Safety, Immunogenicity of RTS,S/AS02A, and RTS,S/AS01B Malaria Vaccines in Malaria-experienced Adults.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Immunogenicity of RTS,S/AS02A, and RTS,S/AS01B Malaria Vaccines in Malaria-experienced Adults. (NCT00197054), a randomized phase 2 study. The primary outcome is Safety: Proportion of Subjects With Grade 3 Solicited and Unsolicited General Reactions After Vaccination of RTS, S/AS02A and RTS, S/AS01B.

2. Clinical Question

The primary question concerns short-term safety observations after vaccination, not whether either vaccine prevents malaria. The registry describes the study as a proof-of-concept trial and says time to first Plasmodium falciparum infection was to be monitored for a preliminary indication of vaccine efficacy. However, the posted primary outcome analyzed is the occurrence of grade 3 general reactions during the seven-day period following vaccination. The efficacy results are not reported in the registry record.

The posted primary-outcome results include 85 participants in each of the two vaccine groups. The registry reports 0.0 for RTS,S/AS02A and 1.0 for RTS,S/AS01B, with a confidence interval for each group. It also reports an unadjusted comparison with p = 0.316. These are observations for the recorded follow-up and endpoint; they do not establish that reactions outside this definition or period did not occur. The registry record does not report a definition of grade 3 or further details about how solicited and unsolicited reactions were collected.

3. Trial Design

This was a phase 2 randomized, controlled study with a parallel-group design. The registry describes masking as quadruple and the study status as completed. It reports 255 participants enrolled. The trial took place among malaria-experienced adults living in western Kenya, according to the official study title. The registry lists Plasmodium falciparum as the condition.

Three biological interventions are listed: RTS,S/AS01B, RTS,S/AS02A, and Rabipur, a rabies vaccine. The arm descriptions state that the two malaria-vaccine regimens were given as intramuscular doses at 0, 1 and 2 months. The Rabipur description also gives a schedule at 0, 1 and 2 months. For the primary safety outcome, the registry identifies RTS,S/AS02A and RTS,S/AS01B as the relevant vaccine groups and says Rabipur was a comparator vaccine whose results were not presented for that outcome. The posted primary comparison therefore concerns the two malaria-vaccine groups, not all three interventions.

The registry lists 85 participants in each of the two groups contributing to the primary outcome. While the overall enrollment is 255, the registry record does not report the allocation of all enrolled participants across the three arms in the primary-outcome results or explain any difference between enrollment and the displayed outcome denominators. Reasons for missing outcome observations, if any, are not reported in the registry record.

The primary completion date is recorded as 2006-09, and the study start is recorded as 2005-07. The sponsor is the U.S. Army Medical Research and Development Command. Specific details about random-sequence generation, allocation concealment, masking procedures, eligibility criteria, or site-level conduct are not reported in the registry record.

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: Rabipur was a comparator vaccine and not relevant to results of this primary outcome. Results for Rabipur were not presented in data table.

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 Safety: Proportion of Subjects With Grade 3 Solicited and Unsolicited General Reactions After Vaccination of RTS, S/AS02A and RTS, S/AS01B, measured over 7 day follow-up (day of vaccination + 6 days).

The primary endpoint is the proportion of participants with grade 3 solicited or unsolicited general reactions after vaccination with RTS,S/AS02A or RTS,S/AS01B. The specified observation window is seven days, defined in the registry as the day of vaccination plus the following six days. The outcome is reported in participants, with a 95% confidence interval.

This endpoint is used to describe the frequency of more severe general reactions during a defined short-term period. Solicited reactions are those actively sought according to a study process; unsolicited reactions are reported without being specifically prompted. That distinction is a general description of these terms. The registry record does not report which symptoms were solicited, how participants reported symptoms, or the grading criteria used to classify a reaction as grade 3.

The endpoint is binary at the participant level: a participant either met the recorded event definition during the follow-up window or did not. This makes the outcome interpretable as an event count or proportion within each group. It does not capture the full range of safety questions. In particular, the endpoint title is restricted to general reactions and a short follow-up period; it should not be read as a complete measure of all adverse events or longer-term safety.

The registry reports 0.0 for RTS,S/AS02A and 1.0 for RTS,S/AS01B, with group-specific confidence intervals. The record does not report the primary endpoint’s results for the Rabipur group. Nor does the primary endpoint answer the study’s separate question about time to first malaria infection.

7. Results Posted in the Registry

• RTS, S/AS01B: 1.2% (1/85) versus 0.0% (0/85) on control; risk difference 1.2 percentage points (95% CI -1.1 to 3.5); unadjusted two-proportion z-test p = 0.316.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level measure: whether a participant had at least one qualifying grade 3 general reaction within the stated follow-up. In general, binary outcomes can be summarized by counting participants with the event and relating that count to the number assessed. The registry reports the group results as 0.0 for RTS,S/AS02A and 1.0 for RTS,S/AS01B, each with 85 participants. The outcome unit is participants. The record does not explain the displayed numeric scale in further detail, so the safest reading is to retain the registry’s reported values rather than infer an unstated presentation convention.

The comparison is identified as a risk difference. In general, a risk difference contrasts the event proportions in two groups by subtracting one group’s proportion from the other’s. A value of zero represents no difference in the estimated risks; positive and negative values indicate opposite directions according to the comparison’s ordering. The registry’s comparative confidence interval extends across zero, so it includes no difference as well as values on either side. The record reports an unadjusted p-value of 0.316. The exact comparative estimate and interval are not repeated because their posted decimal precision exceeds the permitted display precision.

In general, a confidence interval is a range of values generated by a statistical procedure that reflects sampling uncertainty under that procedure and its assumptions. It is not a guarantee that the true value lies in the interval, nor does it assign a probability to a particular value after the data have been observed. Wider intervals indicate less precision than narrower intervals on the same scale. For this endpoint, the group intervals and comparative interval should be considered alongside the point estimates, especially because the observed event values are sparse.

In general, sparse binary outcomes can make estimates and tests sensitive to the method used. When events are rare or absent in one group, different interval and testing procedures may produce different results. The registry provides confidence intervals and an unadjusted p-value, but the specific statistical procedures used to calculate them are not reported in the registry record. It would therefore be inappropriate to attribute these results to a particular exact test, normal approximation, or model.

What does the p-value describe?

In general, a p-value evaluates how compatible the observed data, or data more extreme, are with a statistical null model, given the test’s assumptions. The reported p = 0.316 does not measure the probability that the vaccines have the same effect, and it does not measure the probability that the findings occurred by chance in an everyday sense. It also does not show that a clinically important difference is absent. Interpretation depends on the endpoint, the analysis method, the study design, and the uncertainty in the effect estimate.

What does an unadjusted comparison mean?

The registry labels the comparison unadjusted. In general, an unadjusted comparison summarizes the groups without accounting for additional covariates or other adjustment factors in that comparison. The record does not report whether any adjusted analysis was conducted elsewhere, what variables might have been considered, or whether the displayed comparison was the prespecified primary analysis. No analysis entry is posted in the registry record, so further details of the analytic procedure are not available.

How should planning calculations be understood?

In general, a sample-size calculation is a planning exercise based on assumptions about an effect, variability, significance level, and allocation. It is not an observed study result and does not establish the probability that a particular trial result will be significant. The registry’s stated planning illustration is based on the observed effect and specifies a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such an illustration should not be treated as the original trial’s design justification or as observed power. The trial’s own sample-size justification is not reported in the registry record.

Over-dispersion is a general issue for count outcomes when observed variability exceeds what a simple model assumes. It is not a central modeling description for this participant-level binary primary endpoint, and the registry does not report an over-dispersion analysis. More broadly, the statistical model, test specification, confidence-interval method, and any interim-analysis plan are not reported in the registry record. These methods should not be inferred solely from the posted estimates.

10. Confidence Intervals and Precision

The two group estimates have 95% confidence intervals: 0.0 to 4.2 for RTS,S/AS02A and 0.0 to 6.4 for RTS,S/AS01B. Both intervals include the reported lower endpoint of 0.0 and extend above their point estimates. The interval for the RTS,S/AS01B group extends farther than the one for RTS,S/AS02A, but the estimates are on the registry’s reported scale and the record does not provide more detail on interval construction.

The comparative confidence interval crosses zero. In general, for a risk difference, zero represents no estimated difference between groups. An interval that crosses zero therefore does not rule out no difference under the interval procedure. It also does not rule out all nonzero differences: values on both sides of zero remain compatible with the interval. The posted unadjusted p-value, 0.316, is consistent with the comparison not providing strong evidence against the null model under the reported test, but it does not demonstrate equivalence.

Precision is limited by the modest number of participants in the outcome comparison and by the small number of recorded endpoint events. This is a general statistical consideration, not an alternative result: few events ordinarily leave less information for estimating an event frequency or a between-group contrast. The confidence intervals make that uncertainty visible, and the point estimates alone should not be treated as exact descriptions of the underlying risks.

The confidence intervals do not address systematic error, incomplete outcome collection, or whether the endpoint definition captures every safety outcome of interest. The registry record does not report the method used to calculate the intervals, missing-data handling, or a detailed analysis population. Consequently, the intervals can be described as posted, but their underlying assumptions cannot be fully assessed from the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 43 outcome measures and 4 posted secondary outcomes. The secondary outcomes include serious adverse events and laboratory parameters below or above normal ranges. The primary endpoint is one specific short-term safety measure. When a study evaluates multiple outcomes or comparisons, multiplicity can increase the chance of at least one apparently notable finding. In general, multiplicity procedures may address this by adjusting testing or by defining a hierarchy of outcomes. The registry record does not report a multiplicity strategy, an outcome hierarchy, or adjustment of the posted primary comparison.

The primary comparison is explicitly labeled unadjusted, and its p-value is 0.316. This does not by itself establish whether other analyses were performed or whether any adjustment was planned. The registry has no posted analysis entries. A prespecified statistical analysis plan, interim analyses, and stopping rules are not reported in the registry record, so the relation between the posted analysis and any planned analysis cannot be determined from the record.

The record gives 85 participants for each group in the primary-outcome comparison, but does not describe how missing observations were handled or define the analysis population. It does not report whether all randomized participants were analyzed as assigned, whether participants with incomplete follow-up were excluded, or how any protocol deviations were treated. These details matter because the interpretation of a randomized comparison can depend on which participants contribute to the estimate and how missing outcomes are addressed.

The endpoint’s follow-up is defined as the vaccination day plus six days. The registry does not report the completeness of follow-up or the number of participants with missing endpoint data. It also does not provide a detailed description of symptom ascertainment or grading. Consequently, the posted group estimates can be interpreted as reported, but the impact of missingness, outcome classification, or multiplicity on those results is not assessable from 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: hiv infection (3.5%), anaemia (1.2%), cardiac failure (1.2%), pericardial effusion (1.2%), cataract (1.2%).

The registry reports serious adverse event counts among 85 participants at risk in each intervention group. The counts are 5 for RTS,S/AS01B, 1 for RTS,S/AS02A, and 5 for Rabipur. It reports 0 deaths in each of the three groups. These figures are descriptive counts; they do not establish that an event was caused by a vaccine or that groups differed in risk.

The registry’s listed serious-event terms include HIV infection at 3.5%, and anaemia, cardiac failure, pericardial effusion, cataract, and wound necrosis at 1.2% each. The record does not provide enough detail alongside these terms to reconstruct the full event-level accounting, including whether a participant could contribute more than one event. They should therefore be read as the selected terms and percentages posted, not as a complete description of every serious event.

These serious adverse event figures are separate from the primary endpoint, which concerns grade 3 solicited and unsolicited general reactions during a seven-day period. The serious-event counts are not restricted by that primary endpoint definition. The registry record does not report detailed event narratives, timing, adjudication, relatedness assessments, or follow-up duration for the serious adverse events. Counts alone cannot answer those questions, and comparisons across groups should remain descriptive in the absence of further detail.

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

The result describes the frequency of one narrowly defined safety outcome during a short follow-up period in two vaccine groups. The registry reports 0.0 for RTS,S/AS02A and 1.0 for RTS,S/AS01B, with 85 participants in each group. The comparative p-value is 0.316, and the comparative confidence interval includes zero. Taken together, the posted estimates do not precisely establish a difference between the groups for this endpoint.

This is not the same as demonstrating that the vaccines have identical safety profiles. A nonsignificant comparison can occur when the data are compatible with no difference, but also when they are too imprecise to distinguish among a range of possible effects. The confidence intervals and limited event counts should therefore be considered, rather than treating the p-value as a definitive verdict.

The result does not answer whether either candidate vaccine prevents malaria. The study summary says time to first infection with Plasmodium falciparum was monitored for a preliminary indication of efficacy, but efficacy results are not reported in the registry record. The primary endpoint result also does not answer questions about longer-term safety, other adverse events, or laboratory outcomes. Those questions require their own outcome definitions and results.

Nor does the primary-outcome comparison include a reported result for Rabipur. The registry identifies it as a comparator vaccine but states that results for it were not presented for this primary outcome. The posted comparison is limited to RTS,S/AS01B and RTS,S/AS02A.

Overall, the result should be read as a descriptive and uncertain comparison of short-term grade 3 general reactions in this trial population. It should not be generalized beyond the defined participants, endpoint, and observation window without additional evidence. No treatment recommendation follows from these statistics.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between an observed estimate and a precise conclusion. The primary endpoint produced very few recorded events, and the comparison is accompanied by confidence intervals that include no difference. A point estimate alone can make a small numerical contrast look conclusive; uncertainty intervals and the event count show why that reading would be too strong.

The design also illustrates the importance of keeping endpoints separate. The trial included two candidate malaria vaccines and a rabies-vaccine comparator, while the posted primary safety result addresses only the two malaria-vaccine groups. Serious adverse events and laboratory outcomes appear among the secondary outcomes, and the study summary describes monitoring malaria infection. Those outcomes address different questions and cannot be substituted for one another.

Randomization and masking are important design features stated in the registry: allocation was randomized, the design was parallel, and masking was quadruple. At the same time, the registry record does not report details needed to assess all aspects of conduct and analysis, including allocation procedures, analysis populations, missing data, and multiplicity. This illustrates why a trial’s design labels and numerical outcome estimates are not a complete account of its methods.

The results also highlight why absence of a statistically persuasive difference is not proof of equivalence. The comparative interval crosses zero and the p-value is 0.316, but neither quantity establishes that any possible difference is negligible. A reader needs the endpoint definition, group denominators, uncertainty, and limits of reporting to understand what the evidence can support.

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 safety result covers only grade 3 general reactions recorded during the seven-day period defined by the registry. It does not describe the full safety profile, events beyond that period, or the incidence of every symptom. The registry record does not report the grading criteria, the list of solicited reactions, or how unsolicited events were collected.

The primary outcome is reported for 85 participants in each malaria-vaccine group, while the registry reports 255 participants enrolled overall. The record does not explain how all enrolled participants were distributed across arms for this endpoint, whether all randomized participants contributed data, or why any participants might not appear in the primary-outcome results. Missing-data methods and analysis population definitions are not reported in the registry record.

The comparison is labeled unadjusted, but its specific statistical test and confidence-interval method are not reported. There are 43 outcome measures and 4 posted secondary outcomes, yet a multiplicity plan or testing hierarchy is not reported in the registry record. The record also does not report a detailed statistical analysis plan, interim analyses, or the trial’s own sample-size justification.

Results for Rabipur are not presented for the primary endpoint. The registry’s serious adverse event listings provide counts and selected terms, but do not include event narratives or detailed assessments of timing and relatedness. Finally, although the study summary describes monitoring time to first malaria infection, efficacy results are not reported in the registry record. These reporting limits mean the primary result should be interpreted narrowly as the posted short-term safety comparison, not as a complete account of trial outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Immunogenicity of RTS,S/AS02A, and RTS,S/AS01B Malaria Vaccines in Malaria-experienced Adults. — NCT00197054.
• Registry record last updated 2021-02-12; status last verified 2021-02.
• Results first posted 2020-12-11.
• 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

The registry describes a completed phase 2 randomized, quadruple-masked, parallel controlled study in malaria-experienced adults living in western Kenya. Overall enrollment was 255. The trial evaluated RTS,S/AS01B and RTS,S/AS02A, with Rabipur also listed as an intervention.

The primary outcome was the proportion of participants with grade 3 solicited or unsolicited general reactions during seven days after vaccination. The posted comparison includes 85 participants in each malaria-vaccine group: the registry reports 0.0 for RTS,S/AS02A and 1.0 for RTS,S/AS01B. The unadjusted comparison has p = 0.316, and its confidence interval includes no difference.

The result is limited to this endpoint and follow-up window. The registry record does not report the statistical analysis plan, missing-data handling, or efficacy findings for time to first malaria infection.