A Challenge Study to Assess the Safety, Immunogenicity and Efficacy of a Malaria Vaccine Candidate: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Challenge Study to Assess the Safety, Immunogenicity and Efficacy of a Malaria Vaccine Candidate (NCT02927145), a non-randomized phase 1, phase 2 study. The primary outcome is Efficacy of the RH5.1/AS01 Vaccine by Demonstrating a Reduced PMR in Vaccinated Subjects Compared to Infectivity Controls Against 3D7 Clone Parasites in a CHMI Model..

2. Clinical Question

3. Trial Design

This was a completed, open-label, multi-centre Phase I/IIa trial of the blood-stage malaria vaccine candidate RH5.1/AS01. It used a parallel-group model with non-randomized allocation and no masking. The registry lists enrollment of 88 participants. The study started on 2016-10-17 and had primary completion on 2019-06-27. The sponsor was the University of Oxford.

The Phase Ia stage evaluated safety and immunogenicity across dose levels and regimens. Group 1 was described as receiving three doses of 2µg RH5.1/0.5mL AS01 four weeks apart. Group 2 used 10µg RH5.1/0.5mL AS01. The descriptions also refer to 50µg regimens in Groups 3 and 4, with the intended assessment including a delayed fractional dose; some details of the Group 3 description are incomplete in the registry. The number recruited into Groups 1 and 2 was to depend on immunogenicity, and the record says recruitment could proceed to 12 volunteers in each group if the doses were immunogenic.

In Phase IIa, Group 5 received the 10µg regimen selected following review of safety and exploratory immunology from earlier groups. Groups 5 and 6 were to be recruited after at least 6 Group 4 volunteers completed vaccination. Group 6 served as infectivity controls. Group 7 comprised Group 5 volunteers who received a fourth dose, while Groups 8 and 9 are described as infectivity controls. The record identifies Group 5 versus Group 6 and Group 7 versus Group 9 for the efficacy comparisons. The staged recruitment and non-randomized allocation matter when interpreting any between-group outcome: differences could reflect more than vaccination alone.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Group 5 and 6 volunteers were invited to join the re-challenge study and formed Groups 7 and 8

Only the first 6 of 9 groups are shown.

Initial Recruitment

Reasons for not completing this period:

Invitation for Additional Challenge

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Group 5 vs Group 6 and Group 7 vs Group 9 compared as vaccinees versus primary infectivity controls

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Efficacy of the RH5.1/AS01 Vaccine by Demonstrating a Reduced PMR in Vaccinated Subjects Compared to Infectivity Controls Against 3D7 Clone Parasites in a CHMI Model., measured over Measured during CHMI.

The primary efficacy endpoint was PCR-derived parasite multiplication rate (PMR), measured during CHMI. PMR describes the rate at which parasites multiply over the measurement period; the registry specifies a mean as the summary parameter and standard deviation as the measure of dispersion. The planned comparison concerned vaccinated volunteers and infectivity controls challenged against 3D7 clone parasites.

In general, a continuous endpoint such as PMR can retain information about the magnitude of each participant’s measurement, rather than reducing outcomes to a yes-or-no event. Comparing group means can therefore address whether the average measured multiplication rate differs between groups. The standard deviation describes how spread out participant values are around their group mean. It is distinct from the uncertainty around the estimated mean difference, which would ordinarily be conveyed by a confidence interval.

The registry states that the Group 5 versus Group 6 comparison constituted the primary efficacy analysis, and also identifies Group 7 versus Group 9 as a vaccinee-versus-control comparison. It does not report the PMR observations, group means, standard deviations, estimated contrasts, confidence intervals or p-values. Consequently, the endpoint’s intended role is clear, but the registry record does not establish the direction, size or precision of an observed efficacy difference.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a continuous primary endpoint summarized by a mean and standard deviation. That identifies the type of outcome and the intended descriptive summaries, but it does not specify the full statistical procedure used to compare groups. The registry record does not report a test, model, covariate adjustment, confidence interval method or analysis plan for the efficacy comparison.

What does a mean represent?

In general, the mean is the arithmetic average of observed measurements in a group. For PMR, it would summarize the group’s central measured multiplication rate. It does not show how every participant’s value was distributed, and the same mean can arise from different patterns of individual observations. The standard deviation describes the spread of measurements around the mean; it is not a measure of uncertainty in the mean itself. The registry does not post the group means or standard deviations for this endpoint.

How would a group contrast be interpreted?

In general, an estimated difference between group means expresses the size and direction of the contrast on the endpoint’s measurement scale. A confidence interval gives a range of values compatible with the data and statistical procedure, and conveys precision as well as direction. A narrower interval indicates greater precision than a wider interval, all else being equal. A p-value addresses compatibility with a specified null hypothesis under the assumptions of a statistical test; it does not measure the probability that a treatment works. No estimate, confidence interval or p-value for PMR is reported in the registry record, so these interpretations cannot be applied to a trial result.

Why does allocation matter?

In general, random allocation helps balance measured and unmeasured participant characteristics between study groups on average. This trial is explicitly described as non-randomized and open-label. The groups could therefore differ for reasons other than vaccination, and knowledge of group assignment can affect aspects of study conduct or measurement. The primary outcome is described as PCR-derived, but the record does not state whether laboratory assessment was masked or whether any protections against measurement bias were used. It also does not report adjustment for baseline characteristics. A statistical model can account for specified measured factors, but cannot automatically remove bias from unmeasured differences.

What does the planning illustration mean?

The registry describes planning illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. The illustration considers effects defined as a stated fraction of the observed effect. These are planning scenarios, not observed trial outcomes or observed power. Sample-size estimates derived from them indicate the number of participants per arm for a chosen power under the stated assumptions; they do not establish that the trial had a particular probability of detecting its actual effect. No numerical planning estimates or observed PMR effect are reported in the registry record. The listed assumptions also do not constitute evidence that these were the trial’s original design assumptions; the registry explicitly characterizes the illustration as separate from the trial’s own design.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variability is greater than a statistical model assumes. If the analysis understates variability, standard errors can be too small and confidence intervals too narrow, making evidence appear more precise than it is. This is a general consideration, not a reported property of the PMR data in this trial. The registry supplies no PMR distribution, model diagnostics or analysis details that would show whether over-dispersion was assessed or relevant.

Can the analysis be reproduced from the record?

No efficacy analysis is posted, and the registry reports zero analyses. The participant-level PMR values, group-level outcome summaries, handling of missing measurements and exact analysis procedure are not reported in the registry record. Without those items, an independent recalculation or assessment of the reported statistical uncertainty is not possible. General statistical explanations do not fill those gaps or establish what analysis was actually conducted.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Group 5-Phase IIa", "Group 6-Phase IIa", "Group 7-Phase IIa", "Group 9 -Phase IIa")
n   <- c(14, 14, 8, 4)
m   <- c(8.12, 9.75, 7.62, 11.22)
sp  <- c(1.13, 2.46, 1.44, 1.92)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Group 5-Phase IIa  14  8.120  1.130  7.468  8.772
CARM  Group 6-Phase IIa  14  9.750  2.460  8.330  11.170
CARM  Group 7-Phase IIa  8  7.620  1.440  6.416  8.824
CARM  Group 9 -Phase IIa  4  11.220  1.920  8.165  14.275

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and identifies one primary efficacy endpoint for the Phase IIa stage. It also describes three secondary areas: humoral immunogenicity across doses and regimens, cellular immunogenicity across doses and regimens, and immunological readouts for association with reduced PMR. The record does not report a multiplicity strategy, such as a hierarchy of hypotheses or an adjustment across several comparisons. In general, testing multiple outcomes or comparisons can increase the chance of at least one apparently unusual result; how that concern should be handled depends on the prespecified objectives and analysis plan. Those details are not reported in the registry record.

The efficacy population description identifies Group 5 versus Group 6 and Group 7 versus Group 9 as vaccinee-versus-control comparisons. It does not define an intention-to-treat, per-protocol or other analysis population, nor state which participants would be included in each analysis or how exclusions would be handled. The record does not report missing PMR values, reasons for missingness, methods for handling missing data, or sensitivity analyses. These omissions prevent assessment of whether missing observations could affect the comparison.

The record reports zero analyses. It therefore does not provide evidence of the statistical procedures actually used for multiplicity, missing data or analysis populations. In general, these decisions can influence estimates and uncertainty, particularly when outcomes or comparisons are numerous or when missingness differs across groups. No particular method should be attributed to this trial without a report of that method.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pregnancy (11.1%), psoriasis (8.3%), tonsilectomy (5.9%).

The registry reports serious adverse events affecting 1 participant in Group 3, 1 in Group 5 and 1 in Group 7. It lists 0 serious adverse events for Groups 1, 2, 4, 6, 8 and 9. Deaths are listed as 0 in every group. These are participant counts, not event rates, and should be read alongside the group-specific numbers at risk recorded in the registry.

The record also lists participants affected by other adverse events: 9 in Group 1, 11 in Group 2, 9 in Group 3, 10 in Group 4, 14 in Group 5, 0 in Group 6, 3 in Group 7, 0 in Group 8 and 0 in Group 9. These descriptive counts do not by themselves establish whether event frequency differed between groups or whether an event was caused by vaccination. The registry does not provide a comparative statistical analysis or enough event-level detail to assess severity, timing or attribution.

Pregnancy, psoriasis and tonsilectomy are listed among the top serious terms, with percentages recorded in the registry. The record does not explain the denominator or provide enough context to interpret these terms as a comparative safety signal. Serious-event counts should not be treated as proof that a regimen is safe or unsafe.

13. What the Result Does, and Does Not, Mean

The registry record documents a trial that asked whether RH5.1/AS01 vaccination was associated with a different mean parasite multiplication rate from that in infectivity controls during a challenge model. It also documents a staged assessment of different vaccine doses and regimens, with safety and immunogenicity considered in earlier groups. These are descriptions of the study’s objectives and design, not findings about efficacy.

No primary PMR result, group summary, estimated contrast, confidence interval or p-value is reported. The posted record therefore does not establish whether the vaccinated and control groups had different PMR values, how large any difference was, or how precisely it was estimated. It also cannot support a conclusion that vaccination did or did not reduce parasite multiplication. The absence of a posted result is not evidence of no effect; it means the result cannot be assessed from the registry record.

Even a reported between-group contrast would need to be interpreted in light of non-randomized allocation and the open-label design. The comparisons may be affected by differences between groups other than vaccination. The registry does not report an adjustment approach that would address these concerns, nor the participant-level data needed to examine them.

Safety information is limited to counts by group, including serious adverse events and deaths. These counts are descriptive rather than a complete comparative safety assessment. The record does not provide the detailed timing, attribution or analysis needed to determine the relationship between events and vaccination.

The trial’s scope also matters. It enrolled healthy, malaria-naive adults aged between 18 and 45 years and assessed a specific candidate vaccine in a challenge model involving 3D7 clone parasites. The registry does not establish how results would apply beyond that population or setting. No medical decision should be inferred from this record alone.

14. Why This Trial Matters Statistically

This trial illustrates why a clearly stated primary endpoint is not enough to interpret efficacy: the endpoint definition must be accompanied by the observed data and analysis. PMR is a continuous measure summarized by a mean and standard deviation, but without those summaries or a group contrast there is no basis for evaluating the size or precision of the intended efficacy comparison.

It also highlights the distinction between a planned comparison and a randomized comparison. The registry identifies vaccinee-control contrasts, but allocation was non-randomized. Statistical interpretation must therefore account for the possibility that groups differed in other ways. A p-value or confidence interval, if reported, would quantify uncertainty under an analysis model; neither would, on its own, remove design-related confounding.

The staged dose-escalation structure raises further questions about how later cohorts and comparisons relate to earlier safety and immunology findings. The registry says the Phase IIa dose was selected following review of earlier groups, but does not report the statistical procedures used to incorporate those stages. This is an important distinction between design history and inferential evidence.

Finally, the record shows the value of registry completeness. It states the primary efficacy question, trial population, comparison groups and safety counts, but does not include an efficacy analysis, missing-data approach or multiplicity plan. Without those elements, readers can describe the intended study and some safety observations but cannot evaluate the efficacy estimate or its statistical reliability. Clear reporting of estimates, uncertainty and analysis populations is central to making a clinical trial interpretable.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most immediate limitation is that the registry record contains no primary efficacy results or posted analyses. PMR summaries, between-group estimates and measures of uncertainty are not reported, so the planned efficacy comparison cannot be evaluated. The record also does not report the statistical analysis plan, adjustment methods or analysis populations.

Non-randomized allocation limits causal interpretation because vaccinated participants and infectivity controls may differ for reasons unrelated to vaccination. The trial was open-label, and the record does not state whether outcome assessment or laboratory procedures were masked. It does not describe how potential baseline differences, missing measurements or departures from the intended regimen were handled.

The design was staged, with dose selection for Group 5 following safety and exploratory immunology findings from earlier groups. Recruitment into some groups was conditional on earlier assessments. The registry does not explain how this sequence informed the statistical analysis or whether the primary comparison was prespecified in a detailed analysis plan. Multiple outcomes and comparisons are described, but a multiplicity approach is not reported.

The registry’s group descriptions are not fully detailed: one Phase Ia description is incomplete, and the record does not give enough information to reconstruct all regimen details and analysis procedures. The sample-size planning illustration is described as separate from the trial’s own design; its numerical estimates and the original sample-size justification are not reported in the registry record.

Generalizability is also limited by the specified population of healthy, malaria-naive adults aged between 18 and 45 years and the challenge setting using 3D7 clone parasites. The record does not establish whether findings would extend to other populations or settings. These limitations qualify what can be inferred; they do not replace the missing efficacy results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Challenge Study to Assess the Safety, Immunogenicity and Efficacy of a Malaria Vaccine Candidate — NCT02927145.
• Registry record last updated 2022-02-18; status last verified 2019-08.
• Results first posted 2022-02-18.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT02927145 is a completed, non-randomized, open-label, parallel Phase I/IIa trial of RH5.1/AS01, sponsored by the University of Oxford. It enrolled 88 healthy, malaria-naive adults aged between 18 and 45 years. The study started on 2016-10-17 and had primary completion on 2019-06-27.

The Phase IIa primary efficacy endpoint was PCR-derived parasite multiplication rate during CHMI, with Group 5 versus Group 6 specified as the primary efficacy comparison and Group 7 versus Group 9 also identified as a vaccinee-control comparison. The record lists safety and immunogenicity outcomes, but reports zero analyses and no PMR results. Serious adverse-event and death counts are listed by group; they are descriptive and do not constitute a comparative efficacy or safety analysis.