A Surveillance Study of Diseases Specified as Adverse Events of Special Interest, of Other Adverse Events Leading to Hospitalisation or Death, and of Meningitis in Children in Africa Prior to Implementation of the RTS,S/AS01E Candidate Vaccine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Surveillance Study of Diseases Specified as Adverse Events of Special Interest, of Other Adverse Events Leading to Hospitalisation or Death, and of Meningitis in Children in Africa Prior to Implementation of the RTS,S/AS01E Candidate Vaccine (NCT02374450), a registered phase not stated study. The primary outcome is Number of Participants With at Least One Adverse Events of Specific Interest (AESI) From Month 0 to Month 79.

2. Clinical Question

The central statistical purpose was descriptive: to establish baseline occurrence of specified health events before vaccine implementation. The AESI list comprised events historically associated with vaccines other than RTS,S/AS01E or potentially associated with RTS,S/AS01E, whose components were described as new relative to widely used vaccines at the time. This surveillance context matters when interpreting the data. The groups do not represent treatment and control arms, and contrasts between them cannot be interpreted as estimates of a vaccine effect.

3. Trial Design

This was a prospective cohort surveillance study sponsored by GlaxoSmithKline and registered as NCT02374450. The registry reports enrollment of 36366 and a completed status. The study began on 2015-10-05, with primary completion on 2022-08-02. Its stated purpose was to estimate the incidence of AESI, other adverse events leading to hospitalization or death, meningitis and malaria among children under 5 years of age in sub-Saharan Africa before implementation of RTS,S/AS01E.

Surveillance took place through three differently defined groups. In the active surveillance 6-12 weeks group, children were identified at the first DTP/HepB/Hib vaccination, usually given at 6 weeks of age, and home visits followed that vaccine schedule. In the active surveillance 5-17 months group, children could be identified at that first vaccination with home visits scheduled from 5 months of age, or identified at first encounter with study staff, with home visits starting within one week. Enhanced hospitalization surveillance enrolled eligible children under 5 years in the study areas who were not already in active surveillance during hospitalizations throughout the study period.

These procedures create observational cohorts rather than randomized arms. Entry pathways, age at surveillance and contact with health services differ, so group counts should be read as surveillance summaries rather than direct comparative estimates. The listed intervention was blood collection; the record does not describe an administered study treatment. The study’s baseline findings were intended to inform the post-licensure EPI-MALARIA-003 study of RTS,S/AS01E safety, effectiveness and impact.

The registry also describes an interim analysis in a subgroup enrolled in active surveillance at sites where the vaccine was implemented. Follow-up for that interim analysis was defined in relation to dose 3 of DTP/HepB/Hib in the 6-12 weeks group, or Visit 3 in the 5-17 months group, corresponding to Visit 5. The analysis concerned primary safety endpoints and main secondary endpoints. Further details of the interim analysis methods 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.

Before assignment: Out of the 36366 participants initially enrolled in the study, 12939 participants from the Burkina Faso site were excluded from the According-To-Protocol (ATP) cohort. Therefore, 23427 participants formed the ATP cohort in Ghana and Kenya.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the According-To-Protocol (ATP) cohort, which included all evaluable participants who met all eligibility criteria, complied with the enrollment procedures defined in the protocol, and had no elimination criteria during the study.

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 Participants With at Least One Adverse Events of Specific Interest (AESI) From Month 0 to Month 79, measured over During the entire study period (From Month 0 up to Month 79).

The primary endpoint is the number of participants with at least one adverse event of special interest from Month 0 to Month 79. It is a participant count: each participant is counted according to whether at least one qualifying AESI was recorded over the specified study period. It is not an event rate, because the endpoint as stated does not count repeated events separately or express events per unit of follow-up time.

AESI were a predefined list of events historically associated with vaccines other than RTS,S/AS01E or potentially associated with RTS,S/AS01E. The registry explains that the candidate vaccine contained components that were new relative to widely used vaccines at the time. A defined list allows surveillance to focus on events selected in advance as relevant to safety monitoring, rather than relying only on an unstructured summary of all illnesses.

The endpoint is useful for describing how often participants experienced one or more specified events during the surveillance period. It can contribute to baseline safety context before vaccine implementation, but by itself it does not establish a cause for any event. Because this is a pre-implementation observational study and the groups are not randomized comparators, the count cannot be interpreted as an estimate of vaccine-attributable risk.

The primary endpoint result is not reported in the registry record. The primary population is described as the According-To-Protocol cohort, consisting of evaluable participants meeting eligibility and enrollment requirements without elimination criteria. The record does not provide further detail about how AESI were adjudicated or how incomplete follow-up affected the endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a prospective surveillance cohort. In general, a prospective cohort follows people over time and records events as they occur, rather than assigning participants to treatment groups at random. This design can characterize event occurrence in the population under observation. It does not, on its own, separate the effect of a particular exposure from differences in health, age, setting, access to care or follow-up between groups.

What does a participant count measure?

The primary endpoint is a count of participants with at least one AESI during the stated observation period. A participant who experiences an event is included in the count; the endpoint does not express the number of repeated events. Counts are straightforward to describe, but their interpretation depends on the number of people observed and the duration and completeness of observation. Rates instead relate events to a quantity of time at risk. The primary endpoint is specified as a count, while the registry’s secondary outcomes also include incidence rates for death after the virtual secondary schedule.

Why are the surveillance groups not a direct comparison?

Random allocation can help make comparison groups similar with respect to both measured and unmeasured characteristics, on average. No randomized allocation is described for this study. The groups were defined by surveillance arrangements, including age-related entry pathways and surveillance during hospitalization. Group differences in recorded counts could therefore reflect underlying differences in who was enrolled, when observation began, how long follow-up continued, or how events were detected. A simple contrast between groups would not isolate a causal effect.

What does an uncertainty interval tell a reader?

In general, a confidence interval describes the range of estimates compatible with the observed data under a statistical model and its assumptions. A narrow interval indicates greater precision than a wide interval, but neither an interval nor a point estimate addresses bias from selection, measurement, missing follow-up or confounding. The registry record does not report confidence intervals for the outcomes, nor does it give estimates from which such intervals can be interpreted.

How should the serious-event entries be read?

The posted safety summary gives group-level at-risk and affected-participant counts for serious and other events, alongside deaths. These are descriptive entries, not adjusted rates. A zero affected-participant count in a summary category does not establish that no events of any kind occurred; it only describes that category as recorded in the posted summary. The registry does not list serious-event terms in its summary. The record’s primary AESI endpoint is a separate outcome, and its numerical result is not reported.

What is the role of planning illustrations?

Sample-size illustrations are planning calculations, not evidence that a study had a particular probability of detecting an effect after it was completed. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. For non-time-to-event outcomes, the illustration is expressed as participants per arm. These calculations are not the study’s own design justification, and their assumptions do not turn this observational surveillance study into a randomized comparison. Numerical illustration results and a study-specific sample-size justification are not reported in the registry record.

More generally, statistical significance and clinical importance are different concepts. A p-value, when reported, reflects how compatible data are with a specified null model under its assumptions; it does not measure the size or importance of an effect. The registry record lists 0 analyses and supplies no outcome-specific inferential results in this record summary, so no such significance test can be interpreted. The analytical methods for the planned primary and secondary outcomes, beyond the stated endpoint descriptions and cohort population, 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("Active Surveillance 6-12 Weeks", "Active Surveillance 5-17 Months", "Enhanced Hospitalization Surveillance")
n      <- c(9032, 9694, 4701)
events <- c(12, 11, 16)
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  Active Surveillance 6-12 Weeks  9032  12  0.1  0.1  0.2  0.1  0.2  0.1  0.2
ARM  Active Surveillance 5-17 Months  9694  11  0.1  0.1  0.2  0.1  0.2  0.1  0.2
ARM  Enhanced Hospitalization Surveillance  4701  16  0.3  0.2  0.6  0.2  0.6  0.2  0.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures, including the primary AESI participant count and secondary outcomes concerning meningitis, hospitalization, death, malaria, anemia and risk factors. Assessing many outcomes creates a multiplicity issue: when several statistical tests are performed, the chance of at least one apparently notable result can increase. Researchers may address this through a prespecified hierarchy, adjustment procedure, or careful emphasis on estimation rather than isolated test results. The approach used for multiplicity is not reported in the registry record.

The record describes an interim analysis in a subgroup at sites where the vaccine was implemented, addressing primary safety endpoints and main secondary endpoints after specified follow-up milestones. The analysis is noted, but its statistical plan, decision rules, relationship to final analyses and any multiplicity handling are not reported in the registry record. The record lists 0 analyses, so numerical interim results are not available in the posted summary.

The primary endpoint population is the According-To-Protocol cohort. The record defines this as evaluable participants who met eligibility criteria, complied with enrollment procedures and had no elimination criteria. This definition identifies an analysis population, but it does not explain how participants with incomplete information, missed visits or loss to follow-up were handled. The amount and pattern of missing data, any imputation approach, and sensitivity analyses are not reported in the registry record.

These omissions matter because incomplete follow-up can affect both counts and rates, especially if the chance of remaining under observation is related to health or event occurrence. Without details on follow-up completeness, outcome ascertainment, and missing-data methods, the precision and potential bias of estimates cannot be fully evaluated. The stated population definition should therefore be read as a description of who qualified for the primary analysis, not as a complete account of how missing observations were treated.

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.

The registry’s serious-event summary reports at-risk and affected-participant entries for each surveillance group. The serious affected-participant count is 0 for active surveillance 6-12 weeks, 0 for active surveillance 5-17 months, and 0 for enhanced hospitalization surveillance. The summary separately reports 173 deaths, 183 deaths, and 80 deaths, respectively. These entries are descriptive counts, not rates or risk comparisons.

Zero in the serious-event affected count should not be read as zero illness or as a complete safety conclusion. It refers only to the serious-event category represented in the posted summary. The registry also specifies other outcomes, including the primary AESI count, meningitis, malaria, hospitalization causes and anemia. Numerical results for those outcomes are not reported in the registry record. The serious-event terms are not listed in the record’s summary.

The surveillance groups were not randomized comparators and had different enrollment procedures. The record does not report adjusted comparisons or a common follow-up denominator for these safety figures. Thus, comparing counts across groups does not establish that one group had greater or lesser risk. The listed deaths should also be kept distinct from the serious affected-participant entries; they are separately reported outcomes, and the record does not explain their overlap with other event categories.

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

The study is designed to describe health events in children under 5 years of age before implementation of RTS,S/AS01E and to provide baseline data for a post-licensure study. That role is important: it can help place later surveillance findings in context by documenting events observed in the population and settings under study before vaccine implementation.

The posted serious-event summary reports zero affected participants in each surveillance group for its serious-event category, and reports deaths in all three groups. These entries do not establish whether the candidate vaccine causes or prevents any outcome. The study was conducted before implementation and does not include randomized vaccine and control groups. The surveillance cohorts also differ in how children entered observation, so their counts cannot be treated as a causal contrast.

The primary AESI result is not reported in the registry record. Nor are numerical results reported for the listed secondary outcomes in the registry record for interpretation. Therefore, the serious-event summary does not answer the primary endpoint question, and it cannot support a complete account of the incidence of AESI, meningitis, malaria or other specified outcomes.

In general, an observed count is not the same as an incidence rate, and neither is automatically a measure of causation. Interpretation requires knowing who was observed, for how long, how completely outcomes were detected, and how analyses accounted for relevant differences between participants. The registry record provides some cohort definitions and an ATP population description, but detailed outcome methods, missing-data handling and inferential results are not reported in the registry record.

The appropriate conclusion is limited to the study’s descriptive purpose and the entries actually reported. The data establish neither a vaccine safety effect nor a comparative risk between surveillance groups. They provide a baseline surveillance framework, while the completeness and precision of specific outcome estimates cannot be assessed from the reported numerical results alone.

14. Why This Trial Matters Statistically

Statistically, this study illustrates the value and limits of prospective surveillance as a source of baseline information. Before a health intervention is introduced, systematic observation can characterize the kinds of events that are recorded in the population and help define the context for subsequent monitoring. This can be especially relevant when later research evaluates events of special interest and other outcomes in routine implementation settings.

The design also demonstrates why cohort definition and outcome definition matter. The study distinguishes active surveillance pathways from enhanced hospitalization surveillance, and its primary endpoint focuses on participants with at least one event from a predefined AESI list. These choices shape what is counted and who contributes to the analysis. The ATP population description further identifies eligibility and evaluability requirements for the primary endpoint.

At the same time, surveillance groups are not necessarily comparable. The groups were formed through different enrollment and follow-up procedures, rather than random allocation. Their counts can describe each group but cannot by themselves support a causal interpretation of differences. Statistical reporting should make that distinction clear and provide outcome-specific denominators, follow-up information, uncertainty estimates and methods where available.

The record also raises a reporting lesson: a study may describe a broad outcome program and an interim analysis while offering limited numerical results in its posted summary. Without the primary AESI result and detailed secondary outcome findings, readers cannot fully assess the baseline estimates or their precision. The study’s stated contribution as baseline data for EPI-MALARIA-003 is meaningful, but subsequent interpretation depends on transparent outcome reporting and careful separation of descriptive surveillance from causal evaluation.

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 registry record does not report the primary AESI count by group, despite defining the endpoint and the Month 0 to Month 79 timeframe. It also does not provide numerical results for the listed secondary outcomes in the information. This prevents assessment of the magnitude and precision of the study’s principal baseline estimates.

The three surveillance groups arose from different enrollment routes and are not randomized comparators. Active surveillance began through vaccination-related identification or later contact, while enhanced hospitalization surveillance enrolled eligible children during hospitalization. Such differences may affect participant characteristics, event detection and time under observation. The record does not report adjusted comparisons that would address these differences.

Further limitations are the absence of reported outcome-specific uncertainty estimates, detailed methods for event ascertainment or adjudication, and information about completeness of follow-up. Missing-data handling and sensitivity analyses are not reported in the registry record. The record describes an interim analysis but does not report its statistical plan or numerical findings. Although the primary analysis population is defined as the ATP cohort, the implications of excluding participants who were not evaluable or who met elimination criteria are not quantified.

The serious-event summary is narrow and should not stand in for the study’s full safety and disease outcome set. The registry summary does not list serious-event terms, and the relationship between the serious-event entries and separately reported deaths is not explained. These reporting limitations restrict both clinical interpretation and evaluation of statistical precision. The record supports understanding the study’s intended design and the specific serious-event counts, but not a complete reconstruction of all outcome analyses.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Surveillance Study of Diseases Specified as Adverse Events of Special Interest, of Other Adverse Events Leading to Hospitalisation or Death, and of Meningitis in Children in Africa Prior to Implementation of the RTS,S/AS01E Candidate Vaccine — NCT02374450.
• Registry record last updated 2024-09-19; status last verified 2024-09.
• Results first posted 2024-09-19.
• 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

NCT02374450 is a completed prospective surveillance study sponsored by GlaxoSmithKline. It enrolled 36366 children and was conducted from 2015-10-05, with primary completion on 2022-08-02. Its purpose was to estimate AESI, other adverse events leading to hospitalization or death, meningitis and malaria in children under 5 years of age in sub-Saharan Africa before RTS,S/AS01E implementation.

The primary endpoint was the number of participants with at least one AESI from Month 0 to Month 79, analyzed in the According-To-Protocol cohort. The study used active surveillance groups beginning at 6-12 weeks and 5-17 months, and an enhanced hospitalization surveillance group. The registry reports zero serious affected participants in each group and separate death counts of 173, 183 and 80, respectively. The primary AESI result and detailed methods for missing data, multiplicity and outcome analyses are not reported in the registry record.