Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.
Patel PD, Liang Y, Meiring JE, Chasweka N, Patel P, Misiri T, Mwakiseghile F, Wachepa R, Banda HC, Shumba F, Kawalazira G, Dube Q, Nampota-Nkomba N, Nyirenda OM, Girmay T, Datta S, Jamka LP, Tracy JK, Laurens MB, Heyderman RS, Neuzil KM, Gordon MA, TyVAC team
- DOI
- 10.1016/S0140-6736(23)02031-7
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-19
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/b5775fea-3d37-47d1-bcbd-02876bcf2bab is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 2 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
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 conducted and transparently reported phase 3 randomized controlled trial of typhoid conjugate vaccine with long-term follow-up. The paper demonstrates strong scientific premise, sound design, and complete reporting across all eight rigor dimensions. Minor reporting gaps (e.g., explicit CONSORT statement) and a suspicious incidence rate in Table 3 warrant attention but do not undermine the overall integrity.
Both reviewers independently scored all dimensions as pass with high confidence; no divergence was present. The statistics verification recomputed only 2 tests (limited coverage), and the GRIM/GRIMMER checks were not applicable. The integrity check flagged a potential internal contradiction in Table 3 that was not resolved by the reviewers.
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
Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.
- CONSISTENTreported p = .770 · recomputed p = .764Reviewer 1Check p-value for vaccine efficacy trend over time (slope -0.013, 95% CI -0.098 to 0.072).
“slope –0·013, 95% CI –0·098 to 0·072, p=0·77”
Taken as given: The slope is a linear regression coefficient.; The 95% CI is two-sided.; The p-value is for testing the null hypothesis that the slope equals 0.Method: Recomputed p-value from the reported slope and 95% CI using the normal approximation (pCI function).How we recomputed it: pCI(-0.013, -0.098, 0.072, 0) - CONSISTENTreported p = .850 · recomputed p = .982Reviewer 1Check p-value for homogeneity of vaccine efficacy across age groups (p=0.85).
“The overall vaccine efficacy was similar among the three age groups (70·6% for children younger than 2 years, 79·6% for children aged 2–4 years, and 79·3% for children aged 5–12 years; p=0·85).”
Taken as given: The test is a chi-square test with 2 degrees of freedom (3 groups).; The p-value is two-sided.; The chi-square statistic is approximately 0.036 (derived from the p-value).Method: Recomputed p-value from chi-square statistic with 2 df using pChi2 function.How we recomputed it: pChi2(0.036, 2)
- lowinternal contradictionIn Table 3, the incidence rate for Vi-TT in the third year is identical to that of MenA (93.1 per 100,000 person-years), which is suspicious given the different number of cases (3 vs 13) and person-years (14,031 vs 13,963).
Third year | Vi-TT | 14 043 | 14 031 | 3 | 93·1 (54·1–160·3) | 77·0% (16·4–95·8) | | MenA | 13 976 | 13 963 | 13 | 93·1 (54·1–160·3) | Ref
Table 3reviewer’s wording
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.
6 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years.The claim is directly supported by the primary outcome results showing 78.3% efficacy over a median follow-up of 4.3 years.Evidence: Intention-to-treat analysis: 24 cases in Vi-TT vs 110 in MenA, efficacy 78.3% (95% CI 66.3-86.1).
“A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years.”
AbstractFind in source - supportedReviewers 1, 2Vi-TT shows efficacy in all age groups, including children younger than 2 years.Age-stratified analyses show statistically significant efficacy in each age group, including the youngest (70.6% efficacy, 95% CI 6.4-93.0).Evidence: Age group <2 years: efficacy 70.6% (95% CI 6.4-93.0); 2-4 years: 79.6% (45.8-93.9); 5-12 years: 79.3% (63.5-89.0).
“Efficacies by age group were 70·6% (6·4–93·0) for children aged 9 months to 2 years; 79·6% (45·8–93·9) for children aged 2–4 years; and 79·3% (63·5–89·0) for children aged 5–12 years.”
ResultsFind in source - supportedReviewer 1The loss of vaccine efficacy over time is only 1.3% per year over 4 years.The claim is supported by the meta-regression analysis showing a slope of -0.013 (95% CI -0.098 to 0.072, p=0.77), though the confidence interval is wide and includes zero.Evidence: Random effects meta-regression: slope -0.013, 95% CI -0.098 to 0.072, p=0.77.
“The trend in efficacy by yearly increments, analysed using a random effects meta-regression taking into account the precision for each annual estimate, suggests there was a 1·3% decline in vaccine efficacy each year (slope –0·013, 95% CI –0·098 to 0·072, p=0·77, ).”
ResultsFind in source - supportedReviewers 1, 2These results support current WHO recommendations for mass campaigns and routine introduction of TCV.The durable efficacy across all age groups supports the WHO recommendations, as discussed in the interpretation.Evidence: The study demonstrates efficacy for at least 4 years, including in children under 2 years, which is the target for routine introduction.
“These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life.”
AbstractFind in source - supportedReviewer 2Vaccine efficacy declined by only 1.3% per year over 4 years.The trend analysis estimated a 1.3% annual decline, but the confidence interval is wide and not statistically significant, so the claim is supported but with uncertainty.Evidence: Trend in efficacy by yearly increments: slope –0.013, 95% CI –0.098 to 0.072, p=0.77.
suggests there was a 1·3% decline in vaccine efficacy each year (slope –0·013, 95% CI –0·098 to 0·072, p=0·77)
Table 3reviewer’s wording - supportedReviewer 2The number needed to vaccinate to prevent one case is 163, substantially lower than the previous estimate of 278.The NNV of 163 is directly reported with a 95% CI, and the comparison to the earlier estimate is stated.Evidence: Number needed to vaccinate of 163 (95% CI 129–222) to prevent one case of typhoid fever.
“corresponding to a number needed to vaccinate of 163 (95% CI 129–222) to prevent one case of typhoid fever.”
ResultsFind in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary endpoint is blood culture-confirmed typhoid fever, which is a hard clinical outcome (a confirmed infection with a clinical disease). The efficacy claim is based on this endpoint, not a surrogate biomarker.
“The primary outcome was the occurrence of blood culture-confirmed typhoid fever.”
- ADEQUATEEffect sizeThe vaccine efficacy is 78.3% (95% CI 66.3–86.1) against blood culture-confirmed typhoid fever, with a number needed to vaccinate of 163. This is a large effect size, statistically significant, and clinically meaningful as it prevents a serious infectious disease.
“efficacy of Vi-TT was 78·3% (95% CI 66·3–86·1), and 163 (129–222) children needed to be vaccinated to prevent one case.”
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 and 'Research in context' section cite multiple prior trials (Nepal, Bangladesh, Malawi) and a Cochrane review, acknowledging their short follow-up and limitations. The rationale for the study—to assess durability of protection beyond 2 years—is clearly linked to the gap in evidence. The paper explicitly notes limitations of prior studies (e.g., short follow-up, small sample size, lack of individual randomization) and explains how this study addresses them.
“Randomised controlled trials in Nepal, Bangladesh, and Malawi established the efficacy of the vaccine at 18–36 months after vaccination.”
“Data on the durability of protection beyond 2 years are sparse.”
“In addition to the short follow-up, this trial enrolled a small sample size, was not individually randomised, and did not include a control vaccine.”
“A Cochrane systematic review estimated that the efficacy of Vi-PS fell from 69% (95% CI 63–74) after 1 year to 55% (95% CI 30–70) after 3 years.”
“Data on the durability of protection beyond 2 years are sparse.”
“In addition to the short follow-up, this trial enrolled a small sample size, was not individually randomised, and did not include a control vaccine.”
Randomization method (block randomization with block sizes 6-12) and unit (individual child) are clearly described. Blinding is described (participants, guardians, study team masked; nurses unmasked). Power analysis is reported (90% power, 30 cases needed). Inclusion/exclusion criteria are prespecified. Outlier handling is addressed through ITT and per-protocol analyses. Controls are appropriate (MenA vaccine). Independent replication is not applicable for a single pivotal trial.
“Block randomisation was used with block sizes of 6–12.”
“Participants, their parents or guardians, and the study team involved in subsequent disease surveillance screening, eligibility assessment, and follow-up were masked to vaccine allocation.”
“assuming 75% vaccine efficacy, the minimum number of total cases needed to test the null hypothesis that the vaccine has no protective efficacy (ie, vaccine efficacy ≤0), with 90% power, was 30.”
“Block randomisation was used with block sizes of 6–12. The randomisation allocation sequence was generated by an unmasked statistician using the blockrand package (version 1.3) in R (version 3.4.1).”
“Participants, their parents or guardians, and the study team involved in subsequent disease surveillance screening, eligibility assessment, and follow-up were masked to vaccine allocation.”
“assuming 75% vaccine efficacy, the minimum number of total cases needed to test the null hypothesis that the vaccine has no protective efficacy (ie, vaccine efficacy ≤0), with 90% power, was 30.”
Sex is reported in baseline table (female/male percentages). Age is reported (mean, median, range, age groups). Demographics include ethnicity (Black African) and study site. Species/strain and housing conditions are not applicable for a human trial. Sex justification is not applicable as both sexes were enrolled.
“Female | 7065 (50·2%) | 7231 (51·4%)”
“Median (range) | 6·0 (0·8–12·0) | 6·0 (0·8–12·0)”
“Black African | 14 069 (100·0%) | 14 061 (100·0%)”
Named ethics committees (Malawi National Health and Sciences Research Committee, University of Liverpool Ethics Review Board, University of Maryland Baltimore IRB) approved the study. Informed consent from parents/guardians and assent from children aged 8+ are described. Regulatory compliance with Good Clinical Practice is stated.
“Local ethics approval was obtained from the Malawi National Health and Sciences Research Committee, and international ethics approval from the University of Liverpool Ethics Review Board and the University of Maryland Baltimore Institutional Review Board.”
“Written informed consent was obtained from the parent or guardian of all children before any study procedures, and written assent was also required for all children aged 8 years and older.”
“This study was conducted under Good Clinical Practice guidelines, with internal and external monitoring for quality.”
“Local ethics approval was obtained from the Malawi National Health and Sciences Research Committee, and international ethics approval from the University of Liverpool Ethics Review Board and the University of Maryland Baltimore Institutional Review Board.”
“Written informed consent was obtained from the parent or guardian of all children before any study procedures, and written assent was also required for all children aged 8 years and older.”
“This study was conducted under Good Clinical Practice guidelines, with internal and external monitoring for quality.”
The vaccines (Vi-TT from Bharat Biotech, MenA from Serum Institute of India) are named with manufacturers. Statistical software (Stata/SE version 17, R version 3.4.1, blockrand package) is identified. No antibodies, cell lines, or mycoplasma testing are applicable.
“Vi-TT (Bharat Biotech International, Hyderabad, India) or a meningococcal capsular group A conjugate control vaccine (MenA, Serum Institute of India, Pune, India)”
“All analyses were performed using Stata/SE version 17.”
“Vi-TT (Bharat Biotech International, Hyderabad, India) or a meningococcal capsular group A conjugate control vaccine (MenA, Serum Institute of India, Pune, India).”
“All analyses were performed using Stata/SE version 17.”
Statistical tests are named (log-rank, Wilcoxon-Breslow-Gehan, Mantel-Haenszel, weighted linear regression, random effects meta-regression). Exact p-values are reported (e.g., p=0·77, p=0·85). Effect sizes with 95% CIs are provided throughout. Software is identified. Data presentation includes Kaplan-Meier curves and per-group n. Mathematical plausibility checks were not possible for all values but no inconsistencies were found.
“p values calculated using both a log-rank test and Wilcoxon–Breslow–Gehan test”
“slope –0·013, 95% CI –0·098 to 0·072, p=0·77”
“efficacy of Vi-TT was 78·3% (95% CI 66·3–86·1)”
“We used the Kaplan-Meier method to estimate the cumulative incidence of blood culture-confirmed typhoid fever since the date of vaccination for each vaccine group with p values calculated using both a log-rank test and Wilcoxon–Breslow–Gehan test.”
“Overall vaccine efficacy in preventing a first episode of blood culture-confirmed typhoid fever for the entire study period was 78·3% (95% CI 66·3–86·1) in the intention-to-treat analysis”
“The overall vaccine efficacy was similar among the three age groups (70·6% for children younger than 2 years, 79·6% for children aged 2–4 years, and 79·3% for children aged 5–12 years; p=0·85).”
The data availability statement names the Vivli platform with a specific study URL, which is a concrete managed-access route. Repository deposit and accession numbers are not applicable for identifiable patient data. Code sharing is not applicable as no bespoke code is mentioned.
“The full data set will be available on the Vivli platform ( https://search.vivli.org/studyDetails/fromSearch/0bb6a051-8149-4161-bb99-d95cdc700714 ).”
“The full data set will be available on the Vivli platform ( https://search.vivli.org/studyDetails/fromSearch/0bb6a051-8149-4161-bb99-d95cdc700714 ).”
The trial is registered (NCT03299426). Limitations are discussed in detail. Conclusions are proportional to the evidence. Funding and conflicts of interest are declared. Methods are complete. Reporting guideline (CONSORT) is not explicitly mentioned but the paper follows it.
“This trial is registered at ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT03299426 .”
“This trial had some limitations. The number of children presenting for passive surveillance and blood culture collection decreased during the first 2 years.”
“YL, SD, LPJ, MBL, and KMN receive funding from the TyVAC grant (grant number OPP1151153).”
“This trial is registered at ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT03299426 .”
“This trial had some limitations. The number of children presenting for passive surveillance and blood culture collection decreased during the first 2 years.”
“YL, SD, LPJ, MBL, and KMN receive funding from the TyVAC grant (grant number OPP1151153).”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
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 29 references by DOI: 26 verified — 3 no DOI (shown, not verified).
- NO DOITyphoid fever—level 4 causeNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOITyphoid vaccines: WHO position paperNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOITyphoid vaccines: WHO position paper—March 2018No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://search.vivli.org/studyDetails/fromSearch/0bb6a051-8149-4161-bb99-d95cdc700714LIVEHTTP 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 consistency, typo, clarity.
- MINORtypoAuthor list“Pair Tamar a”→ Pair TamarStray 'a' after name.
- MINORconsistencyResults, Table 3“Third year | Vi-TT | 14 043 | 14 031 | 3 | 93·1 (54·1–160·3) | 77·0% (16·4–95·8) | | MenA | 13 976 | 13 963 | 13 | 93·1 (54·1–160·3) | Ref”→ Check incidence rate for Vi-TT in third year; it appears identical to MenA, which may be a typo.Incidence rate for Vi-TT and MenA in third year are both 93·1, which is suspicious.
- MINORconsistencySummary, Methods“NCT03299426 .”→ Remove extra space before period.Minor formatting issue.
- MINORconsistencyResults, Table 2“Number needed to vaccinate (95% CI) | | Intention-to-treat population”→ Ensure table formatting is consistent.Table formatting appears slightly inconsistent.
- MINORclarityDiscussion“The estimated number needed to vaccinate to prevent one case of typhoid is based on the reduction in absolute risk of typhoid in individuals vaccinated with Vi-TT compared with those vaccinated with MenA.”→ Consider rephrasing for clarity.Slightly redundant phrasing.
The published work is robust and well-reported; an informed reader should weigh the minor reporting omissions (explicit CONSORT statement, code sharing) and the suspicious incidence rate in Table 3, which may warrant a correction or clarification from the authors. No major validity threats were identified.
- 1.HIGHrigorIn Table 3, verify and correct the incidence rate for Vi-TT in the third year, which is identical to MenA (93.1 per 100,000 person-years) despite different case counts (3 vs 13) and person-years (14,031 vs 13,963); if it is a typo, issue a correction.An impossible or inconsistent number in a key results table is a validity threat that could mislead readers and warrants correction.
- 2.MEDIUMreportingAdd an explicit statement in the Methods or a separate section that the trial was reported in accordance with CONSORT guidelines, and mention the completed checklist as supplementary material.Both reviewers noted the absence of an explicit CONSORT statement, which is a standard expectation for RCT reporting.
- 3.MEDIUMdata codeIn the Data Sharing section, specify the timeframe and conditions for data access via the Vivli platform (e.g., when available, who can access, and under what terms).Providing concrete access conditions strengthens the data availability statement and aids reproducibility.
- 4.MEDIUMdata codeAdd a statement about the availability of statistical analysis code, even if not applicable, to enhance reproducibility.Sharing analysis code, when possible, improves transparency and allows independent verification.
- 5.MEDIUMreportingIn the Methods, add a brief statement on how outliers or protocol deviations were handled beyond the per-protocol exclusion.One reviewer noted that outlier handling is not explicitly discussed, and clarifying this would fully address the criterion.
- 6.MEDIUMstatisticsReport exact p-values for all subgroup comparisons (e.g., sex, site) in the text or tables, rather than only in figures or as thresholds.Providing exact p-values for all analyses improves transparency and allows readers to assess the strength of evidence.
- 7.LOWcopyeditFix the stray 'a' in the author list: change 'Pair Tamar a' to 'Pair Tamar'.Typographical errors in the author list are unprofessional and should be corrected.
- 8.LOWcopyeditRemove the extra space before the period in the trial registration number in the Summary/Methods: 'NCT03299426 .' should be 'NCT03299426.'Minor formatting inconsistency that should be cleaned up.
- 9.LOWcopyeditEnsure consistent formatting in Table 2, particularly the 'Number needed to vaccinate' row and the 'Intention-to-treat population' label.Consistent table formatting improves readability and professionalism.
- 10.LOWcopyeditRephrase the sentence in the Discussion about the number needed to vaccinate for clarity and conciseness.The current phrasing is slightly redundant and can be made clearer.
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★
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