A Study to Evaluate the Efficacy, Immunogenicity and Safety in a Sporozoite Challenge Model of a Fractional Booster Dose of GSK Biologicals' Candidate Malaria Vaccine Administered to Previously Vaccinated Healthy Malaria-naïve Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Efficacy, Immunogenicity and Safety in a Sporozoite Challenge Model of a Fractional Booster Dose of GSK Biologicals' Candidate Malaria Vaccine Administered to Previously Vaccinated Healthy Malaria-naïve Adults (NCT03824236), a non-randomized phase 2 study. The primary outcome is Number of Subjects Reporting Plasmodium Falciparum (P. Falciparum) Parasitemia (Defined by a Positive Blood Slide) Following Sporozoite Challenge (in All Study Groups Versus Infectivity Controls).

2. Clinical Question

3. Trial Design

This completed Phase 2 study evaluated a fractional booster dose of RTS,S/AS01E in a controlled human malaria infection model. It followed MALARIA-092, a study of vaccine schedules and formulations in healthy malaria-naïve adults. In the follow-up study, previously vaccinated participants received a fractional booster and underwent a second sporozoite challenge three to four weeks after vaccination. Newly enrolled participants did not receive an immunization in this study and underwent challenge as infectivity controls.

The registry describes a parallel, non-randomized, unmasked design. Participants were grouped according to their history in MALARIA-092: the P-Fx group had been protected after the first challenge and received a fractional booster; the NP-Fx group had not been protected and also received a fractional booster. The infectivity control group consisted of newly enrolled participants who underwent challenge without immunization in this study. The groups therefore reflect different prior histories and enrollment pathways, rather than randomized assignments to interchangeable treatments.

Total enrollment was 61. The registry lists 25 participants at risk in the P-Fx group, 24 in the NP-Fx group and 12 in the infectivity control group for the reported adverse-event summaries. These safety denominators are not necessarily the denominators for every efficacy or immunogenicity analysis. The study began on 2019-02-05, had primary completion on 2019-04-30 and is recorded as completed.

The primary outcome was the number of participants with P. falciparum parasitemia after challenge, defined by a positive blood slide. The stated follow-up period was Day 22 up to Day 50. Other outcomes included time to parasitemia, antibody concentrations and adverse events. The registry record does not report randomization, masking, a placebo comparison, or a statistical analysis plan beyond the endpoint description and analysis-population information it lists.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on Per-Protocol Set which included all subjects fulfilling eligibility criteria, who received or not the Fx dose of study vaccine according to protocol, did not report any underlying medical condition influencing the efficacy response, underwent P. falciparum challenge and had available data concerning outcome measures.

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects Reporting Plasmodium Falciparum (P. Falciparum) Parasitemia (Defined by a Positive Blood Slide) Following Sporozoite Challenge (in All Study Groups Versus Infectivity Controls), measured over During the sporozoite challenge dose follow-up period (from Day 22 up to Day 50).

The primary endpoint counts participants who developed P. falciparum parasitemia after sporozoite challenge. The registry defines parasitemia as a positive blood slide, with infection identified by detecting asexual blood-stage parasites in microscopy of Giemsa-stained thick blood films. The stated timeframe is during challenge follow-up from Day 22 up to Day 50.

A binary endpoint records whether each participant did or did not meet the defined event criterion. In a challenge model, this offers a direct way to describe the occurrence of detectable blood-stage infection after exposure. Comparing the proportions affected across groups can describe how often the endpoint occurred in the booster groups and in the infectivity controls. The registry specifies an analysis of the proportion affected, described as relative risk, but does not report the observed event counts, proportions, relative-risk estimate or uncertainty interval.

The endpoint’s interpretation depends on its operational definition and follow-up. A positive blood slide is the stated criterion; it is not a measure of every possible biological response to challenge. The registry says that participants in the proportion analysis were considered at risk of infection and that no censoring or elimination was applied for participants who did not complete the full protocol-defined post-challenge follow-up. The actual primary endpoint results and any accompanying precision estimates are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

A binary endpoint has two possible states for each participant: the event is observed, or it is not observed under the endpoint definition. Here, the event is P. falciparum parasitemia established by a positive blood slide after sporozoite challenge. The registry describes microscopy of Giemsa-stained thick blood films and defines infection as detection of asexual blood-stage parasites. The endpoint is therefore tied to a specified measurement procedure, rather than a broader, unspecified judgment of infection.

What does a count or proportion describe?

A count reports how many participants met the event definition. A proportion places that count in relation to the number of participants included in the relevant group and analysis. These are descriptive quantities: they characterize observed participants under the stated follow-up and endpoint rules. The registry record provides safety denominators, but does not report the primary endpoint counts or denominators by group. The primary proportions therefore cannot be interpreted from the registry record.

The registry describes the primary analysis as a comparison of the proportion affected, using relative risk. A relative risk compares the event proportion in one group with the event proportion in another. Its interpretation depends on which groups are compared, how the populations were defined and the observed events in each. The record states that the comparison is all study groups versus infectivity controls, but does not report the actual relative-risk estimates or the full analysis details. No relative-risk value can be inferred from the endpoint description alone.

Why does uncertainty matter?

An estimate from a study is subject to sampling variability: another group of participants from a similar setting could produce a different estimate. A confidence interval conveys the uncertainty around an estimate under a specified statistical method. A narrower interval indicates greater precision, while a wider interval indicates less precision. It does not guarantee that the true value lies in the interval, and it does not resolve design limitations such as non-random allocation. No confidence interval for the primary result is reported in the registry record.

A p-value, when reported, describes how compatible the observed data are with a specified null model, under the assumptions of the analysis. It is not the probability that a treatment works, nor does it measure the size or practical importance of an effect. The registry record does not report a primary-endpoint p-value. Without a reported estimate and its uncertainty, a significance test cannot stand in for an assessment of the magnitude and precision of the result.

What does the non-randomized design imply?

Random allocation can help balance measured and unmeasured participant characteristics across comparison groups. This study is recorded as non-randomized, and participants entered groups based on prior challenge history or newly enrolled control status. The groups may therefore differ for reasons other than receipt of a fractional booster. In particular, P-Fx and NP-Fx participants were distinguished by protection status in the earlier study, while infectivity controls had a different enrollment history. Statistical adjustment could address measured differences if planned and if the necessary information were available, but the registry record does not report an adjustment strategy.

The design is also unmasked. That describes the absence of masking in the registry record; it does not establish how outcome assessment was conducted in practice beyond the stated microscopy method. The record does not report whether blood-slide readers were masked or whether any other procedures were used to reduce assessment bias. This distinction matters because a clear endpoint definition and a measurement procedure do not, by themselves, establish that all possible assessment biases were prevented.

How should follow-up be understood?

The primary endpoint timeframe is during post-challenge follow-up from Day 22 up to Day 50. The registry states that all participants included in the proportion analysis were considered at risk of infection, with no censoring or elimination for participants who did not complete the full protocol-defined follow-up through Day 50, described as 28 days post challenge. This means the specified proportion analysis did not remove such participants on that basis. The record does not give the number affected by incomplete follow-up or report additional missing-data rules.

Time to onset of parasitemia is a separate secondary outcome. Time-to-event analyses use information about both whether an event occurred and when it occurred, while accounting for the way follow-up ends. The registry lists this outcome but does not report its results or analysis details. The primary endpoint’s proportion analysis should not be conflated with a time-to-event analysis.

What can sample-size planning illustrations show?

A sample-size calculation is a planning exercise based on assumptions about the effect to detect, the significance level, allocation and statistical method. The registry record’s stated illustration assumptions include a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. It describes planning for a stated fraction of an observed effect. Such illustrations are not observed power and are not evidence that a result was likely to be statistically significant. The participant counts for planning illustrations are not reported in the registry record.

Planning based on an observed effect is particularly sensitive to the uncertainty in that observed effect. An effect estimate from a small study can vary substantially, so planning illustrations should be read as conditional on their assumptions rather than as a guarantee of adequate precision. The registry record does not report the trial’s own sample-size justification, so it is not possible to establish whether these planning assumptions were used to design the study.

The registry record lists two analyses, but it does not give sufficient detail to determine their full specifications. It does not report the analysis software, model covariates, handling of ties or the detailed procedures for confidence intervals and hypothesis tests. Those aspects of the statistical plan are not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("P-Fx Group", "NP-Fx Group", "Infectivity Control Group")
n      <- c(25, 24, 11)
events <- c(12, 11, 11)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  P-Fx Group  25  12  48.0  27.8  68.7  30.0  66.5  29.9  66.6
ARM  NP-Fx Group  24  11  45.8  25.6  67.2  27.9  64.9  27.8  65.1
ARM  Infectivity Control Group  11  11  100.0  71.5  100.0  74.1  100.0  73.5  99.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and multiple secondary outcomes, including time to parasitemia, antibody concentrations and several adverse-event outcomes. Considering several outcomes or comparisons can increase the chance of at least one apparently unusual result when many tests are conducted. Statistical approaches to address this include prioritizing a primary endpoint, adjusting significance thresholds, or treating secondary analyses as exploratory. The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or whether any results were adjusted for multiple comparisons.

The record describes an analysis population as the Per-Protocol Set, including participants who met eligibility criteria, received or did not receive the fractional dose according to protocol, had no underlying medical condition influencing the efficacy response, and underwent challenge. Its description ends before the full criteria are stated. Additional membership requirements and the complete definition of the analysis set are not reported in the registry record. The record does not give the number of participants included in the primary analysis.

For the proportion affected, the registry says all included participants were considered at risk of infection and that no censoring or elimination was applied for participants who did not complete the full protocol-defined post-challenge follow-up. This provides a specific rule for incomplete follow-up in that analysis, but does not explain how missing blood-slide assessments were handled, how other missing data were handled, or whether any sensitivity analyses were conducted. Those procedures are not reported in the registry record.

The study’s non-randomized grouping and distinct participant histories also affect interpretation independently of missing-data methods. The registry record does not report adjustment for baseline differences or a strategy for addressing confounding. The full statistical analysis plan, including the prespecified handling of multiplicity, missing data and analysis populations, is not reported in the registry record.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypobarism (4.0%), injury (4.0%), road traffic accident (4.0%).

The registry’s adverse-event summaries report participants at risk and participants affected in each group. For serious adverse events, the P-Fx group had 25 participants at risk and 2 affected; the NP-Fx group had 24 at risk and 0 affected; and the infectivity control group had 12 at risk and 0 affected. These are counts for the reported groups and should be read alongside their different histories and non-randomized allocation.

The record also lists other adverse-event counts: 21 of 25 participants in P-Fx, 22 of 24 in NP-Fx, and 12 of 12 in the infectivity control group were affected. It reports 0 deaths in each group. These summaries do not establish whether an event was caused by vaccination or challenge. The registry record does not provide detailed event-level context for these counts.

Among the listed serious-event terms, Hypobarism, Injury and Road traffic accident are each reported as 4.0%. The record does not explain the context needed to attribute these events to the booster, challenge or other circumstances. Counts from a study of this size describe what was recorded in these participants; they do not rule out events that were not observed. The registry record does not report further detail on severity, timing or causality assessment.

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

The registry describes a controlled challenge study designed to examine parasitemia after a fractional booster in previously vaccinated participants, with newly enrolled infectivity controls. Its primary endpoint is a defined binary outcome based on blood-slide detection during post-challenge follow-up. These design and measurement details explain what the study set out to assess, but they are not themselves evidence of an observed effect.

The primary endpoint results are not reported in the registry record. In particular, the record does not give the affected participant counts by group, the group proportions, a relative-risk estimate or a confidence interval. It is therefore not possible, from this record, to quantify the observed difference or its precision. No conclusion about whether the booster extended protection or protected participants who had not been protected previously can be drawn from the endpoint description alone.

Even if a group difference were reported, the non-randomized design would require careful interpretation. Participants in the two booster groups were categorized according to prior protection status, and the infectivity controls were newly enrolled. Those differences mean that the groups are not interchangeable by design. A group contrast would describe the observed participants and would not automatically isolate the effect of the booster.

The registry lists immunogenicity and safety outcomes as well as the primary parasitemia endpoint. Antibody concentrations and adverse events address different questions and should not be treated as substitutes for the primary outcome. The safety counts show reported events in the listed groups, but do not by themselves establish causation or provide a complete account of risks beyond the follow-up and reporting described.

Overall, the record supports a description of the study’s design, endpoint definition, follow-up window and reported safety counts. It does not provide the primary efficacy results needed to assess the direction, magnitude or precision of the endpoint comparison. The study’s stated purpose should therefore be distinguished from evidence of an observed result.

14. Why This Trial Matters Statistically

This study illustrates how a clinical question can be addressed using a controlled challenge model and a defined biological endpoint. The primary endpoint links a challenge exposure to a measurable outcome: P. falciparum parasitemia detected by blood-slide microscopy during a specified follow-up period. Clear operational definitions make it possible to understand what an event count represents and what it does not encompass.

The design also highlights why the construction of comparison groups matters. The booster recipients were selected from participants in an earlier study and separated according to prior protection status, whereas infectivity controls were newly enrolled and did not receive immunization in this study. Since allocation was non-randomized, the observed groups cannot be assumed to differ only in booster exposure. This is a central distinction between a descriptive contrast and a causal estimate.

The registry record is also a useful reminder that a stated endpoint and analysis do not substitute for reported results. Without group event counts, an effect estimate and its uncertainty, readers cannot assess the magnitude or precision of the primary comparison. The result’s absence from the registry record limits what can be concluded, even though the endpoint definition and follow-up rules are described.

Finally, the study brings together several distinct forms of evidence: parasitemia, time to parasitemia, antibody concentrations and adverse events. Each addresses a different aspect of the research question. Keeping those outcomes separate, while considering the design and analysis population, is essential to a statistically careful reading of a clinical challenge study.

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 primary limitation for interpreting efficacy from the registry record is that primary endpoint results are not reported. The record gives neither group-specific parasitemia counts nor the estimated comparison and its uncertainty. It therefore does not permit assessment of the observed effect or its precision.

The design is non-randomized and unmasked. Booster recipients were classified by their protection status in the previous study, and infectivity controls were newly enrolled. These groups differ in history and selection, so comparisons can be affected by factors other than the booster. The registry record does not report an adjustment strategy or enough baseline information to evaluate the extent of such differences.

The analysis-population description is incomplete, and the number of participants in the primary analysis is not reported. Although the registry specifies that participants in the proportion analysis were considered at risk and were not removed for failure to complete the full follow-up, it does not give the number with incomplete follow-up or explain how missing blood-slide data were handled. Further missing-data methods are not reported in the registry record.

The registry record does not report the full statistical analysis plan, including a multiplicity strategy, detailed estimation procedures or the trial’s own sample-size justification. Secondary outcome results are also not reported in the record. Safety summaries are available as group counts, but detailed event timing, context and causality assessments are not reported. These gaps limit both the statistical and clinical interpretation of the study record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Evaluate the Efficacy, Immunogenicity and Safety in a Sporozoite Challenge Model of a Fractional Booster Dose of GSK Biologicals' Candidate Malaria Vaccine Administered to Previously Vaccinated Healthy Malaria-naïve Adults — NCT03824236.
• Registry record last updated 2020-08-14; status last verified 2020-08.
• Results first posted 2020-05-15.
• 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

This completed Phase 2 study evaluated a fractional RTS,S/AS01E booster in a sporozoite challenge model among healthy malaria-naïve adults. It followed MALARIA-092 and included previously vaccinated participants categorized by protection status after their first challenge, along with newly enrolled, unvaccinated infectivity controls. Allocation was non-randomized and masking was none.

The primary endpoint was the number of participants with P. falciparum parasitemia, defined by a positive blood slide during follow-up from Day 22 up to Day 50. The record describes the endpoint and analysis population but does not report primary endpoint results, group comparisons or precision estimates. Safety counts are reported for serious and other adverse events, alongside 0 deaths in each group. The registry lists antibody and time-to-parasitemia outcomes, but their results are not reported in the registry record.