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Kaimen Rigor review

Anti-sporozoite monoclonal antibody for malaria prevention: secondary efficacy outcome of a phase 2 randomized trial.

Skinner J, Kayentao K, Ongoiba A, Healy SA, Hu Z, Preston AC, Niangaly A, Schwabl P, Cisse H, Doumbo S, Doumtabe D, Traore A, Li S, Peterson ME, Seilie AM, Chavtur C, Staubus W, Chang M, Kelley K, Traore H, Djiguiba A, Keita M, Ouattara A, Doucoure M, Keita M, Diarra D, Sylla M, Diakite D, Konate M, Traore S, Zéguimé A, Dolo A, Neafsey DE, Murphy SC, Traore B, Seder RA, Crompton PD

DOI: 10.1038/s41591-025-03739-y
Record issued: 2026-08-15
Engine: 7.39.0
Exported: 2026-09-21

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/2fa17cb7-5f5c-4bc3-a043-1c5ee7b00ec6 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

3 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ReportingData & code availability partially met−0.25★
CitationsUnresolved reference−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on detection of P. falciparum infection by 18S qRT-PCR, a molecular biomarker for parasitemia, not a hard clinical outcome. Although the assay is more sensitive than thick blood smear, it is still a surrogate for clinical disease. The paper does not provide evidence linking 18S qRT-PCR-detected infection to clinical outcomes such as symptomatic malaria or severe disease, nor does it demonstrate target engagement at the tested doses beyond the antibody's known mechanism.
“the prespecified secondary efficacy endpoint that used a Plasmodium 18S rRNA quantitative reverse transcription–PCR (qRT–PCR) assay that is ~2,000-fold more sensitive than TBS”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 105AvailabilityBroken references and links 06Copyedit3 minor suggestions

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 and well-reported phase 2 randomized controlled trial with a strong scientific premise, rigorous design, and transparent reporting. The main weakness is the vague data availability statement, which lacks a concrete access mechanism, and minor reporting gaps such as not explicitly naming the CONSORT guideline and not reporting exact p-values.

Both reviewers classified the study as interventional, and this synthesis adopts that classification. The evaluation covered the full text, including methods, results, and supplementary information. Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification recomputed only 4 tests (all consistent); the remaining statistics were not machine-verified and should not be assumed correct.

Numerical inconsistencies

1 finding · worst low

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.

Internal contradictions in the reported numbersAssessed

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

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

CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1
Efficacy of 40 mg/kg vs placebo: HR = 0.126 (since efficacy = 87.4%), 95% CI 0.077-0.205. Recompute p from CI.
“At 6 months, efficacy of CIS43LS against qRT–PCR-detected infection assessed in a time-to-event analysis was 87.4% for 40 mg kg −1 (adjusted 95% confidence interval (CI), 79.5–92.3; P < 0.001)”
Find in source
Taken as given: The efficacy is 1 - HR, so HR = 0.126.; The CI is for the HR, derived from the efficacy CI (79.5-92.3) by 1 - CI.; The p-value is from a two-sided Wald test on the log HR.
Method: Used pCI with log=1 for a hazard ratio, assuming the CI is for the HR.
How we recomputed it: pCI(0.126, 0.077, 0.205, 1)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1
Efficacy of 10 mg/kg vs placebo: HR = 0.23, 95% CI 0.16-0.35. Recompute p from CI.
“At 6 months, efficacy of CIS43LS against qRT–PCR-detected infection assessed in a time-to-event analysis was 87.4% for 40 mg kg −1 (adjusted 95% confidence interval (CI), 79.5–92.3; P < 0.001) and 77.0% for 10 mg kg −1 (adjusted 95% CI, 65.0–84.0; P < 0.001) versus placebo.”
Find in source
Taken as given: The efficacy is 1 - HR, so HR = 0.23.; The CI is for the HR, derived from the efficacy CI (65.0-84.0) by 1 - CI.; The p-value is from a two-sided Wald test on the log HR.
Method: Used pCI with log=1 for a hazard ratio.
How we recomputed it: pCI(0.23, 0.16, 0.35, 1)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 2
Check the reported p-value for the 18S qRT-PCR efficacy of 10 mg/kg vs placebo (P < 0.001) using the reported HR and CI.
“At 6 months, the 18S qRT–PCR-defined efficacy of 10 mg kg−1 of CIS43LS compared with placebo was 77.0% (adjusted 95% CI, 65.0–84.0%; P < 0.001)”
Find in source
Taken as given: The efficacy is 1 - HR, so HR = 0.23.; The 95% CI for efficacy (65.0-84.0%) corresponds to a 95% CI for HR of (0.16, 0.35).; The p-value is from a two-sided Wald test from the Cox model.
Method: pCI function using the estimate (0.77) and 95% CI (0.65, 0.84) on the log scale (log=1 for HR).
How we recomputed it: pCI(0.77, 0.65, 0.84, 1)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 2
Check the reported p-value for the 18S qRT-PCR efficacy of 40 mg/kg vs placebo (P < 0.001) using the reported HR and CI.
“At 6 months, the 18S qRT–PCR-defined efficacy of 10 mg kg−1 of CIS43LS compared with placebo was 77.0% (adjusted 95% CI, 65.0–84.0%; P < 0.001) and the efficacy of 40 mg kg−1 of CIS43LS compared with placebo was 87.4% (adjusted 95% CI, 79.5–92.3%; P < 0.001)”
Find in source
Taken as given: The efficacy is 1 - HR, so HR = 0.126.; The 95% CI for efficacy (79.5-92.3%) corresponds to a 95% CI for HR of (0.077, 0.205).; The p-value is from a two-sided Wald test from the Cox model.
Method: pCI function using the estimate (0.874) and 95% CI (0.795, 0.923) on the log scale (log=1 for HR).
How we recomputed it: pCI(0.874, 0.795, 0.923, 1)

lowinternal contradiction
The abstract reports 5,015 dried blood spots analyzed, but the text also mentions 5,015 paired DBS and TBS samples. This is consistent, but the number of DBS analyzed by gametocyte qRT-PCR (838 + 204 = 1042) is not explicitly reconciled with the total.
“We analyzed 5,015 dried blood spots collected before CIS43LS or placebo administration and biweekly thereafter over a 6-month malaria season.”
AbstractFind in source
lowinternal contradiction
The paper reports that 838 DBS were qualitatively positive by 18S qRT-PCR, and 139 were low positive. The sum of low positive and quantitatively positive (838 - 139 = 699) is not explicitly stated, but the numbers are consistent with the text.
“Of the 5,015 paired DBS and TBS samples, 838 (16.7%) were qualitatively positive by 18S qRT–PCR (Fig. ) and 232 (4.6%) were positive by TBS (Fig. ). Among the DBS, 139 (2.8%) were deemed low positive by the 18S qRT–PCR”
ResultsFind in source

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

10 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

partialReviewer 1
Anti-sporozoite mAbs could be used in mass administration campaigns to reduce malaria burden and transmission.
The paper provides proof of concept but acknowledges that additional trials are needed to evaluate this strategy directly.
Evidence: The paper discusses the potential and limitations, but no direct trial of mass administration is presented.
“This study provides evidence to support the development of anti-sporozoite mAbs as a strategy to reduce the burden of malaria disease while simultaneously decreasing transmission to accelerate malaria elimination.”
DiscussionFind in source
partialReviewer 2
CIS43LS provides sterile protection (complete prevention of infection).
The high efficacy (87.4% and 77.0%) indicates near-sterile protection for most participants, but the term 'sterile' implies 100% prevention, which was not achieved in all participants. The paper acknowledges this by reporting efficacy rates rather than 100% protection.
Evidence: Results: Efficacy of 87.4% and 77.0% against qRT-PCR-detected infection, not 100%.
“These data indicate that a single dose of anti-sporozoite monoclonal antibodies can achieve durable, sterile protection against P. falciparum infection”
AbstractFind in source
supportedReviewer 1
A single dose of CIS43LS can achieve durable, sterile protection against P. falciparum infection.
The claim is supported by the primary efficacy results showing high efficacy against qRT-PCR-detected infection, which indicates sterile protection (no blood-stage infection).
Evidence: Efficacy of 87.4% (40 mg/kg) and 77.0% (10 mg/kg) against 18S qRT-PCR-detected infection at 6 months.
“These data indicate that a single dose of anti-sporozoite monoclonal antibodies can achieve durable, sterile protection against P. falciparum infection”
AbstractFind in source
supportedReviewer 1
CIS43LS reduces the risk of gametocytemia, potentially reducing transmission.
The post hoc analysis shows significant efficacy against gametocytemia, supporting the claim.
Evidence: Efficacy against gametocytemia of 87.7% (40 mg/kg) and 73.0% (10 mg/kg) at 6 months.
“A post hoc analysis with a gametocyte mRNA-specific qRT–PCR assay showed 6-month efficacy against gametocytemia of 87.7% for 40 mg kg −1 (adjusted 95% CI, 75.6–93.8; P < 0.001) and 73.0% for 10 mg kg −1 (adjusted 95% CI, 54.0–84.0; P < 0.001), versus placebo.”
AbstractFind in source
supportedReviewer 1
The 18S qRT-PCR assay is ~2,000-fold more sensitive than TBS.
The LoD of 20 parasites/ml vs 40,000 parasites/ml for TBS supports the claim.
Evidence: LoD of 18S qRT-PCR is 20 parasites/ml; LoD of TBS is 40,000 parasites/ml.
“a highly sensitive Plasmodium 18S rRNA quantitative reverse transcription–PCR (18S qRT–PCR) assay that detects asexual blood-stage parasites as well as gametocytes with a LoD of ~20 parasites per milliliter of blood”
IntroductionFind in source
supportedReviewer 1
CIS43LS efficacy against infection is similar to TBS-defined efficacy previously reported.
The paper states the qRT-PCR efficacy is similar to the TBS-defined efficacy, and the numbers are consistent.
Evidence: Previously reported TBS efficacy was 88.2% and 75.0% for 40 and 10 mg/kg, respectively; current qRT-PCR efficacy is 87.4% and 77.0%.
This is similar to the TBS-defined efficacy that was previously reported for this trial.
Discussionreviewer’s wording
supportedReviewer 2
A single dose of anti-sporozoite monoclonal antibodies can achieve durable, sterile protection against P. falciparum infection.
The claim is supported by the primary analysis showing 87.4% and 77.0% efficacy against qRT-PCR-detected infection over 6 months, with narrow confidence intervals and highly significant p-values.
Evidence: Results: 18S qRT-PCR-defined efficacy of 87.4% (95% CI 79.5-92.3) for 40 mg/kg and 77.0% (95% CI 65.0-84.0) for 10 mg/kg vs placebo, both P < 0.001.
“These data indicate that a single dose of anti-sporozoite monoclonal antibodies can achieve durable, sterile protection against P. falciparum infection, underscoring their potential to reduce malaria disease burden and transmission.”
AbstractFind in source
supportedReviewer 2
CIS43LS reduces the risk of gametocytemia by preventing liver-stage infection.
The post hoc analysis shows 87.7% and 73.0% efficacy against gametocytemia, consistent with the hypothesis that preventing liver-stage infection reduces subsequent gametocytemia.
Evidence: Results: Gametocytemia efficacy of 87.7% (95% CI 75.6-93.8) for 40 mg/kg and 73.0% (95% CI 54.0-84.0) for 10 mg/kg vs placebo, both P < 0.001.
A post hoc analysis with a gametocyte mRNA-specific qRT–PCR assay showed 6-month efficacy against gametocytemia of 87.7% for 40 mg kg−1 (adjusted 95% CI, 75.6–93.8; P < 0.001) and 73.0% for 10 mg kg−1 (adjusted 95% CI, 54.0–84.0; P < 0.001), versus placebo.
Abstractreviewer’s wording
supportedReviewer 2
The 18S qRT-PCR assay is ~2,000-fold more sensitive than TBS microscopy.
The paper provides the LoD for both assays (20 parasites/ml for qRT-PCR vs 40,000 parasites/ml for TBS), which is a 2,000-fold difference, and demonstrates that qRT-PCR detects many more infections.
Evidence: Results: LoD of 20 parasites/ml for qRT-PCR vs 40,000 parasites/ml for TBS; 838 (16.7%) samples positive by qRT-PCR vs 232 (4.6%) by TBS.
The LoD for the Plasmodium 18S qRT–PCR assay is 20 parasites ml−1 (1.3 log10 parasites ml−1) and the limit of quantification (LoQ) is 100 parasites ml−1 (2.0 log10 parasites ml−1). For this study, the stated LoD and LoQ of TBS is 40,000 parasites ml−1 (4.6 log10 parasites ml−1).
Resultsreviewer’s wording
supportedReviewer 2
The efficacy of CIS43LS is similar to that previously reported using TBS.
The paper states that the qRT-PCR-defined efficacy is similar to the TBS-defined efficacy previously reported (88.2% and 75.0%), which is consistent with the data presented.
Evidence: Discussion: 'This is similar to the TBS-defined efficacy that was previously reported for this trial.'
This is similar to the TBS-defined efficacy that was previously reported for this trial.
Discussion ¶1reviewer’s wording

Premise concern: surrogate not validated for clinical benefit.

INADEQUATESurrogate endpoint
The primary efficacy claim is based on detection of P. falciparum infection by 18S qRT-PCR, a molecular biomarker for parasitemia, not a hard clinical outcome. Although the assay is more sensitive than thick blood smear, it is still a surrogate for clinical disease. The paper does not provide evidence linking 18S qRT-PCR-detected infection to clinical outcomes such as symptomatic malaria or severe disease, nor does it demonstrate target engagement at the tested doses beyond the antibody's known mechanism.
“the prespecified secondary efficacy endpoint that used a Plasmodium 18S rRNA quantitative reverse transcription–PCR (qRT–PCR) assay that is ~2,000-fold more sensitive than TBS”
Find in source
ADEQUATEEffect size
The reported efficacy is high (77.0% and 87.4% reduction in infection risk) and statistically significant with narrow confidence intervals. The effect is anchored to a meaningful reduction in infection, which is a prerequisite for preventing clinical disease and transmission. The magnitude is large and clinically relevant.
“efficacy of CIS43LS against qRT–PCR-detected infection assessed in a time-to-event analysis was 87.4% for 40 mg kg −1 (adjusted 95% confidence interval (CI), 79.5–92.3; P < 0.001) and 77.0% for 10 mg kg −1 (adjusted 95% CI, 65.0–84.0; P < 0.001) versus placebo”
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

1 finding · worst medium

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.

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

The introduction cites prior research on malaria epidemiology, the limitations of current vaccines (RTS,S/AS01, R21/Matrix-M) and the need for tools that block sporozoite infection. It acknowledges the poor sensitivity of thick blood smear (TBS) as a limitation of prior trials and explains how the current study addresses this by using a more sensitive qRT-PCR assay. The rationale linking the premise to the study objectives is logical and well-supported.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a strong scientific premise by citing prior work on malaria burden, sporozoite biology, and the limitations of TBS-based efficacy assessment, and clearly justifies the need for a more sensitive endpoint.

Evidence

paraphrase[Introduction, paragraph 2]

“In phase 3 trials of RTS,S/AS01 and R21/Matrix-M, the primary efficacy endpoint was symptomatic blood-stage infection, as detected by microscopic examination of thick blood smears (TBS).”

paraphrase[Introduction, paragraph 3]

“Although TBS examination is historically the standard diagnostic assay to assess efficacy in trials of malaria vaccines and drugs in endemic areas, TBS has poor analytical sensitivity, with a limit of detection (LoD) of ~40,000 parasites per milliliter of blood.”

paraphrase[Introduction, paragraph 2]

“Because blood-stage infections can be asymptomatic, the efficacy of RTS,S/AS01 and R21/Matrix-M in preventing infection in these trials is uncertain.”

PASSReviewer 2· 95% conf

The paper clearly establishes the scientific premise by citing prior work on malaria burden, the need for new interventions, and the rationale for targeting sporozoites with CIS43LS.

Evidence

paraphrase[Introduction, paragraphs 1-3]

“The mosquito-transmitted parasite Plasmodium falciparum causes more than 200 million cases of malaria each year, resulting in approximately 600,000 deaths, mostly among children in Africa.”

paraphrase[Introduction, paragraph 4]

“Here, we present the results of a prespecified analysis of this trial in which the secondary efficacy endpoint was P. falciparum infection detected by a highly sensitive Plasmodium 18S rRNA quantitative reverse transcription–PCR (18S qRT–PCR) assay that detects asexual blood-stage parasites as well as gametocytes with a LoD of ~20 parasites per milliliter of blood.”

Randomization method (block randomization with varying block size) and unit (individual participant) are stated. Blinding is described for participants, trial team, and laboratory personnel. The modified intention-to-treat population is defined. Inclusion/exclusion criteria are referenced to the protocol. The analysis population and missing-data approach (mITT) are defined, satisfying outlier_handling. Controls (placebo arm) are appropriate. Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

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· 95% conf

The trial design is rigorous: randomized, double-blind, placebo-controlled, with block randomization, blinding of participants and assessors, and a prespecified secondary endpoint analysis.

Evidence

“Block randomization was used with block size varying from six to nine.”

MethodsFind in source

“Trial participants and trial team members were also unaware of the trial-group assignments.”

MethodsFind in source

“The analysis used the modified intention-to-treat dataset, which included all randomized participants who received the study agent and were analyzed according to the randomized assignment.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The study design is rigorous: a double-blind, randomized, placebo-controlled trial with prespecified endpoints, appropriate blinding, and a clear analysis plan.

Evidence

“Block randomization was used with block size varying from six to nine.”

Methods ¶3Find in source

“Trial participants and trial team members were also unaware of the trial-group assignments.”

Methods ¶3Find in source

“The laboratory that performed the Gen3.5DBS Plasmodium 18S qRT–PCR was blinded to the trial-group assignments.”

MethodsFind in source

Table 1 reports age (mean, median, range), sex (male/female percentages), ethnicity, weight, and other baseline characteristics. Both sexes are included (57% male, 43% female), so sex_justified is not applicable. Age and weight are reported with means and standard deviations. Demographics include ethnicity and study site. The study population is healthy adults, and health status is implied by inclusion criteria.

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· 90% conf

Biological variables are well reported: sex, age, weight, and demographics are provided in Table 1, and the study population is described.

Evidence

“The study population consisted of healthy men (57%) and nonpregnant women (43%) with a median age of 35 years (range 18–54 years).”

ResultsFind in source

“Table 1 Baseline characteristics of study participants”

Table 1Find in source

PASSReviewer 2· 95% conf

Key biological variables (sex, age, weight, demographics) are reported in Table 1 and are well-characterized.

Evidence

“Sex | Male | 59 (53.6) | 63 (57.3) | 66 (60) | | Female | 51 (46.4) | 47 (42.7) | 44 (40)”

Table 1Find in source

“Age (years) | Mean (s.d.) | 33.8 (9.3) | 34.4 (9.7) | 34.1 (9.7) | | Median | 34 | 35 | 35 | | Minimum, maximum | 18, 54 | 18, 53 | 18, 53”

Table 1Find in source

“Ethnicity | Bambara | 107 (97.3) | 103 (93.6) | 107 (97.3)”

Table 1Find in source

The paper names the ethics committee (Faculté de Médecine et d’Odonto-Stomatologie and Faculté de Pharmacie at the University of Sciences, Techniques and Technologies of Bamako) and national regulatory authorities. Written informed consent is explicitly stated. Compliance with ICH-GCP and applicable regulations is stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are clearly documented: named ethics committees approved the protocol, written informed consent was obtained, and regulatory compliance is stated.

Evidence

“The protocol and informed consent forms were approved by the ethics committee at Faculté de Médecine et d’Odonto-Stomatologie and Faculté de Pharmacie at the University of Sciences, Techniques and Technologies of Bamako and by the national regulatory authorities of Mali.”

MethodsFind in source

“all participants provided written informed consent.”

MethodsFind in source

“The trial was conducted in accordance with International Council for Harmonisation Good Clinical Practice guidelines and applicable regulations in Mali.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are clearly reported: a named ethics committee approved the protocol, written informed consent was obtained, and regulatory compliance is stated.

Evidence

Methods ¶4Find in source

paraphrase[Methods, paragraph 4]

“Community permission was obtained from participating sites, and all participants provided written informed consent.”

“The trial was conducted in accordance with International Council for Harmonisation Good Clinical Practice guidelines and applicable regulations in Mali.”

Methods ¶4Find in source

CIS43LS is described as a human IgG1 mAb derived from a Chinese hamster ovary DG44 cell line, manufactured by the Vaccine Clinical Materials Program, and vialed at 100 mg/ml. The qRT-PCR reagents and primers are specified. Software tools (JMP v.16.2.0, RStudio v.2024.04.1, R packages 'icenReg' v.2.0.16, 'bpcp' v.1.4.2) are identified. No antibodies, cell lines (beyond the manufacturing cell line, which is not used in the trial itself), or organisms are used as reagents in the trial, so those sub-criteria are not applicable.

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· 90% conf

The investigational product (CIS43LS) is identified with source and formulation, and the software tools used for analysis are named with versions.

Evidence

paraphrase[Methods, Trial product]

“CIS43LS is a human IgG1 mAb derived from a Chinese hamster ovary DG44 stably transfected clonal cell line. It was manufactured according to Current Good Manufacturing Practice requirements by the Vaccine Clinical Materials Program (operated under contract with Leidos Biomedical Research) and vialed in a buffered formulation at a concentration of 100 mg ml −1 .”

“Analyses were performed with JMP v.16.2.0 and RStudio v.2024.04.1, and the R packages ‘icenReg’ (v.2.0.16) and ‘bpcp’ (v.1.4.2) were used for time-to-event and proportional analysis, respectively.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The investigational product (CIS43LS) is identified with source and formulation, and software tools are identified with versions. Other resources (antibodies, cell lines, organisms) are not applicable.

Evidence

paraphrase[Methods, 'Trial product']

Statistical analysisFind in source

“The qRT–PCR primers and probes targeted the P. falciparum 18S rRNA (forward, PfDDT1451F21: 5′-GCGAGTACACTATATTCTTAT-3′; reverse, PfDDT1562R21: 5′-ATTATTAGTAGAACAGGGAAA-3′; probe, 5′-[6-FAM]-ATTTATTCAGTAATCAAATTAGGAT-3′ [Black Hole Quencher 1 PLUS]; LGC BioSearch Technologies)”

MethodsFind in source

The primary analysis uses a Cox proportional hazards model with interval censoring. Schoenfeld residuals are reported to verify the proportional hazards assumption. Exact p-values (e.g., P < 0.001) and adjusted 95% CIs are reported. Effect sizes (efficacy percentages) are reported with CIs. The statistical software is identified. Data presentation includes Kaplan-Meier curves with CIs and per-group n. The analysis is appropriate for a time-to-event endpoint.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are well described: tests are named, effect sizes with CIs are reported, software is identified, and data presentation follows clinical trial norms.

Evidence

“Time-to-event efficacy was calculated as Efficacy (%) = (1 − HR) × 100, in which HR is the hazard ratio of infection in each CIS43LS arm versus the placebo arm, estimated from the Cox proportional hazards model that accounts for interval censoring.”

Statistical analysisFind in source

“Schoenfeld residuals indicated no violation of the proportional hazards assumption.”

ResultsFind in source

“At 6 months, efficacy of CIS43LS against qRT–PCR-detected infection assessed in a time-to-event analysis was 87.4% for 40 mg kg −1 (adjusted 95% confidence interval (CI), 79.5–92.3; P < 0.001)”

AbstractFind in source

PASSReviewer 2· 95% conf

Statistical methods are appropriate and well-described: Cox proportional hazards models with interval censoring, Schoenfeld residuals, exact p-values, and adjusted CIs are reported. Software is identified.

Evidence

Statistical analysisFind in source

“Schoenfeld residuals indicated no violation of the proportional hazards assumption.”

Results ¶3Find in source

paraphrase[Results, paragraph 3]

“At 6 months, the 18S qRT–PCR-defined efficacy of 10 mg kg−1 of CIS43LS compared with placebo was 77.0% (adjusted 95% CI, 65.0–84.0%; P < 0.001) and the efficacy of 40 mg kg−1 of CIS43LS compared with placebo was 87.4% (adjusted 95% CI, 79.5–92.3%; P < 0.001)”

The data availability statement says requests can be submitted to the corresponding author and will be responded to within 2 weeks, but it does not specify a managed-access platform or data-access committee. This is considered 'reported_but_inadequate' per the tiered grading. No custom code repository is provided. The trial registration number is provided, and supporting clinical documents are available as supplementary information.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

A data availability statement exists but is vague, offering data 'on reasonable request' without a clear mechanism or platform, which is inadequate for a clinical trial.

Evidence

“Requests for access to the individual deidentified trial participant dataset (including data dictionaries) can be submitted to corresponding author P.D.C. Upon reasonable request, the corresponding author will respond within 2 weeks.”

Data availabilityFind in source

“In addition, reported results from this trial are publicly available at https://clinicaltrials.gov/study/NCT04329104?intr=cis43ls&rank=1 .”

Data availabilityFind in source

WARNReviewer 2· 90% conf

A data availability statement is present but is vague ('available on reasonable request' without a platform or timeframe), and no code is shared. The trial is registered on ClinicalTrials.gov.

Evidence

Data availabilityFind in source

absence[Data availability section]

No code repository is mentioned.

“ClinicalTrials.gov identifier: NCT04329104 (https://clinicaltrials.gov/study/NCT04329104)”

AbstractFind in source

Methods are comprehensive, including detailed descriptions of the trial design, randomization, blinding, laboratory assays, and statistical analysis. The trial is registered (NCT04329104). A reporting summary is linked. All outcomes (primary and secondary) are reported, including negative/null results (e.g., the post hoc analysis showing no significant sex difference for the 40 mg/kg dose). Limitations are explicitly discussed (e.g., post hoc decision on day 21 start, IV route, lack of direct transmission assessment). Conclusions are proportional to the evidence. Funding sources and competing interests are disclosed.

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

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

Evidence

“ClinicalTrials.gov identifier: NCT04329104”

AbstractFind in source

“This study has several limitations. First, it was not designed to directly assess the efficacy of combining anti-sporozoite mAbs with antimalarial drugs to reduce transmission, and additional trials are needed to evaluate this strategy.”

Discussion ¶7Find in source

“This study was supported by the Division of Intramural Research and the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This work was also supported by the Bill and Melinda Gates Foundation (grant nos. INV-052365 to D.E.N. and INV-061041 to S.C.M.).”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

The paper is well-reported: methods are detailed, the trial is registered, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT04329104 (https://clinicaltrials.gov/study/NCT04329104)”

AbstractFind in source

paraphrase[Discussion, paragraph 5]

“This study has several limitations. First, it was not designed to directly assess the efficacy of combining anti-sporozoite mAbs with antimalarial drugs to reduce transmission...”

“This study was supported by the Division of Intramural Research and the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.”

AcknowledgementsFind in source

Registered (4 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

ClinicalTrials.gov

ClinicalTrials.gov

ClinicalTrials.gov

ClinicalTrials.gov

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 55 references by DOI: 49 verified — 1 DOI unresolved, 5 no DOI (shown, not verified).

UNRESOLVED10.5281/zenodo.13772087
cggh/scikit-allel: v1.3.13
Cited DOI does not resolve to any Crossref record.
NO DOI
World Malaria Report 2024
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Malaria vaccines: WHO position paper
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT)
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
stringr: simple, consistent wrappers for common string operations
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

3 data/code links checked; 3 live.

datahttps://clinicaltrials.gov/study/NCT04329104?intr=cis43ls&rank=1LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttps://clinicaltrials.gov/study/NCT04329104LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
codeGitHubLIVEHTTP 200
https://github.com/broadinstitute/malaria-amplicon-pipeline.git
Resolves to GitHub (code repository).

Copyediting

3 minor

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

No major wording or formatting errors. 3 minor suggestions below.

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

MINORconsistencyAbstract
“P < 0.001”
→ Consider reporting exact p-values (e.g., P = 0.001) for precision, though thresholds are acceptable.
The paper consistently uses P < 0.001, which is common but less precise.
MINORclarityData availability
“Requests for access to the individual deidentified trial participant dataset (including data dictionaries) can be submitted to corresponding author P.D.C. Upon reasonable request, the corresponding author will respond within 2 weeks.”
→ Clarify the access mechanism (e.g., data access committee) and conditions.
The statement is vague and could be improved for transparency.
MINORtypoAbstract
“CIS43LS is a long-acting monoclonal antibody specific for the Plasmodium falciparum circumsporozoite protein expressed on sporozoites.”
→ No change needed; this is correct.
No significant copyediting issues found.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is methodologically robust and the reported findings are credible, but an informed reader should weigh the vague data-sharing statement and the lack of a formal power analysis for the secondary endpoint. No erratum is warranted for the core results, but the authors should consider clarifying data access and reporting exact p-values in any correction or follow-up.

1.
HIGHdata code
In the Data availability section, specify a concrete data-access mechanism (e.g., a data-access committee or a platform like Vivli) and the conditions for access, rather than a vague 'on reasonable request' statement.
A vague data-sharing statement is inadequate for a clinical trial and undermines reproducibility.
2.
HIGHdata code
Share custom analysis code in a public repository (e.g., GitHub, Zenodo) with a persistent identifier to enable reproducibility.
No code is currently shared, which limits the ability of others to reproduce the analyses.
3.
HIGHstatistics
Report a formal power analysis for the secondary endpoint (18S qRT-PCR) to justify the sample size for this analysis.
The secondary endpoint analysis lacks an explicit power justification, which is a common reviewer concern.
4.
MEDIUMreporting
In the Methods or Reporting summary, explicitly state adherence to the CONSORT reporting guideline and provide the checklist.
The CONSORT diagram is present but the guideline is not explicitly named, which is a minor reporting gap.
5.
MEDIUMstatistics
In the Statistical analysis section, consider reporting exact p-values (e.g., P = 0.001) instead of only thresholds (P < 0.001) to improve precision.
Threshold-only p-values are less informative and were flagged by both reviewers and the copyedit pass.
6.
MEDIUMdata code
Clarify whether the deidentified dataset can be deposited in a repository or if managed access is the only route.
Clarifying the data access route improves transparency and aligns with modern data-sharing standards.
7.
MEDIUMreporting
Provide a more detailed description of the randomization sequence generation and allocation concealment mechanism (e.g., sealed envelopes, central randomization).
The current description is brief and could be strengthened for full reproducibility.
8.
MEDIUMstatistics
Report the exact p-values for all comparisons, including non-significant ones, rather than just thresholds like 'P < 0.001'.
Exact p-values allow readers to assess the strength of evidence more precisely.
9.
MEDIUMstatistics
Include a statement on whether the proportional hazards assumption was tested for the gametocytemia analysis.
The assumption was tested for the primary analysis but not explicitly for the gametocytemia analysis.
10.
MEDIUMreporting
Add a CONSORT flow diagram for the secondary analysis population (e.g., number of DBS samples analyzed per arm).
A flow diagram for the secondary analysis would improve transparency about the sample analyzed.
11.
MEDIUMreporting
Clarify whether the 18S qRT-PCR assay was performed on all DBS samples or only a subset, and describe the testing algorithm more clearly.
The testing algorithm is not fully clear, which could affect interpretation of the results.
12.
LOWother
Provide the RRID or catalog number for the CIS43LS antibody to facilitate identification.
A persistent identifier for the antibody would improve resource identification.
13.
LOWreporting
In the Methods, provide a brief justification for the sample size (power analysis) or reference the primary trial publication where it is described.
A sample size justification is expected for a clinical trial, even if it was reported in the primary publication.
14.
LOWdata code
Consider depositing de-identified individual participant data in a controlled-access repository (e.g., ClinicalStudyDataRequest) to meet modern data-sharing standards.
Depositing data in a recognized repository would strengthen the data-sharing statement.

Full text (64,411 chars)Analyzed: Aug 15, 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.

Anti-sporozoite monoclonal antibody for malaria prevention: secondary efficacy outcome of a phase 2 randomized trial.

DOI

10.1038/s41591-025-03739-y

Record issued

2026-08-15

Engine

7.39.0

Exported

2026-09-21