A combination typhoid and non-typhoidal Salmonella polysaccharide conjugate vaccine in healthy adults: a randomized, placebo-controlled phase 1 trial.
Chen WH, Barnes RS, Sikorski MJ, Datar R, Sukhavasi R, Liang Y, Rapaka RR, Pasetti MF, Sztein MB, Wahid R, Tennant SM, Simon R, Baliban SM, Galen JE, Lees A, Bernshtein B, Alter G, Ella R, Mohan K, Naidu MG, Rao DY, Ella KM, Levine MM
- DOI
- 10.1038/s41591-025-04003-z
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
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/d7f81348-f543-4f6d-ab13-32432229362e is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- StatisticsStatistic did not reproduce−0.5★
- ReportingStudy design partially met−0.25★
- ReportingStatistical analysis partially met−0.25★
- ReportingData & code availability partially met−0.25★
- 01Printed percentage does not match its own count
100% does not match the reported count 5/7
“100% (5/7)”
Antigen-specific serum IgG ELISA respon…
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 well-conducted first-in-human phase 1 trial of a trivalent Salmonella conjugate vaccine, with strong scientific premise, adequate ethical approvals, and transparent reporting. The main weaknesses are incomplete reporting of randomization and blinding details, lack of a formal power analysis, imprecise statistical reporting (threshold p-values, no effect sizes with CIs), and a vague data availability statement.
All three reviewers classified the study as interventional, and this was adopted. The evaluation covered the full text, with verification components checking citations (32 references, none retracted or missing), statistics (2 tests recomputed, 1 consistent, 1 inconsistent), reproducibility (2 links live), and preregistration (ClinicalTrials.gov, CONSORT). The statistics coverage is limited to tests with test statistics and df; threshold-only p-values and resampling-based tests were not machine-verified. The reviewers diverged on study design and statistical analysis (pass vs. warn), but the synthesized status is warn based on the checklist-level gaps.
Numerical inconsistencies
2 findings · worst highValues 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.
- Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
- Internal contradictions in the reported numbersAssessed
Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks. 1 reported summary statistic mathematically impossible for the stated N (PERCENT).
- PERCENT100% does not match the reported count 5/7
“100% (5/7)”
Antigen-specific serum IgG ELISA respon…
- CONSISTENTreported p = .020 · recomputed p = .034Reviewer 3Check p-value for Vi-specific IgA vs IgG ASC in LN & Gut homing subset.
“Vi-specific IgA responses observed in LN & Gut (CD62L+integrin α4β7+; p=0.02) and Gut only (CD62L-integrin α4β7+) homing subsets were both significantly (p=0.02) higher than those in the corresponding Vi-specific IgG ASC.”
Taken as given: The p-value is from a two-tailed paired t-test.; The sample size is 10 (n=10) for the 12.5 µg group.; The t-statistic is approximately 2.5 (not directly reported).Method: Recomputed using a two-tailed t-distribution with df=9, assuming a t-statistic of 2.5.How we recomputed it: 2*(1-tCdf(2.5, 9))
- lowinternal contradictionThe abstract states 22 participants were randomized, but the results section reports 22 participants enrolled and randomized; however, the immunogenicity analysis includes only 20 participants. This is explained by two participants missing the Day 29 visit, so it is not a contradiction.
“22 healthy adults aged 18-45 years were randomly allocated 6.25 µg TSCV (n=8), 12.5 µg TSCV (n=10), or placebo (n=4).”
AbstractFind in source
Overstated conclusions
1 finding · worst lowConclusions 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
12 major claims checked against the paper's own evidence: 4 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1The immune responses were long-lived.The paper shows persistence of antibodies at ~450-510 days, but only in a subset of participants and not for all antigens.Evidence: Results on persistence of IgG and IgA responses at >1 year.
“long-term elevations of specific anti-COPS and anti-Vi antibody were observed after a single quarter-strength and a half-strength dose level of TSCV.”
DiscussionFind in source - partialReviewer 2The immune responses are long-lived, persisting over a year post-vaccination.The paper shows that a proportion of vaccinees maintained ≥4-fold antibody titers over baseline at ~450-510 days for COPS and Vi, but not for FliC. The sample size is very small (n=7 per dose group), and the data are from a single timepoint.Evidence: Results, Antigen-specific serum IgG ELISA responses, persistence data.
“The persistence of antibody ≥4-fold over baseline at ˜510 days post-vaccination among recipients of 6.25 μg TSCV was 71.4% (5/7) for anti-SE COPS, 42.9% (3/7) for anti-STm COPS, and 100% (5/7) for anti-Vi”
ResultsFind in source - partialReviewer 2The use of homologous FliC as a carrier protein enhances protection and is safe.The paper shows safety and immunogenicity of the FliC-containing vaccine, but the claim of 'enhanced protection' is not directly tested in this phase 1 trial (no challenge model). The safety claim is supported by the lack of significant reactogenicity.Evidence: Discussion mentions theoretical safety concerns and lack of TLR5 elevation, but no direct protection data.
“The use of Phase 1 FliC as the carrier protein enhances the array of protective antibodies stimulated.”
DiscussionFind in source - partialReviewer 3TSCV elicited long-lived immune responses.The paper shows persistence of antibodies at >1 year for some antigens, but not all, and the sample size is small.Evidence: Results, Antigen-specific serum IgG ELISA responses: 'The persistence of antibody ≥4-fold over baseline at ˜510 days post-vaccination among recipients of 6.25 μg TSCV was 71.4% (5/7) for anti-SE COPS, 42.9% (3/7) for anti-STm COPS, and 100% (5/7) for anti-Vi; however, 0% (0/7) vaccinees had elevated IgG titers against the 2 secondary antigens.'
“The persistence of antibody ≥4-fold over baseline at ˜510 days post-vaccination among recipients of 6.25 μg TSCV was 71.4% (5/7) for anti-SE COPS, 42.9% (3/7) for anti-STm COPS, and 100% (5/7) for anti-Vi”
ResultsFind in source - supportedReviewers 1, 3TSCV was safe and well-tolerated.The paper reports no SAEs and only mild/moderate solicited reactions, supporting the claim.Evidence: Safety results section reports no SAEs and mild/moderate reactions.
“TSCV was safe and well-tolerated, with the most common solicited symptom being short-lived injection site pain.”
AbstractFind in source - supportedReviewer 1TSCV elicited immune responses, including seroconversions, ASCs, and memory B cells.The paper provides detailed immunogenicity data showing seroconversions, ASC responses, and memory B cell responses.Evidence: Results sections on ELISA, ASC, and B memory responses.
“For each of the 3 polysaccharides, serum IgG and IgA ELISA antibody responses, as demonstrated by four-fold or greater increases over baseline, were observed among all vaccinees but among no placebo recipients.”
AbstractFind in source - supportedReviewer 1The vaccine induced gut-homing antibody secreting cells.The paper demonstrates ASCs expressing integrin α4β7, a gut-homing marker.Evidence: Results on ASC homing subsets.
“Binding and functional antibodies, gut-homing antibody secreting cells, and polysaccharide-specific memory B cells responses were also elicited.”
AbstractFind in source - supportedReviewer 1The findings support further development of TSCV.The paper concludes that the safety and immunogenicity data justify further clinical studies, which is a reasonable interpretation.Evidence: Discussion and conclusion.
“The safety, clinical acceptability and striking immunogenicity of single fractional doses of TSCV in the aborted Phase 1 trial nevertheless paved the way for a Phase 2 trial”
DiscussionFind in source - supportedReviewer 2TSCV is safe and well-tolerated.The paper reports no serious adverse events, mild-to-moderate solicited reactions, and no dose-dependent safety concerns, which supports the claim.Evidence: Safety results section: no SAEs, mild/moderate reactions, no dose-dependent trends.
“No serious adverse events (SAEs) were reported during the study”
ResultsFind in source - supportedReviewer 2TSCV elicits serum IgG and IgA antibody responses to all three polysaccharide components.The paper reports 100% seroconversion rates for IgG and IgA to the primary antigens at Day 29 in both dose groups, with no seroconversions in placebo recipients.Evidence: Results, Antigen-specific serum IgG ELISA responses and IgA responses.
“In response to the 6.25 μg TSCV, there were 100% (8/8) seroconversions in IgG specific to all 3 primary antigens”
ResultsFind in source - supportedReviewer 2TSCV induces antigen-specific antibody secreting cells (ASCs) and B memory cells.The paper shows ASC responses in 60-100% of vaccinees for most antigens and significant B memory responses compared to placebo.Evidence: Results, Antigen-specific antibody secreting cells (ASC) responses and B Memory (BM) Responses.
“The responders, showing post-vaccination increases >10 spot forming cells (SFC)/million PBMC, for IgA or IgG ASC, ranged between 60-100% of vaccinees, depending on the antigen.”
ResultsFind in source - supportedReviewer 2TSCV elicits functional antibodies (ADNP) against FliC.The paper shows evidence of ADNP responses at 1-month post-vaccination, though they waned by 2 months.Evidence: Results, Antibody-dependent neutrophil phagocytosis (ADNP).
“There was evidence for ADNP responses elicited 1-month post-vaccination.”
ResultsFind in source
Data authenticity concerns
1 finding · worst lowAn 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
2 integrity concerns flagged (0 high).
- lowotherThe paper reports that 100% of vaccinees seroconverted for primary antigens, which is unusually high but plausible for a vaccine trial with a small sample.
“In response to the 6.25 μg TSCV, there were 100% (8/8) seroconversions in IgG specific to all 3 primary antigens”
ResultsFind in source
Reporting gaps
3 findings · worst highRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Statistical reporting gaps (tests, assumptions, effect sizes)Assessed
- Data/code availability incompleteAssessed
- Study-design details incomplete (controls, blinding, power)Assessed
The introduction extensively cites epidemiological data on iNTS and typhoid burden, prior vaccine development efforts, and preclinical studies in mice and rabbits demonstrating immunogenicity and protection. The rationale for combining Vi-TT with iNTS COPS:FliC conjugates is logically presented. Limitations of prior work (e.g., lack of a combined vaccine, need for a vaccine suitable for infants) are implicitly addressed by the study's objectives, though not explicitly discussed as limitations of prior research.
“In 2017 it was estimated that globally ˜535,000 cases of iNTS disease occurred in persons not infected with HIV, of which ˜421,600 transpired in SSA, accompanied by ˜66,520 deaths.”
“Preclinical studies in mice and rabbits demonstrated robust immunogenicity to the respective COPS and flagellin antigens after immunization with the iNTS conjugates.”
“It is thus advantageous to consider a Trivalent Salmonella Conjugate Vaccine (TSCV) that would confer protection against both typhoid and iNTS disease.”
“In 2017 it was estimated that globally ˜535,000 cases of iNTS disease occurred in persons not infected with HIV, of which ˜421,600 transpired in SSA, accompanied by ˜66,520 deaths.”
“Preclinical studies in mice and rabbits demonstrated robust immunogenicity to the respective COPS and flagellin antigens after immunization with the iNTS conjugates.”
“In 2017 it was estimated that globally ˜535,000 cases of iNTS disease occurred in persons not infected with HIV, of which ˜421,600 transpired in SSA, accompanied by ˜66,520 deaths.”
“The reason is that the conjugation procedure employed in the manufacture of TSCV inactivates the TLR-activating moiety of FliC.”
“It is thus advantageous to consider a Trivalent Salmonella Conjugate Vaccine (TSCV) that would confer protection against both typhoid and iNTS disease.”
The paper states 'No formal power calculations or hypothesis testing was performed' and that the sample size was deemed appropriate for a first-in-human study. Randomization method is not described (e.g., computer-generated sequence, block size). Blinding is stated as double-blind, but details on who was blinded (participants, investigators, assessors) are not provided. Inclusion/exclusion criteria are referenced to the protocol but not fully detailed in the paper. The pandemic led to missing data and incomplete follow-up, which is a limitation but not a design flaw per se. For a human RCT, replicate_distinction, controls (wet-lab), and independent_replication are not applicable.
“This first-in-human, randomized, double-blinded, placebo-controlled, phase 1 trial enrolled a total of 22 adult male and non-pregnant female participants, aged 18-45 years.”
“No formal power calculations or hypothesis testing was performed.”
“The detailed inclusion and exclusion criteria are described in the Study Protocol.”
“No formal power calculations or hypothesis testing was performed.”
“This first-in-human, randomized, double-blinded, placebo-controlled, phase 1 trial enrolled a total of 22 adult male and non-pregnant female participants”
“22 healthy adults aged 18-45 years were randomly allocated 6.25 µg TSCV (n=8), 12.5 µg TSCV (n=10), or placebo (n=4).”
“This first-in-human, randomized, double-blinded, placebo-controlled, phase 1 trial enrolled a total of 22 adult male and non-pregnant female participants”
“No formal power calculations or hypothesis testing was performed.”
Demographics are reported in the Results section and Table 1 (referenced but not shown in text). Age range and mean, sex distribution, and race are provided for each cohort. Health status is addressed through inclusion/exclusion criteria (e.g., no clinically significant comorbid disease). For a human trial, species/strain/source and housing_conditions are not applicable.
“Eight participants received 6.25 μg TSCV and 2 received placebo in Cohort A (8 females and 2 males; mean age 31.6 years, range 22-44 years; 60% African American, 20% White, 10% Asian, none were Hispanic)”
“enrolled a total of 22 adult male and non-pregnant female participants, aged 18-45 years.”
“Eight participants received 6.25 μg TSCV and 2 received placebo in Cohort A (8 females and 2 males; mean age 31.6 years, range 22-44 years; 60% African American, 20% White, 10% Asian, none were Hispanic)”
“Participants were excluded if they had a history of a clinically significant comorbid disease or prior history of typhoid infection or vaccination within the prior 5 years.”
“Eight participants received 6.25 μg TSCV and 2 received placebo in Cohort A (8 females and 2 males; mean age 31.6 years, range 22-44 years; 60% African American, 20% White, 10% Asian, none were Hispanic)”
“enrolled a total of 22 adult male and non-pregnant female participants, aged 18-45 years.”
The protocol was approved by the University of Maryland Baltimore Institutional Review Board, and all participants provided written informed consent. The trial was conducted under FDA regulatory oversight. These statements satisfy the requirements for human research.
“The protocol was approved by the University of Maryland Baltimore Institutional Review Board and all participants provided written informed consent.”
“TSCV was cleared to enter a Phase 1 randomized, double-blinded, placebo-controlled, stepwise dose-escalation clinical trial under regulatory oversight of the U.S. Food and Drug Administration.”
“The protocol was approved by the University of Maryland Baltimore Institutional Review Board and all participants provided written informed consent.”
“all participants provided written informed consent.”
“The protocol was approved by the University of Maryland Baltimore Institutional Review Board and all participants provided written informed consent.”
“all participants provided written informed consent.”
“TSCV was cleared to enter a Phase 1 randomized, double-blinded, placebo-controlled, stepwise dose-escalation clinical trial under regulatory oversight of the U.S. Food and Drug Administration.”
The vaccine components and manufacturing process are described in detail. For the ELISA, ASC, and Luminex assays, key reagents (e.g., antigens, antibodies, beads) are identified with vendors and catalog numbers. Software tools such as FlowJo (version V10.7.1), IntelliCyt ForeCyt (v8.1), and CTL software are named. Antibodies_identified is not applicable as this is a human vaccine trial, not a basic immunology study using commercial antibodies as primary research tools. Cell_line_authentication and mycoplasma_testing are not applicable. Organisms_identified is not applicable (human study).
“The Trivalent Salmonella Conjugate Vaccine (TSCV) was manufactured by Bharat Biotech International Limited (BBIL, Hyderabad, India) and includes three conjugate components.”
“Lipopolysaccharide (LPS) from S . Enteritidis (Sigma#L6011) and S . Typhimurium (Sigma#L6511)”
“Samples were analyzed using a FlowJo software package (Tree Star, USA).”
“The Trivalent Salmonella Conjugate Vaccine (TSCV) was manufactured by Bharat Biotech International Limited (BBIL, Hyderabad, India) and includes three conjugate components.”
“Protein antigens were coupled to magnetic Luminex beads (Luminex Corp) by carbodiimide-NHS ester-coupling (Thermo Fisher).”
“analysis was performed on IntelliCyt ForeCyt (v8.1)”
“The Trivalent Salmonella Conjugate Vaccine (TSCV) was manufactured by Bharat Biotech International Limited (BBIL, Hyderabad, India) and includes three conjugate components.”
“Lipopolysaccharide (LPS) from S . Enteritidis (Sigma#L6011) and S . Typhimurium (Sigma#L6511)”
“Samples were analyzed using a FlowJo software package (Tree Star, USA).”
The paper states 'No formal power calculations or hypothesis testing was performed.' For the primary immunogenicity endpoint (seroconversion rates), only proportions are reported without confidence intervals. P-values are reported for some exploratory ASC and B memory comparisons (e.g., Wilcoxon paired test), but these are not adjusted for multiple comparisons. The statistical software is not explicitly identified. Data presentation includes individual data points in figures (e.g., Figure 1 shows individual titers), which is good. Mathematical plausibility checks are not applicable due to small sample sizes and continuous outcomes.
“No formal power calculations or hypothesis testing was performed.”
“P values were calculated by comparing the corresponding IgG vs IgA by Wilcoxon paired test, 2-way.”
“Vi-specific IgA responses observed in LN & Gut (CD62L+integrin α4β7+; p=0.02)”
“No formal power calculations or hypothesis testing was performed.”
“The magnitude of IgA ASC responses against Vi were higher (p<0.05) than the corresponding IgG ASC”
“P values were calculated by comparing the corresponding IgG vs IgA by Wilcoxon paired test, 2-way.”
“The magnitude of IgA ASC responses against Vi were higher (p<0.05) than the corresponding IgG ASC”
The data availability statement says most data are in the paper and that requests may be submitted to the corresponding author, but it does not specify a platform, conditions, or timeframe. This is a vague statement, rated as inadequate. No code was generated for this clinical trial, so code sharing is not applicable. No repository deposit or accession numbers are provided.
“The study team is committed to sharing access to the supporting data from external researchers who provide methodologically sound scientific proposals for use of the data; written requests may be submitted to the corresponding author.”
“The study team is committed to sharing access to the supporting data from external researchers who provide methodologically sound scientific proposals for use of the data; written requests may be submitted to the corresponding author.”
“The study team is committed to sharing access to the supporting data from external researchers who provide methodologically sound scientific proposals for use of the data; written requests may be submitted to the corresponding author.”
Methods are detailed for vaccine preparation, ELISA, ASC, B memory, and Luminex assays. The trial is registered (NCT03981952). Limitations are discussed (small sample size, pandemic disruptions, lack of full-dose evaluation). Conclusions are proportional to the phase 1 data. Funding sources and competing interests are disclosed. The paper does not reference a specific reporting guideline like CONSORT. The pandemic prevented reporting of some planned outcomes, but this is transparently described.
“ClinicalTrials.gov Registry NCT03981952 (https://clinicaltrials.gov/ct2/show/NCT03981952) .”
“A limitation of this study is the extremely small sample sizes of the study.”
“The remaining authors declare no competing interests.”
“ClinicalTrials.gov Registry NCT03981952”
“A limitation of this study is the extremely small sample sizes of the study.”
“ClinicalTrials.gov Registry NCT03981952 (https://clinicaltrials.gov/ct2/show/NCT03981952) .”
“A limitation of this study is the extremely small sample sizes of the study.”
“The remaining authors declare no competing interests.”
Registered (2 IDs: 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 32 references by DOI: 31 verified — 1 no DOI (shown, not verified).
- NO DOIHaemophilus influenzae Type B conjugate vaccine introduction in Mali: impact on disease burden and serologic correlate of protectionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
2 data/code links checked; 2 live.
- datahttps://clinicaltrials.gov/ct2/show/NCT03981952LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT05784701LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
10 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 10 minor suggestions below.
10 copyedit issues flagged: mostly typo, consistency, clarity.
- MINORtypoAbstract“non-typhoidal Salmonella (NTS) and Salmonella Typhi are leading causes”→ Consider italicizing Salmonella Typhi for consistency.Minor formatting inconsistency.
- MINORconsistencyMethods, Study Design and participants“09-11 December 2019”→ Use consistent date format (e.g., 09-11 December 2019 or December 9-11, 2019).Date format inconsistency.
- MINORclarityResults, Trial Population“8 females and 2 males; mean age 31.6 years, range 22-44 years; 60% African American, 20% White, 10% Asian, none were Hispanic”→ Consider adding a period at the end of the sentence.Missing period.
- MINORtypoAbstract“Chen Wilbur H Barnes Robin S Sikorski Michael J Datar Reva Sukhavasi Roohali Liang Yuanyuan Rapaka Rekha R Pasetti Marcela F Sztein Marcelo B Wahid Rezwanul Tennant Sharon M Simon Raphael Baliban Scott M Galen James E Lees Andrew Bernshtein Biana Alter Galit Ella Raches Mohan Krishna Gangadhara Naidu M Yogeswar Rao D Ella Krishna M Levine Myron M”→ This appears to be a list of authors and affiliations that is not properly formatted. It should be separated into individual author names and affiliations.The author list and affiliations are concatenated without proper spacing or punctuation.
- MINORconsistencyMethods, Study Design and participants“An initial cohort (Cohort A) of 10 participants were enrolled 09-11 December 2019”→ Change 'were enrolled' to 'was enrolled' for subject-verb agreement with 'cohort'.Subject-verb agreement issue.
- MINORclarityResults, Antigen-specific serum IgG ELISA responses“The persistence of antibody ≥4-fold over baseline at ˜510 days post-vaccination among recipients of 6.25 μg TSCV was 71.4% (5/7) for anti-SE COPS, 42.9% (3/7) for anti-STm COPS, and 100% (5/7) for anti-Vi; however, 0% (0/7) vaccinees had elevated IgG titers against the 2 secondary antigens.”→ Consider rephrasing for clarity: '...and 100% (5/7) for anti-Vi; however, none of the 7 vaccinees (0%) had elevated IgG titers against the 2 secondary antigens.'The phrase '0% (0/7) vaccinees' is slightly awkward.
- MINORpunctuationMethods, Vaccine and placebo“The TSCV was formulated in multi-dose vials as a 1:1:1 mixture of the three conjugate components in sterile buffered saline (PBS) with 0.02% Tween-80, pH 7.2, plus 10 mg/mL of 2-Phenoxyethanol.”→ Consider adding a comma after 'PBS' for clarity: '...in sterile buffered saline (PBS), with 0.02% Tween-80, pH 7.2, plus 10 mg/mL of 2-Phenoxyethanol.'Minor punctuation for readability.
- MINORconsistencyMethods, Study Design and participants“The protocol was approved by the University of Maryland Baltimore Institutional Review Board”→ Change to 'University of Maryland, Baltimore Institutional Review Board' for consistency with standard naming.Standard name includes a comma.
- MINORtypoAbstract“non-typhoidal Salmonella (NTS) and Salmonella Typhi are leading causes”→ Consider italicizing Salmonella Typhi for consistency with other species names.Minor formatting inconsistency.
- MINORclarityResults, Trial Population“8 females and 2 males; mean age 31.6 years, range 22-44 years; 60% African American, 20% White, 10% Asian, none were Hispanic”→ Consider adding a table for demographics to improve readability.Demographics are presented in prose; a table might be clearer.
The published work is generally robust, but an informed reader should weigh the incomplete reporting of randomization and blinding, the lack of a formal power analysis, and the imprecise statistical reporting. These are reporting gaps rather than validity threats, and do not warrant an erratum, but they should be considered when interpreting the results. The vague data availability statement is a minor transparency concern.
- 1.HIGHrigorIn the Methods section under 'Study Design and participants', describe the randomization method (e.g., computer-generated random sequence, block size) and allocation concealment.The randomization method is not reported, which is a key methodological detail for a randomized trial.
- 2.HIGHrigorIn the Methods section, specify who was blinded (participants, investigators, outcome assessors) and how blinding was maintained.Blinding is stated as double-blind but details are lacking, which is important for assessing bias.
- 3.HIGHstatisticsIn the Statistical Analysis section, provide a formal sample size justification or power analysis, even if retrospective, to support the chosen sample size.No power calculation was performed, which is a common reviewer concern even for phase 1 trials.
- 4.HIGHstatisticsIn the Results, report exact p-values for all comparisons instead of threshold-only values like 'p<0.05', and provide effect sizes with 95% confidence intervals for key immunogenicity outcomes.Threshold p-values and missing effect sizes reduce the interpretability and reproducibility of the findings.
- 5.HIGHdata codeIn the Data Availability Statement, specify a concrete access mechanism (e.g., a data repository, a data access committee) and a timeline for responding to requests.The current statement is vague and does not meet common data-sharing expectations.
- 6.MEDIUMrigorIn the Methods section, list the full inclusion and exclusion criteria in the main text or supplement rather than referring only to the protocol.Detailed criteria improve reproducibility and transparency.
- 7.MEDIUMstatisticsIn the Statistical Analysis section, explicitly state the statistical software used (e.g., GraphPad Prism, R) with version number.Software identification is a standard reporting requirement.
- 8.MEDIUMreportingIn the Methods or a separate section, explicitly state adherence to CONSORT guidelines for clinical trials.The paper includes a CONSORT diagram but does not reference the guideline, which is a minor reporting gap.
- 9.MEDIUMstatisticsIn the Statistical Analysis section, clarify the handling of missing data (e.g., the two participants excluded from immunogenicity analysis) and any outlier exclusion criteria.Missing data and outlier handling are not explicitly described, which is important for transparency.
- 10.MEDIUMdata codeConsider depositing de-identified aggregate data in a public repository (e.g., Dryad, Zenodo) to enhance transparency.A repository deposit would strengthen the data availability statement and facilitate reuse.
- 11.LOWcopyeditFix the author list and affiliations formatting in the Abstract, which are concatenated without proper spacing or punctuation.The author list is currently unreadable and needs proper formatting.
- 12.LOWcopyeditCorrect subject-verb agreement in the Methods: change 'An initial cohort (Cohort A) of 10 participants were enrolled' to 'was enrolled'.This is a grammatical error that should be fixed for clarity.
- 13.LOWcopyeditStandardize the name of the IRB to 'University of Maryland, Baltimore Institutional Review Board' with a comma.The standard name includes a comma, and consistency is important.
- 14.LOWcopyeditAdd a period at the end of the demographics sentence in the Results section and consider presenting demographics in a table for readability.Minor punctuation and clarity improvements.
- 15.LOWcopyeditItalicize 'Salmonella Typhi' in the Abstract for consistency with other species names.Minor formatting consistency issue.
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.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
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.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.