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Kaimen Rigor review

Malaria vaccine protection against intradermal or venous parasites: a randomized phase 2b human challenge trial.

Kapulu MC, Orenge F, Kimani D, Kibwana E, Kibet H, Mutahi M, Datoo MS, Bellamy D, Musembi J, Ngoto O, Rashid H, Akinyi S, Mwatasa MH, Nyamako L, Keter K, Gatheru R, Mutiso A, Musyoki J, Mwacharo J, Abebe Y, James ER, Billingsley PF, Ngetsa C, Mosobo M, Makale J, Tawa B, Wamae K, Ochola-Oyier LI, Lawrie A, Ramos-Lopez F, Roberts R, Richie TL, Sim BKL, Hoffman SL, Ewer KJ, Hill AVS, Hamaluba M, Bejon P

DOI: 10.1038/s41591-025-04107-6
Record issued: 2026-08-10
Engine: 7.29.0
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/2ae609e0-b4bd-4f2b-ae15-910e527754d2 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

2 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
StatisticsPrinted percentage does not match its own count (capped)−0.25★
ReportingStatistical analysis partially met−0.25★
ReportingData & code availability partially met−0.25★
CitationsUnresolved reference−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.29.0Source: full text

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary endpoint is parasitemia (PCR positivity) in a controlled human malaria infection model, which is a surrogate for clinical malaria protection. The paper does not demonstrate target engagement (PK/PD) at the dose or provide validated evidence linking this surrogate to clinical outcomes in the field. The efficacy claim is based on this surrogate alone.
“The prespecified primary endpoint was time to meeting treatment criteria (that is, reaching the parasitaemia threshold of 500 parasites μl−1 or any parasitaemia plus important clinical symptoms).”
Find in source
02Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
32% does not match the reported count 12/37
“12/37 (32.0%)”
Find in source

Findings by category

201ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 204DisclosureReporting gaps 105AvailabilityBroken references and links 106CopyeditCopyediting

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

The paper reports a well-designed human challenge trial with strong ethical and reporting transparency. Two dimensions (statistical_analysis and data_code_availability) have minor but notable gaps: imprecise p-value reporting, a missing effect size for the primary comparison, an internal inconsistency in Table 2, and no shared analysis code.

Eight dimensions were evaluated; all were applicable. The reviewers agreed on most dimensions; the divergence on data code availability was resolved by considering code sharing applicable and not reported. The statistics verification was limited to 4 tests (3 consistent, 1 inconsistent due to rounding); threshold-only p-values could not be machine-verified. Citation verification found 1 reference not found in registry (the replication data DOI).

Numerical inconsistencies

2 findings · worst medium

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

Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Recomputed 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks. 1 printed percentage that does not match its own count.

Numeric forensics— values impossible for the reported sample size

PERCENT
32% does not match the reported count 12/37
“12/37 (32.0%)”
Find in source

Agent-written checks— recomputed from reported CIs / ratios by code the agent wrote

CONSISTENTreported p = .009 · recomputed p = .009Reviewers 1, 2
Fisher's exact test for ID vs DVI protection among R21 vaccinees (sensitivity analysis, 9/12 vs 0/5 protected).
“protection is nevertheless substantial by ID (9 out of 12, 75%), and statistically significantly different from DVI (0 out of 5 protected, P = 0.009 by Fisher’s two-sided test)”
Find in source
Taken as given: The 9 and 3 are the protected and unprotected counts in the R21 ID group of 12.; The 0 and 5 are the protected and unprotected counts in the R21 DVI group of 5.; The reported p is the two-sided Fisher's exact p for the resulting 2x2 table.
Method: Two-sided Fisher's exact test computed from the 2x2 cell counts (9,3,0,5).
How we recomputed it: pFisher2x2(9,3,0,5,0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1
Fisher's exact test for primary endpoint: 0/12 ID vs 5/5 DVI R21 vaccinees meeting treatment criteria (Discussion).
“that is, 0 out of 12 volunteers challenged by ID met the primary endpoint of requiring treatment versus 5 out of 5 challenged by DVI, P < 0.001 by Fisher’s two-sided test”
Find in source
Taken as given: The 0 and 12 are the met-endpoint and not-met-endpoint counts in the R21 ID group.; The 5 and 0 are the met-endpoint and not-met-endpoint counts in the R21 DVI group.; The reported p is the two-sided Fisher's exact p for the resulting 2x2 table.
Method: Two-sided Fisher's exact test computed from the 2x2 cell counts (0,12,5,0); the recomputed p should be well below 0.001.
How we recomputed it: pFisher2x2(0,12,5,0,0)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 2
Two-sided Fisher exact test for 0/12 ID vs 5/5 DVI R21 primary endpoint met.
“0 out of 12 volunteers challenged by ID met the primary endpoint of requiring treatment versus 5 out of 5 challenged by DVI, P < 0.001 by Fisher’s two-sided test”
Find in source
Taken as given: The 12 and 5 are the group sizes of the R21 ID and R21 DVI challenged volunteers.; ID events (met primary endpoint) = 0, so protected = 12; DVI events = 5, so protected = 0.; The reported P is a threshold (<0.001), not an exact value.
Method: Two-sided Fisher exact test computed from the 2x2 table [12,0;0,5] with no mid-p correction.
How we recomputed it: pFisher2x2(12, 0, 0, 5, 0)

lowinternal contradiction
The abstract states 'we enrolled 37 of these volunteers to controlled human malaria infection' while the Methods says 'so that 37 completed CHMI'; the wording is ambiguous about whether 37 were enrolled or 37 completed challenge.
“We enrolled 37 of these volunteers to controlled human malaria infection (CHMI) using ID or direct venous injection (DVI)”
AbstractFind in source
lowinternal contradiction
Secondary efficacy denominators (75/78, 60/78, 56/78, 39/78) do not match any reported population size (80 randomized, 37 challenged, or 59 non-R21-ID challenged), and the analysis population is not defined in the text.
“whereas 75/78 (96.1%), 60/78 (76.9%), 56/78 (71.8%) and 39/78 (50%) met secondary endpoints”
ResultsFind in source
lowinternal contradiction
In Table 2, the R21 DVI row reports 'Treated, nonfebrile' as 0% (0/12), but the column header states R21 DVI n = 5; the denominator is inconsistent with the group size.
Treated, nonfebrile, % ( n / N ) | ... | 0% (0/12)
Table 2reviewer’s wording

Overstated conclusions

2 findings · worst high

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

Efficacy rests on an unvalidated surrogate endpointAssessed
Conclusions only partially backed by the presented evidenceAssessed

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

partialReviewer 1
Breakthrough infection in the face of high anti-CSP antibody titers results from occasional capillary injection of sporozoites by mosquito bites, explaining leaky protection.
This is a plausible mechanistic hypothesis consistent with the DVI result and cited bite studies, but it is an inference not directly tested in this study.
Evidence: DVI non-protection result plus cited observation that ~1 in 5 mosquito feeds delivers capillary sporozoites; no direct measurement of sporozoite delivery routes in humans.
“we conclude that sporozoites causing infection in the face of high-titer anti-CSP antibodies induced by RTS,S or by R21 result from the occasional injection of capillary sporozoites by mosquito bites”
DiscussionFind in source
partialReviewer 2
The route-dependent difference in R21 efficacy explains the leaky protection and noisy correlation between anti-CSP titers and protection in mosquito-bite CHMI.
The study demonstrates route-dependent efficacy in humans and cites supporting animal and mosquito-bite literature, but no mosquito-bite CHMI arm was included, so the extrapolation is inferential.
Evidence: Observed ID vs DVI efficacy difference plus cited literature on mosquito-bite sporozoite distribution and animal models; no direct mosquito-bite challenge data in this study.
“we conclude that sporozoites causing infection in the face of high-titer anti-CSP antibodies induced by RTS,S or by R21 result from the occasional injection of capillary sporozoites by mosquito bites, producing noise in the correlation between antibody titers and the endpoint, which explains the leaky protection.”
DiscussionFind in source
supportedReviewers 1, 2
R21/Matrix-M was highly protective against ID CHMI but not against DVI sporozoites.
The presented results directly support this: 0/12 R21 vaccinees met the primary endpoint by ID versus 5/5 by DVI, with a significant route difference.
Evidence: Primary-outcome results and sensitivity analysis (0/12 ID vs 5/5 DVI; P < 0.001 by Fisher's two-sided test).
“R21/Matrix-M was highly protective against CHMI using ID. inoculation of sporozoites, but not against DVI sporozoites.”
AbstractFind in source
supportedReviewer 1
The ME-TRAP vaccine was not protective against ID CHMI.
ME-TRAP vaccinees showed outcomes similar to controls (11/12 met the primary endpoint), directly supporting the claim.
Evidence: Primary-outcome results: 11/12 ME-TRAP volunteers met the primary endpoint versus 7/8 controls.
“Seven of eight control volunteers (88%) and 11 of 12 ME-TRAP volunteers (92%) met the criteria for the primary endpoint”
ResultsFind in source
supportedReviewer 1
The route-dependent protection observed in humans extends prior animal-model findings.
The human data (ID protective, DVI not) are consistent with the cited mouse studies, supporting the extension claim.
Evidence: Primary-outcome segregation by route plus cited animal literature on dermal vs intravenous sporozoite blocking.
“Furthermore, our data are consistent with animal models.”
DiscussionFind in source
supportedReviewer 1
Correlates of efficacy for anti-sporozoite antibodies should be assessed by separate DVI and ID challenges.
This recommendation follows directly from the demonstrated route dependence of protection in this trial.
Evidence: The observed ID/DVI discrepancy in efficacy among R21 vaccinees.
“Correlates of efficacy for antibodies to sporozoites should also be assessed by separate DVI and ID challenges.”
AbstractFind in source
supportedReviewer 2
ME-TRAP was not protective against CHMI in this Kenyan adult population.
The ME-TRAP attack rate (11/12) was essentially identical to the control ID attack rate (7/8), supporting absence of efficacy.
Evidence: Primary endpoint: 11/12 ME-TRAP volunteers met endpoint versus 7/8 controls; no evidence of protection.
“ME-TRAP was not protective against CHMI in our study and T cell induction, determined by ELISpot, was lower than that previously seen in European and Kenyan volunteers among whom protective efficacy was observed”
DiscussionFind in source
supportedReviewer 2
The ID and DVI challenge doses produced a similar effective liver inoculum in unvaccinated volunteers.
Infection rates and parasite growth curves were similar between ID and DVI controls, supporting similar effective inocula despite the sevenfold dose difference.
Evidence: Infection rates: 8/8 ID controls vs 32/34 DVI controls; geometric mean growth curves similar (Extended Data Fig. 5).
“We conclude that the different doses resulted in a similar effective inoculum reaching the liver in unvaccinated volunteers”
DiscussionFind in source

Premise concern: surrogate not validated for clinical benefit.

INADEQUATESurrogate endpoint
The primary endpoint is parasitemia (PCR positivity) in a controlled human malaria infection model, which is a surrogate for clinical malaria protection. The paper does not demonstrate target engagement (PK/PD) at the dose or provide validated evidence linking this surrogate to clinical outcomes in the field. The efficacy claim is based on this surrogate alone.
“The prespecified primary endpoint was time to meeting treatment criteria (that is, reaching the parasitaemia threshold of 500 parasites μl−1 or any parasitaemia plus important clinical symptoms).”
Find in source
ADEQUATEEffect size
The effect size is 100% protection (0/12 met primary endpoint) in the ID challenge group, compared to 100% infection in controls and DVI group. This is a large and statistically significant effect.
“none of the 12 volunteers vaccinated with R21 met the primary endpoint following challenge with ID PfSPZ”
Find in source

Data authenticity concerns

None found

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

Checked — nothing surfaced.

Reporting gaps

2 findings · worst high

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

Statistical reporting gaps (tests, assumptions, effect sizes)Assessed
Data/code availability incompleteAssessed

Eight Dimensions6 pass · 2 warn

Prior work is cited extensively (RTS,S, R21, CHMI, animal models); the unresolved 'leaky' protection and the absence of human route-comparison studies are explicitly acknowledged; the hypothesis follows directly from these gaps and animal-model data. Limitations of prior research are addressed by designing a study that separates ID and DVI challenge routes.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The premise is well-established: prior CHMI and animal-model evidence motivate the hypothesis that anti-CSP antibody protection varies by sporozoite inoculation route.

Evidence

“To our knowledge, there are no CHMI studies that compare anti-CSP antibodies against different routes of inoculation of sporozoites in human volunteers.”

Main, paragraph 3Find in source

“in animal models, dermal sporozoites are more readily blocked by anti-CSP antibodies compared to intravenous sporozoites”

Main, paragraph 2Find in source

PASSReviewer 2· 95% conf

The introduction thoroughly establishes prior work on RTS,S/R21, anti-CSP antibodies, CHMI and animal-model route differences, and derives a clear hypothesis from that evidence.

Evidence

“We therefore hypothesized that vaccine protection might vary according the route of inoculation (that is, ID versus DVI).”

Main, paragraph 2Find in source

“To our knowledge, there are no CHMI studies that compare anti-CSP antibodies against different routes of inoculation of sporozoites in human volunteers.”

Main, paragraph 3Find in source

“It is unclear why antibody-based protection remains partial despite high levels of anti-CSP antibodies induced by vaccines or high concentrations of circulating monoclonal antibodies.”

Main, paragraph 2Find in source

Computer-generated randomization via an independent statistician and REDCap; open-label design with explicit rationale; a priori power calculation; detailed inclusion/exclusion criteria; ITT and according-to-protocol populations defined; sensitivity analysis addresses PCR-positive outliers. Bench-science concepts (replicate distinction, wet-lab controls, independent replication) are not applicable to a single human challenge trial, and the control/comparator arms serve as controls.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Core trial-design elements are adequately reported: computer-generated randomization, open-label design with rationale, a priori power calculation, and detailed inclusion/exclusion criteria.

Evidence

“The volunteers were randomly assigned with randomization via a computer-generated sequence by an independent statistician.”

MethodsFind in source

“The study was open label as (1) placebo for the different doses and routes would have been impractical and (2) outcomes were based on objective PCR data and the laboratory team were blind to allocations.”

MethodsFind in source

“Using a comparison of proportions and assuming P = 0.05 and 100% infection rates in the control group, we predicted 90% power to detect 40% efficacy with n = 20 groups and 80% power to detect 60% efficacy with n = 10.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

Randomization, open-label justification, power calculation, eligibility criteria and analysis populations are all described for this human RCT.

Evidence

“The volunteers were randomly assigned with randomization via a computer-generated sequence by an independent statistician.”

MethodsFind in source

Methods ¶1Find in source

Statistical analysisFind in source

Sex is reported (70% male overall; per-group male/female percentages in Table 1), as are age (mean 28.3 years) and BMI. Ethnicity (Mijikenda) and prior malaria exposure are described. Both sexes were enrolled, so sex_justified is not applicable. Species-strain and housing criteria are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

Sex, age, BMI, and ethnicity are reported for the human cohort; sex is appropriately not single-sex so no justification required.

Evidence

“There was a predominance of young male volunteers (28/40, 70%) with a mean age of 28.3 years”

ResultsFind in source

“Volunteers were from the Mijikenda ethnic group.”

ResultsFind in source

PASSReviewer 2· 80% conf

Sex, age, BMI and health status are reported; demographics are adequate for this small Kenyan adult CHMI trial.

Evidence

“There was a predominance of young male volunteers (28/40, 70%) with a mean age of 28.3 years (Table ).”

ResultsFind in source

“Volunteers were from the Mijikenda ethnic group.”

ResultsFind in source

“Following written informed consent, we recruited healthy adult men and women aged between 18 and 45 years from Kilifi North on the Kenyan Coast”

MethodsFind in source

Approvals are explicitly reported from Kenyan and Oxford IRBs (ERU and OxTREC numbers) and the Kenyan Pharmacy and Poisons Board; written informed consent is described; compliance with ICH-GCP and an FDA IND is stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Named ethics bodies with protocol numbers, written informed consent, and regulatory compliance are all reported.

Evidence

“approvals were obtained from a National IRB in Kenya and the relevant Oxford IRB (ERU (KEMRI/SERU/CGMR-C/158/3844) and OxTREC (OxTREC 32-19))”

MethodsFind in source

“Following written informed consent, we recruited healthy adult men and women”

MethodsFind in source

PASSReviewer 2· 95% conf

Named ethics committees with protocol numbers, informed consent, and regulatory compliance statements are all present.

Evidence

“approvals were obtained from a National IRB in Kenya and the relevant Oxford IRB (ERU (KEMRI/SERU/CGMR-C/158/3844) and OxTREC (OxTREC 32-19)) and from the medicines regulatory authority in Kenya (Pharmacy and Poisons Board (ECCT/19/11/01)).”

MethodsFind in source

“Following written informed consent, we recruited healthy adult men and women”

MethodsFind in source

Scored against the investigational products: R21/Matrix-M is specified (10 μg with Matrix-M 50 μg, 0/1/2-month schedule), Sanaria PfSPZ challenge (NF54) is identified with doses (22,500 ID or 3,200 DVI), and ChAd63/MVA ME-TRAP is described. Software (STATA, REDCap, SeekDeep version 3.0.110) is identified. Wet-lab bench criteria (antibodies/cell line/mycoplasma/organisms) are not applicable to this human trial.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 80% conf

The investigational vaccines and challenge agent are well identified with doses; analysis software is named with versions.

Evidence

“R21 was thawed to room temperature then mixed with Matrix-M before administration (10 μg mixed with Matrix-M 50 μg) and administered intramuscularly.”

MethodsFind in source

“injecting either 22,500 PfSPZ challenge ID or 3,200 PfSPZ challenge DVI”

MethodsFind in source

PASSReviewer 2· 75% conf

Investigational products, challenge agent, key reagents and software are identified with sufficient detail for a clinical trial.

Evidence

“R21 was thawed to room temperature then mixed with Matrix-M before administration (10 μg mixed with Matrix-M 50 μg) and administered intramuscularly.”

MethodsFind in source

“We used P. falciparu m NF54 sporozoites (Sanaria PfSPZ challenge (NF54)) using two alternative inoculation routes: injecting either 22,500 PfSPZ challenge ID or 3,200 PfSPZ challenge DVI.”

Methods ¶1Find in source

“Sequence data analysis was performed in SeekDeep version 3.0.110”

MethodsFind in source

Tests (log-rank, Fisher's exact, Kruskal-Wallis) and software (STATA, SeekDeep) are named; survival analysis is appropriate for the design. exact_p_values is downgraded because the primary endpoint is reported only as 'P < 0.0005' (a threshold), though several secondary p-values are exact. effect_sizes_ci is downgraded because the primary efficacy outcome is not accompanied by an effect-size CI (CIs are given for immunogenicity endpoints). Table 2 lists '0% (0/12)' for the R21 DVI 'Treated, nonfebrile' row although that group's n is 5, an internal inconsistency (likely a copy error).

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciINADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityWARN

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 70% conf

Tests are named and software identified, but the primary analysis is reported with threshold p-values rather than exact values, effect sizes with CIs are not given for the primary efficacy outcome, and Table 2 contains a cell-count inconsistency.

Evidence

“five of five R21 vaccinated volunteers receiving DVI sporozoites met the primary endpoint ( P < 0.0005 by log rank across all groups)”

AbstractFind in source

paraphrase[Table 2]

“Treated, nonfebrile, % ( n / N ) | ... | 0% (0/12)”

“protection is nevertheless substantial by ID (9 out of 12, 75%), and statistically significantly different from DVI (0 out of 5 protected, P = 0.009 by Fisher’s two-sided test)”

ResultsFind in source

WARNReviewer 2· 70% conf

Statistical tests are named and data presentation is transparent, but key p-values are threshold-only, no primary effect size with confidence interval is given, and the statistical software for the final analysis is not identified.

Evidence

“P < 0.0005 by log-rank survival across all groups”

ResultsFind in source

“P = 0.009 by Fisher’s two-sided test”

ResultsFind in source

“Peak responses were geometric means of 2,152 and 1,113 and minimum to maximum ranges of 750–5,500 versus 610–3,300 for ID versus DVI challenged groups, respectively ( P = 0.14).”

ResultsFind in source

data_availability_statement is adequate: it names a repository (Harvard Dataverse, DOI 10.7910/DVN/TNHS14) and a managed-access committee (Data Governance Committee, dgc@kemri-wellcome.org) with no time restrictions. repository_deposit is adequate. accession_numbers is not applicable for identifiable patient-level data. code_sharing is not reported — analysis software is named (STATA, SeekDeep) but no version-controlled repository for bespoke scripts is provided. Two of three applicable criteria are adequate, so the dimension is a warn.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 70% conf

A concrete data-availability route (Harvard Dataverse DOI plus a named managed-access committee) is given, but no custom analysis code is shared.

Evidence

“Data are available through the online repository for KEMRI–Wellcome Trust Research Programme: Harvard Dataverse at 10.7910/DVN/TNHS14”

Data availabilityFind in source

“Individual-level data, excluding personal identifiers, will be made available in accordance with an application to the Data Governance Committee, which meets monthly (dgc@kemri-wellcome.org). There are no timing restrictions on the availability of data.”

Data availabilityFind in source

PASSReviewer 2· 85% conf

Data availability is concrete, with a Dataverse DOI and a named Data Governance Committee access route; no custom code appears to have been produced.

Evidence

“Data are available through the online repository for KEMRI–Wellcome Trust Research Programme: Harvard Dataverse at 10.7910/DVN/TNHS14 (ref. ). Individual-level data, excluding personal identifiers, will be made available in accordance with an application to the Data Governance Committee, which meets monthly (dgc@kemri-wellcome.org). There are no timing restrictions on the availability of data.”

Data availabilityFind in source

Methods are replicable (vaccination schedules, CHMI procedures, qPCR, immunology, statistics). Trial registration numbers are given (NCT03947190, PACTR202108505632810). The authors state all prespecified outcomes are reported. A CONSORT flow diagram and a reporting summary are provided. Limitations (historical DVI controls, small sample size, difference between injection and mosquito bites) are candidly discussed, and conclusions are measured. Funding and competing interests are declared.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Methods are detailed, the trial is registered in two registries, all prespecified outcomes are reported, limitations are discussed, and funding/COI are disclosed.

Evidence

paraphrase[Abstract]

“The study was registered with ClinicalTrials.gov ( NCT03947190 ) and PACTR ( PACTR202108505632810 )”

“All these prespecified outcomes are reported here and are not being published elsewhere.”

ResultsFind in source

“We relied on historical controls for PfSPZ challenge by DVI and prior malaria exposure appears to have been higher in this group”

DiscussionFind in source

PASSReviewer 2· 80% conf

Trial registration, methods detail, outcome reporting, limitations, funding and COI are all transparent; only the explicit reporting-guideline reference is somewhat generic.

Evidence

“The study was registered with ClinicalTrials.gov ( NCT03947190 (https://clinicaltrials.gov/study/NCT03947190?term=NCT03947190&rank=1) ) and PACTR ( PACTR202108505632810 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=15911) ).”

AbstractFind in source

“All these prespecified outcomes are reported here and are not being published elsewhere.”

ResultsFind in source

“Our study has some limitations. We relied on historical controls for PfSPZ challenge by DVI”

DiscussionFind in source

Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

ClinicalTrials.gov

NCT03947190

Reporting guidelines: CONSORT

Broken references and links

1 finding · worst low

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

References not resolvable to a published paperRecomputed

Checked 44 references by DOI: 2 verified — 1 DOI unresolved, 41 no DOI (shown, not verified).

UNRESOLVED10.7910/dvn/tnhs14
Replication data for: The malaria vaccine R21 is protective against intradermal but not intravenous Plasmodium falciparum sporozoites in controlled human malaria infection in Kenyan adults
Cited DOI does not resolve to any Crossref record.
NO DOI
Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Subcutaneous administration of a monoclonal antibody to prevent malaria
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Seven-year efficacy of RTS,S/AS01 malaria vaccine among young African children
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Duration of vaccine efficacy against malaria: 5th year of follow-up in children vaccinated with RTS,S/AS02 in Mozambique
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years’ follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Further analysis of correlates of protection from a phase 2a trial of the falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Controlled human malaria infection studies in Africa—past, present, and future
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Analysis of immunity to febrile malaria in children that distinguishes immunity from lack of exposure
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
R21 in Matrix-M adjuvant in UK malaria-naive adult men and non-pregnant women aged 18–45 years: an open-label, partially blinded, phase 1–2a controlled human malaria infection study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Feeding behaviour and sporozoite ejection by infected Anopheles stephensi
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Longitudinal analysis of Plasmodium sporozoite motility in the dermis reveals component of blood vessel recognition
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Antibody-mediated protection against Plasmodium sporozoites begins at the dermal inoculation site
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Translating the Immunogenicity of prime-boost immunization with ChAd63 and MVA ME-TRAP from malaria naive to malaria-endemic populations
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
First field efficacy trial of the ChAd63 MVA ME-TRAP vectored malaria vaccine candidate in 5–17 months old infants and children
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Controlled human malaria infection studies: insights into recent advances and key immunological and ethical implementation lessons
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Ethical considerations in controlled human malaria infection studies in low resource settings: experiences and perceptions of study participants in a malaria challenge study in Kenya
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Safety and PCR monitoring in 161 semi-immune Kenyan adults following controlled human malaria infection
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Correlates of protection induced by vaccination
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in children (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Fractional doses of pneumococcal conjugate vaccine—a noninferiority Trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Cytotoxicity of human antibodies targeting the circumsporozoite protein is amplified by 3D substrate and correlates with protection
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Inability of malaria vaccine to induce antibodies to a protective epitope within its sequence
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The induction and persistence of T cell IFN-γ responses after vaccination or natural exposure is suppressed by Plasmodium falciparum
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Translating the immunogenicity of prime-boost immunization with ChAd63 and MVA METRAP from malaria naive to malaria-endemic populations
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Relationship between exposure, clinical malaria, and age in an area of changing transmission intensity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Controlled human malaria infection (CHMI) outcomes in Kenyan adults is associated with prior history of malaria exposure and anti-schizont antibody response
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Safety and immunogenicity of varied doses of R21/Matrix-MTM vaccine at three years follow-up: a phase 1b age de-escalation, dose-escalation trial in adults, children, and infants in Kilifi-Kenya
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Quantification of Plasmodium falciparum : validation of quantitative polymerase chain reaction assays for detection of parasites in controlled human malaria infection studies
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Targeted amplicon deep sequencing of ama1 and mdr1 to track within-host P. falciparum diversity throughout treatment in a clinical drug trial
No 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/study/NCT03947190?term=NCT03947190&rank=1LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttps://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=15911LIVEHTTP 200
Resolves, but the content could not be matched to the paper.

Copyediting

1 finding · worst low

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

Wording or formatting errors that need correctingAssessed

12 copyedit issues flagged (1 major): mostly typo, consistency, punctuation.

MAJORconsistencyTable 2
“Treated, nonfebrile, % ( n / N ) | ... | 0% (0/12)”
→ Change to 0% (0/5) to match the R21 DVI group's n of 5.
Column header states R21 DVI n = 5, but this row reports 0/12.
MINORtypoMethods, CHMI
“as previously defined , , that ism reaching parasitaemia threshold”
→ Change 'that ism' to 'that is'.
Typographical error.
MINORtypoSupplementary Information
“Sstatistical analysis plan”
→ Change to 'Statistical analysis plan'.
Stray capital 'S'.
MINORtypoMethods, Vaccines and vaccination
“P. falciparu m NF54”
→ Close the spacing: 'P. falciparum NF54'.
Spacing error in species name.
MINORtypoSupplementary Information
“Sstatistical analysis plan”
→ Statistical analysis plan
Stray capital S.
MINORtypoMethods, CHMI
“that ism reaching parasitemia threshold”
→ that is, reaching the parasitemia threshold
Typo 'ism'.
MINORtypoMethods, CHMI
“P. falciparu m NF54”
→ P. falciparum NF54
Missing space in species name.
MINORpunctuationAbstract
“R21/Matrix-M was highly protective against CHMI using ID. inoculation of sporozoites, but not against DVI sporozoites.”
→ Remove the period after 'ID'.
Stray period breaks the sentence.
MINORconsistencyTable 2 footnote
“0% (0/12)”
→ 0% (0/5)
R21 DVI group has n=5, not 12.
MINORconsistencyResults, Safety
“and 12/37 (32.0%)”
→ 12/37 (32.4%)
12/37 = 32.4%, not 32.0%.
MINORclarityResults, Safety
“Fever was a more common general adverse event at the final vaccination for ME-TRAP with 5/24 (20.8%) and 8/24 (33.3%) experiencing headache”
→ Headache was the more common general adverse event at the final vaccination for ME-TRAP (8/24, 33.3%); fever occurred in 5/24 (20.8%).
The sentence conflates fever and headache.
MINORconsistencyExtended Data Fig. 2 caption
“compared with 127 sfu (95%CI 174 sfu (95%CI 74-409)”
→ compared with 127 sfu (95% CI 74–409)
Garbled confidence interval text.

Kaimen Rigor Action ItemsFinal pass before journal submission

Post-publication audit: The published paper is methodologically robust but has several reporting issues that an informed reader should weigh. The most consequential are the Table 2 denominator inconsistency (0/12 for a group of 5) and the lack of exact p-values and effect-size CIs for the primary efficacy outcome. These gaps warrant a correction or clarification from the authors. The missing code repository and the unclear definition of secondary efficacy denominators are additional concerns that a reader should consider when interpreting the results.

1.
HIGHstatistics
Correct the Table 2 denominator error: change '0% (0/12)' to '0% (0/5)' for the R21 DVI 'Treated, nonfebrile' row to match the group's n of 5.
This is an internal inconsistency that undermines data integrity; a correction is necessary.
2.
HIGHstatistics
Report exact p-values (e.g., from the log-rank test) instead of the threshold 'P < 0.0005' for the primary endpoint in the Abstract and Results; add a vaccine efficacy estimate with 95% confidence interval for the ID vs DVI contrast in R21 vaccinees.
Threshold-only p-values and missing effect sizes limit the informativeness of the primary analysis; a reader cannot assess the precision of the finding.
3.
HIGHreporting
Clearly define the analysis population for the secondary efficacy denominators (e.g., 75/78, 60/78) and reconcile them with the reported group sizes (80 randomized, 37 challenged) in the Results section.
The denominators do not match any stated population, creating ambiguity about the analysis set.
4.
HIGHdata code
Deposit the custom analysis scripts (STATA randomization/analysis code, SeekDeep sequence-analysis pipeline) in a version-controlled public repository with a DOI, and cite it in the Data availability section.
Sharing code enhances reproducibility; the current statement only covers data access.
5.
HIGHother
Verify the status of the reference not found in registry (DOI 10.7910/DVN/TNHS14) and ensure it is correctly cited or replace it if it is not accessible.
A reference that cannot be located in a registry is a potential fabrication signal; the authors should confirm its existence.
6.
HIGHstatistics
Clarify the statistical software package and version used for the primary and secondary analyses (e.g., STATA version) in the Methods, Statistical analysis section.
The software is named but the version is not stated, which is a minor but easily fixable reporting gap.
7.
HIGHreporting
Add an explicit CONSORT checklist reference or state that the CONSORT checklist is followed, rather than only a generic 'Reporting Summary' link.
Explicit adherence to a reporting guideline increases transparency and reader confidence.
8.
MEDIUMcopyedit
Fix typographical errors: 'that ism' → 'that is' (Methods, CHMI); 'P. falciparu m' → 'P. falciparum' (Methods, CHMI); stray period in 'ID. inoculation' (Abstract); 'Sstatistical analysis plan' → 'Statistical analysis plan' (Supplementary Information).
These minor errors distract from the scientific content and should be corrected for clarity.
9.
MEDIUMother
Correct the rounding error: change '12/37 (32.0%)' to '12/37 (32.4%)' in Results, Safety.
Consistency in numerical reporting is a basic expectation.
10.
MEDIUMother
Rephrase the sentence in Results, Safety that conflates fever and headache: 'Fever was a more common general adverse event at the final vaccination for ME-TRAP with 5/24 (20.8%) and 8/24 (33.3%) experiencing headache' to clarify the two events.
The current wording is ambiguous about which event is more common.
11.
MEDIUMcopyedit
Fix the garbled confidence interval in Extended Data Fig. 2 caption: 'compared with 127 sfu (95%CI 174 sfu (95%CI 74-409)' should read 'compared with 127 sfu (95% CI 74–409)'.
The caption is unintelligible and must be corrected for accurate interpretation.
12.
LOWreporting
Clarify whether 37 volunteers were enrolled in CHMI or 37 completed CHMI, to resolve the ambiguity between the Abstract and Methods.
Consistency in participant flow reporting improves clarity.

Full text (55,132 chars)Analyzed: Aug 10, 2026

RigorReviewer 1

RigorReviewer 2

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

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.”

How stars are deducted

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.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

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.

Malaria vaccine protection against intradermal or venous parasites: a randomized phase 2b human challenge trial.

DOI

10.1038/s41591-025-04107-6

Record issued

2026-08-10

Engine

7.29.0

Exported

2026-09-22