.
“Ad26.ZEBOV, MVA-BN-Filo did not raise concerns regarding adverse maternal/fetal or neonatal/infant outcomes, had no unexpected safety issues”
AbstractFind in source - supportedReviewers 1, 2The vaccine regimen is immunogenic in pregnant women, inducing binding antibody responses.The paper reports high responder rates and durable antibody responses, supporting the claim.Evidence: Figure 2 and Extended Data Table 5 show antibody responses in ≥90% of women at 1 year postdose 1.
“Anti-Ebola virus glycoprotein-specific binding antibody response (secondary endpoint) was sustained in ≥90% of women at 1 year postdose 1.”
AbstractFind in source - supportedReviewers 1, 2Antibodies are transferred to offspring through passive transfer.The paper reports detection of binding antibodies in cord blood and infant serum, supporting the claim.Evidence: Results section reports 99% positivity in cord blood and 95% in infant serum at 14 weeks.
“In group A, binding antibodies were detected in cord blood (99%) and infant serum (95%) samples 14 weeks postbirth.”
AbstractFind in source - supportedReviewers 1, 2The trial met all primary and secondary objectives.The paper reports that all planned endpoints were presented and the primary and secondary objectives were met.Evidence: Results section states 'Endpoints from all planned primary and secondary objectives are presented.'
“The trial met all primary and secondary objectives.”
AbstractFind in source
Data authenticity concerns
None foundAn 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.
Checked — nothing surfaced.
Reporting gaps
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The introduction cites multiple prior studies on the Ad26.ZEBOV, MVA-BN-Filo regimen in nonpregnant populations and notes the lack of data in pregnant women. The rationale for the study is logically derived from the high mortality of Ebola in pregnancy and the absence of vaccine safety data in this population. Limitations of prior research are implicitly addressed by the study's design to fill the gap in pregnant populations.
“Previous studies have found that the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen is well-tolerated and immunogenic, with mild-to-moderate adverse events (AEs) of short duration and no sequelae”
“to date, no data are available on the safety, reactogenicity or immunogenicity of Ebola vaccination in pregnant populations”
“The objective of the present study was to evaluate the safety, reactogenicity and immunogenicity of the two-dose Ebola vaccine regimen in healthy pregnant women in Rwanda.”
“Previous studies have found that the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen is well-tolerated and immunogenic, with mild-to-moderate adverse events (AEs) of short duration and no sequelae”
“However, to date, no data are available on the safety, reactogenicity or immunogenicity of Ebola vaccination in pregnant populations”
“The objective of the present study was to evaluate the safety, reactogenicity and immunogenicity of the two-dose Ebola vaccine regimen in healthy pregnant women in Rwanda.”
Randomization method (Excel RNG) and unit (individual woman) are stated. Blinding is described as open-label with a rationale. Power analysis is not a formal hypothesis test but sample size justification is provided. Inclusion/exclusion criteria are detailed. Outlier handling is addressed through missing data and analysis population definitions. Controls are the unvaccinated group B. Independent replication is not applicable for a single pivotal trial.
“An allocation template was created by coauthor S.A. at Emory University using simple randomization based on the Microsoft Excel random number generator function.”
“There was no masking in this study. An open-label design was selected so that group B women could receive the benefits of the vaccine regimen.”
“A target sample size of 1,000 participants in group A and 1,000 participants in group B was determined based on feasibility and the estimated background incidence of key pregnancy outcomes.”
“An allocation template was created by coauthor S.A. at Emory University using simple randomization based on the Microsoft Excel random number generator function.”
“There was no masking in this study. An open-label design was selected so that group B women could receive the benefits of the vaccine regimen.”
“The study is not powered for any formal statistical hypothesis testing. A target sample size of 1,000 participants in group A and 1,000 participants in group B was determined based on feasibility and the estimated background incidence of key pregnancy outcomes.”
Sex of infants is reported, and all women are female by design. Age, weight, and health status are reported for women; gestational age, birth weight, and Apgar scores for infants. Demographics including race and HIV status are reported. Species/strain and housing are not applicable for a human trial.
“Female | 504 (52.3%) | 497 (50.7%) | 1001 (51.5%)”
“Age, year, median (Q1; Q3) | 26.0 (22.0; 30.0) | 26.0 (22.0; 30.0) | 26.0 (22.0; 30.0)”
“Race—Black | 992 (100%) | 1,020 (100%) | 2,012 (100%)”
“Age, year, median (Q1; Q3) | 26.0 (22.0; 30.0) | 26.0 (22.0; 30.0) | 26.0 (22.0; 30.0)”
The protocol was approved by the Rwanda National Ethics Committee, Rwanda FDA, and Emory University IRB, with protocol numbers. Written informed consent was obtained. Regulatory compliance is stated. All applicable criteria are met.
“The protocol was approved by the Rwanda National Ethics Committee (821/RNEC/2020), the Rwanda FDA (003/CT/RWANDA FDA/2020) and the Emory University Institutional Review Board (STUDY00000367).”
“Written informed consent to participate was obtained.”
“The study complies with all relevant ethical regulations.”
“The protocol was approved by the Rwanda National Ethics Committee (821/RNEC/2020), the Rwanda FDA (003/CT/RWANDA FDA/2020) and the Emory University Institutional Review Board (STUDY00000367).”
“Written informed consent to participate was obtained.”
The vaccines (Ad26.ZEBOV, MVA-BN-Filo) are named with manufacturer and dose. The FANG ELISA is identified. Statistical software (SAS v9.4) is named. Other bench resources are not applicable.
“Study vaccines were manufactured and provided under the responsibility of Janssen Vaccines and Prevention B.V.”
“IgG binding antibodies against EBOV GP were measured using the validated and FDA-endorsed FANG ELISA, performed by Q2 Solutions Vaccine Testing Laboratory.”
“Data were analyzed using SAS v9.4.”
“Study vaccines were manufactured and provided under the responsibility of Janssen Vaccines and Prevention B.V. Ad26.ZEBOV is a nonreplicating monovalent vaccine that encodes the full-length GP from EBOV Mayinga.”
“Data were analyzed using SAS v9.4.”
The study is descriptive with CIs, so exact p-values are not applicable. Effect sizes are reported as risk differences with CIs. Software is identified. Data presentation includes per-group n and CIs. Mathematical plausibility checks on reported percentages and counts show no inconsistencies.
“No formal statistical hypothesis testing was planned. To aid understanding of the uncertainty around the estimates, CIs for primary endpoint estimates and the risk differences between groups A and B were computed post hoc.”
“Percentage difference (group A–group B) % (95% CI)”
“Adverse maternal/fetal outcomes of interest were reported in 51 of 977 (5.2%; 95% CI = 3.9–6.8%) women in group A and 73 of 1,000 (7.3%; 95% CI = 5.8–9.1%) women in group B.”
“Adverse maternal/fetal outcomes of interest were reported in 51 of 977 (5.2%; 95% CI = 3.9–6.8%) women in group A and 73 of 1,000 (7.3%; 95% CI = 5.8–9.1%) women in group B.”
“No formal statistical hypothesis testing was planned.”
The data availability statement names the YODA Project as the managed-access platform with conditions and timeframe. Code availability is also via YODA. Repository deposit and accession numbers are not applicable for identifiable patient data.
“requests for access to the CSRs and participant-level data, including individual participant-level data, can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu”
“Requests for access to the analytic code can be submitted through YODA Project site at http://yoda.yale.edu”
“Requests for access to the CSRs and participant-level data, including individual participant-level data, can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu .”
“Requests for access to the analytic code can be submitted through YODA Project site at http://yoda.yale.edu .”
The trial is registered (NCT04556526). CONSORT checklist is mentioned. All outcomes are reported. Limitations are discussed. Conclusions are proportional. Funding and COI are stated.
“ClinicalTrials.gov registration: NCT04556526”
“Supplementary Figs. 1–3, Supplementary Tables 1–6 and CONSORT checklist.”
“The data should be interpreted considering limitations. This is not a masked trial”
“ClinicalTrials.gov registration: NCT04556526”
“Supplementary Figs. 1–3, Supplementary Tables 1–6 and CONSORT checklist.”
“The data should be interpreted considering limitations. This is not a masked trial, although it should be noted that the labor and delivery staff do not know which group the women are in, which may have reduced assessment bias.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None foundReferences 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 30 references by DOI: 28 verified — 2 no DOI (shown, not verified).
- NO DOIExtraordinary meeting of the Strategic Advisory Group of Experts on Immunization on Ebola vaccination, May 2024: conclusions and recommendationsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGuidelines for the management of pregnant and breastfeeding women in the context of Ebola virus diseaseNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
5 data/code links checked; 5 live.
- datahttps://clinicaltrials.gov/study/NCT04556526LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT04556526LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://www.janssen.com/clinical-trials/transparencyLIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttp://yoda.yale.eduLIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://yoda.yale.edu/wp-content/uploads/2022/11/YODA-Project-Data-Release-Procedures-January-2025.pdfLIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly typo, consistency, clarity.
- MINORtypoAbstract“Maternal/fetal and neonatal/infant SAE frequencies were comparable between groups (9.8% in group A, 9.0% in group B and 21.9% in group A, 15.9% in group B, respectively).”→ Consider rephrasing for clarity: 'Maternal/fetal SAE frequencies were 9.8% in group A and 9.0% in group B; neonatal/infant SAE frequencies were 21.9% in group A and 15.9% in group B.'The sentence is ambiguous due to the use of 'respectively' with two pairs.
- MINORconsistencyResults, Patient disposition“Of the 3,484 women screened, 2,013 were enrolled and randomized (group A, n = 993; group B, n = 1,020).”→ Ensure consistency in the use of 'enrolled' and 'randomized' throughout the manuscript.The term 'enrolled' is used interchangeably with 'randomized' in some places.
- MINORclarityMethods, Statistical analysis“The CI of the risk differences should be interpreted with caution, given the highly inflated type I error due to the numerous primary outcomes.”→ Consider clarifying that the CIs are not adjusted for multiplicity.The statement is clear but could be more explicit about the lack of adjustment.
- MINORtypoResults, Primary outcomes“In group B, outcomes with at least 1.0% frequency included stillbirth (14/1,000 (1.4%), 95% CI = 0.8–2.3%)), preeclampsia/eclampsia (11/1,000 (1.1%), 95% CI = 0.6–2.0%) and postpartum hemorrhage (11/1,000 (1.1%), 95% CI = 0.6–2.0%)).”→ Remove extra closing parenthesis after each percentage.Extra parentheses appear in the text.
- MINORconsistencyResults, Secondary outcomes“Anti-EBOV GP-specific binding antibody response was observed in 99.2–100% of women at 21 days postdose 2, regardless of group or trimester at randomization.”→ Consider specifying the exact number of women in the denominator for clarity.The range is clear but the denominator is not stated.
The published work is robust and well-reported; an informed reader should weigh the minor reporting gaps (e.g., unexplained denominator of 977 for primary outcomes, lack of formal power analysis) and the copyedit issues, but none threaten the validity of the conclusions. No erratum is warranted for the identified issues, though clarifying the denominator and fixing typographical errors would improve the record.
- 1.HIGHreportingIn Results, Primary outcomes, clarify why the denominator for group A is 977 rather than the FAS of 992 (e.g., exclusions for missing outcome data) and state this explicitly.The unexplained denominator is an internal inconsistency that an informed reader will notice and could raise questions about the analysis population.
- 2.HIGHreportingIn Methods, Statistical analysis, add a sentence explicitly stating that the reported CIs for risk differences are not adjusted for multiplicity, given the numerous primary outcomes.The current statement about inflated type I error is clear but could be more explicit to prevent misinterpretation of the CIs.
- 3.MEDIUMcopyeditIn Results, Primary outcomes, remove the extra closing parentheses after each percentage (e.g., '95% CI = 0.8–2.3%))' should be '95% CI = 0.8–2.3%)').Typographical errors in reported statistics can undermine confidence in the accuracy of the data.
- 4.MEDIUMcopyeditIn Abstract, rephrase the sentence about SAE frequencies to avoid ambiguity: 'Maternal/fetal SAE frequencies were 9.8% in group A and 9.0% in group B; neonatal/infant SAE frequencies were 21.9% in group A and 15.9% in group B.'The current use of 'respectively' with two pairs is confusing and could be misread.
- 5.MEDIUMreportingIn Results, Secondary outcomes, specify the exact number of women in the denominator for the antibody response range (99.2–100%).Providing the denominator improves clarity and allows readers to assess the precision of the estimate.
- 6.MEDIUMreportingIn Methods, Statistical analysis, clarify how missing data were handled in the denominators for primary outcomes (e.g., whether women with missing outcomes were excluded from the denominator).The current text states 'Missing data were not imputed' but does not specify how missing outcomes affected the analysis population.
- 7.MEDIUMreportingIn Methods, Randomization and masking, specify whether outcome assessors or adjudicators were blinded to group assignment, even though the trial was open-label.Clarifying the blinding status of outcome assessors helps readers assess potential bias in outcome ascertainment.
- 8.MEDIUMreportingIn Methods, Statistical analysis, add a statement about whether the study was powered for the secondary immunogenicity endpoint, as the sample size justification focuses on safety.Readers need to know whether immunogenicity findings are adequately powered or exploratory.
- 9.LOWreportingIn Results, Patient disposition, ensure consistent use of 'enrolled' and 'randomized' throughout the manuscript.Inconsistent terminology can confuse readers about the exact study flow.
- 10.LOWreportingIn Data availability, add a note about the specific conditions for accessing data through YODA, such as the review process and timeline.Making the access route more concrete helps readers understand how to request data.
- 11.LOWreportingIn Results, report the number of women screened but not enrolled for each exclusion reason to improve transparency of the screening process.Detailed screening data strengthen the transparency of the trial's conduct.
- 12.LOWreportingIn Methods, Statistical analysis, clarify the role of the IDMC (Independent Data Monitoring Committee) in the statistical analysis section.The IDMC is mentioned but its role in the analysis is not detailed, which could be clarified for completeness.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
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Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
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