Safety and Immunogenicity of Different Schedules of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Immunogenicity of Different Schedules of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Healthy Participants (NCT02302066), a randomized phase 2 study. The primary outcome is Geometric Mean Titers (GMTs) of Neutralizing Antibodies (Microneutralization Test [MNT50]) for Each of the Four DENV Serotypes for Participants in the Immunogenicity Subset.

2. Clinical Question

The trial asked how neutralizing-antibody responses and safety outcomes varied across different TDV vaccination schedules in healthy young people living in dengue-endemic countries in Asia and Latin America. The central immunogenicity measure was the geometric mean titer for each of the four dengue virus serotypes, assessed in the immunogenicity subset through Month 48. The trial also listed seropositivity and several adverse-event outcomes.

3. Trial Design

This was a Phase II, randomized, quadruple-masked, parallel-group, controlled trial of TDV and placebo. It enrolled 1800 healthy participants aged 2 and <18 years living in dengue-endemic countries in Asia and Latin America. The registry record gives a study start date of 2014-12-05 and a primary completion date of 2019-02-18, and lists the trial status as completed.

The four groups differed in the timing of TDV and placebo-matching injections. Group 1 received TDV on Days 1 and 91, followed by placebo on Day 365. Group 2 received TDV on Day 1 and placebo on Days 91 and 365. Group 3 received TDV on Days 1 and 365, with placebo on Day 91. The placebo-control group received placebo-matching injections on Days 1, 91 and 365. Each scheduled injection was described as 0.5 mL, administered subcutaneously.

The primary outcome was immunogenicity, measured as geometric mean titers of neutralizing antibodies for each of the four dengue serotypes. Measurements were collected at Months 1, 3, 6, 12, 13, 18, 24, 36 and 48. The primary outcome description identifies the analysis population as the Per Protocol Set within the immunogenicity subset. The record also lists seropositivity for each serotype and safety outcomes, including solicited and unsolicited adverse events, serious adverse events, and febrile episodes of virologically confirmed dengue.

The registry record does not report the method used to generate the randomization sequence, how masking was maintained, or the planned statistical comparisons among groups. The enrollment figure is not a report of the number analyzed for each outcome. The number analyzed for the primary endpoint, by group and visit, is 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: Healthy volunteers were enrolled in a 1:2:5:1 ratio into 4 study groups: Group 1 received two doses of Tetravalent Dengue Vaccine (TDV), Group 2 received one dose of TDV, Group 3 received one dose of TDV along with booster vaccination and Group 4 received placebo.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per Protocol Set (PPS): All participants who received at least 1 dose of trial vaccine, who had a valid pre-dose and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. PPS included only participants from Immunogenicity Subset. Number analyzed are participants with data available at the given timepoint.

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.

Population: Safety Analysis Set included all participants who received at least 1 dose of trial vaccine.

6. Primary Endpoint

The registry lists the primary outcome as Geometric Mean Titers (GMTs) of Neutralizing Antibodies (Microneutralization Test [MNT50]) for Each of the Four DENV Serotypes for Participants in the Immunogenicity Subset, measured over Up to Month 48.

The primary endpoint was the geometric mean titer of neutralizing antibodies to each of the four dengue virus serotypes, measured by the MNT50 microneutralization test. It was assessed in the immunogenicity subset, with measurements described through Month 48. The registry lists the measure as a titer with a 95% confidence interval.

Neutralizing-antibody measurements characterize the antibody response detected by the laboratory test. Reporting a separate titer for DENV-1, DENV-2, DENV-3 and DENV-4 matters because an overall measure could conceal differences among serotypes. A geometric mean is often used for measurements such as antibody titers because they may be distributed asymmetrically and vary multiplicatively; this is a general statistical rationale, not a reported explanation of the trial’s analysis choices.

A confidence interval conveys the precision of an estimated mean under the analysis assumptions. A narrower interval indicates greater precision than a wider interval, but does not by itself establish that schedules differ. The registry describes the endpoint, assay, population and assessment visits, but numerical GMT estimates, confidence limits and direct comparisons are not reported in the registry record. The endpoint definition therefore identifies what was intended to be measured, not the size or pattern of the observed antibody responses.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation of this trial requires separating the endpoint definition from the analysis results. The registry describes the primary measure as a geometric mean titer for each serotype, with a 95% confidence interval, but does not report numerical GMTs or the method used to calculate them. The concepts below explain how such measures are generally read; they do not establish which unreported procedures were used in this trial.

What does a geometric mean summarize?

In general, a geometric mean is calculated by taking the mean on a logarithmic scale and transforming it back to the original measurement scale. This approach is often suitable for positive measurements that vary multiplicatively, such as antibody titers. It reduces the influence that a few unusually large values can have on a conventional arithmetic mean when measurements are strongly right-skewed. The geometric mean remains a summary of the observed values; it does not describe every participant’s response or the distribution’s full shape.

Interpreting a GMT requires knowing the analysis population, handling of values below or above assay limits, transformations, and any adjustments. These details can affect both the point estimate and its uncertainty. The registry record identifies the assay and the Per Protocol Set but does not report the calculation details or how assay-limit values were handled. They should not be inferred from the endpoint label alone.

How should a confidence interval be read?

In general, a confidence interval describes uncertainty around an estimate under a specified statistical model and sampling procedure. A narrower interval indicates a more precise estimate than a wider one. The interval does not show the range of individual participant values, and it is not a statement that a fixed proportion of participants had titers inside it. Under the usual repeated-sampling interpretation, the method would cover the underlying parameter at its stated rate over repeated studies if its assumptions held. That interpretation does not guarantee that assumptions are appropriate in a particular analysis.

Intervals for separate groups can help describe uncertainty, but overlap or non-overlap between them is not a substitute for a direct comparison. A comparison should report the estimated contrast and its uncertainty using an appropriate method. The registry record does not give the planned contrast, an estimated contrast, or its confidence interval for the primary endpoint. It therefore does not support a statistical claim that one schedule had higher or lower titers than another.

Why do the visits and serotypes matter?

The primary outcome was collected at Months 1, 3, 6, 12, 13, 18, 24, 36 and 48 for DENV-1, DENV-2, DENV-3 and DENV-4. These repeated assessments can describe how measured responses vary over follow-up, but observations from the same participant are generally related rather than independent. In general, an analysis of repeated measurements needs to account for that relationship if it models multiple visits together. Alternatively, separate visit-specific summaries can be reported, but they create many estimates that must be interpreted in context. The registry record does not state whether the analysis modeled repeated measures jointly or reported visit-specific summaries.

Serotypes are also distinct outcome categories. A schedule’s result for one serotype should not be assumed to represent its result for the others. Comparing several schedules, serotypes and visits can raise multiplicity concerns: the more inferences considered, the greater the chance that some appear notable by chance if no adjustment or hierarchy is used. This is a general concern. The registry does not report a multiplicity strategy or identify a hierarchy of confirmatory comparisons.

What can safety counts tell readers?

Event counts and numbers at risk are descriptive quantities. In general, their interpretation depends on the outcome definition, observation period, ascertainment, and whether the comparison accounts for follow-up and other design features. Counts alone do not indicate whether events were caused by an intervention. A formal comparison requires a defined estimand and analysis method, and may require accounting for unequal follow-up or other relevant factors. The record gives serious adverse-event counts and at-risk figures by group, but it does not report a comparative model or attribution of events.

The registry also describes safety outcomes at different levels: solicited local and systemic events, unsolicited events, serious adverse events, and virologically confirmed febrile dengue episodes. These categories should not be collapsed into one general safety result. The listed outcome definitions and available counts vary, and the registry does not report all numerical results for these outcomes.

Planning illustrations based on observed effects are not observed trial power. The stated assumptions for those illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such calculations are hypothetical planning scenarios, not evidence that the trial had a particular probability of detecting a result. They do not replace a description of the trial’s design justification, which is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome includes four serotypes measured at multiple visits through Month 48, and the registry also lists seropositivity and several safety outcomes. This creates many possible summaries and comparisons. In general, examining many hypotheses can increase the chance of a false-positive finding if each is assessed without an appropriate plan. A prespecified outcome hierarchy, adjustment procedure, or clearly designated exploratory analysis can help readers distinguish confirmatory findings from descriptive ones. A multiplicity strategy is not reported in the registry record.

The primary endpoint population is the Per Protocol Set within the immunogenicity subset. It included participants who received at least 1 dose, had a valid pre-dose measurement and at least 1 valid post-dose immunogenicity measurement, and had no major protocol violations. This definition identifies exclusions relevant to the primary analysis, but the registry does not report the number meeting the criteria by group or visit. It also does not report an intention-to-treat analysis population for the primary endpoint.

Repeated visits can have different numbers of observations if participants miss assessments or are excluded from a particular analysis. In general, missing data can affect estimates when the likelihood of missingness is associated with outcomes or participant characteristics. Methods such as imputation or models using incomplete repeated measurements involve assumptions that should be stated and assessed. The registry record does not report the extent or reasons for missing immunogenicity data, how missing values were handled, or whether sensitivity analyses were conducted.

The record identifies secondary outcomes and gives selected safety counts, but does not report a full statistical analysis plan, outcome-specific analysis populations, or methods for handling multiplicity and missing data. These omissions limit the ability to assess whether the posted summaries represent prespecified analyses and how robust they may be to alternative assumptions.

11. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: appendicitis (1.0%), amoebic dysentery (0.5%), gastroenteritis (0.5%), abscess limb (0.5%), appendicitis perforated (0.5%).

The registry lists serious adverse events by group alongside the number at risk. Group 1 had 10 serious adverse events among 200 at risk; Group 2 had 18 among 398; Group 3 had 65 among 998; and Group 4, the placebo-control group, had 10 among 198. The listed deaths were 0 in Group 1, 1 in Group 2, 1 in Group 3 and 0 in Group 4. These figures should be read as group-specific counts and denominators, not as a causal comparison.

The record also lists serious-event terms with percentages: Appendicitis, 1.0%; Amoebic Dysentery, 0.5%; Gastroenteritis, 0.5%; Abscess Limb, 0.5%; Appendicitis Perforated, 0.5%; and Burkholderia Cepacia Complex Sepsis, 0.5%. The registry excerpt does not provide context sufficient to determine how those percentages relate to specific groups or to establish whether events were considered intervention-related. That attribution is not reported in the registry record.

Serious-event counts are not interchangeable with the listed solicited or unsolicited adverse-event outcomes. The record does not provide a comparative statistical analysis, adjustment for follow-up, or detailed event narratives. Differences in counts should therefore be treated descriptively; they do not, by themselves, establish that a schedule caused more or fewer serious events.

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

The registry record establishes that a randomized Phase II study compared three TDV schedules with a placebo-control schedule in healthy participants aged 2 and <18 years. It identifies a primary immunogenicity endpoint, the four serotypes assessed, the measurement method, the analysis population, and the visits through Month 48. It also documents selected serious adverse-event counts and deaths by group. These registry entries describe what the trial was designed to examine and some of the safety information recorded.

The record does not report numerical GMTs, confidence intervals, seropositivity results, or direct primary endpoint comparisons. Consequently, the relative size and precision of antibody responses across schedules cannot be evaluated from the posted record. The endpoint definition alone does not show whether titers were higher, lower or similar between groups. Nor does the absence of numerical results in the record establish that no such results were collected or analyzed.

The serious adverse-event counts are likewise descriptive. Without reported attribution, analysis methods and comparative estimates, they do not establish whether an event was caused by TDV or placebo, or whether the schedules differed in risk. The record’s selected counts also do not represent every safety outcome listed in the trial description.

Randomization and masking describe important design features, but statistical conclusions still depend on outcome reporting and analysis. Interpretation of the primary endpoint would require the group-by-visit estimates, uncertainty intervals, analysis denominators, and a clear account of the intended comparisons. Interpretation of safety would benefit from fuller outcome reporting and the rules used to classify and analyze events. Until those results and methods are available in the registry record, conclusions about comparative immunogenicity or safety cannot be drawn from the available information.

13. Why This Trial Matters Statistically

This trial illustrates how a clinical study can have a multidimensional primary outcome. The antibody endpoint was not a single score: it comprised measurements for each of the four dengue serotypes over visits extending through Month 48. The vaccination groups also differed by timing, including schedules with TDV on Days 1 and 91, on Day 1 alone, or on Days 1 and 365. These design features make it important to define which schedule comparisons are central and how results across serotypes and visits will be interpreted.

It also shows why an endpoint label is not enough for statistical interpretation. The registry specifies a geometric mean, a 95% confidence interval and the analysis population, but numerical GMT results and the method for comparing schedules are not reported. Without estimates and uncertainty, the clinical question remains identifiable while the size and precision of any observed differences remain unknown.

The trial’s safety listings demonstrate a related distinction between descriptive counts and comparative evidence. Serious adverse events are reported with group-specific at-risk figures, but the registry does not state event attribution or report a comparative analysis. Readers need these contextual details before treating group counts as evidence of a schedule-related difference.

Finally, the per-protocol immunogenicity population, repeated assessments and multiple serotypes make transparent reporting of analysis populations, missing data and multiplicity especially relevant. Reporting those elements alongside estimates would allow readers to understand which participants contributed to each result and how much uncertainty remains. The registry record supplies an outline of the question and design, but not enough numerical outcome information to resolve the comparative statistical question.

14. 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.

A key limitation for interpreting the posted record is that numerical primary endpoint results are not reported. The record gives no GMT estimates or confidence intervals by group, serotype and visit, and no direct contrast among schedules. It therefore cannot show the observed pattern of antibody responses or their precision. Numerical results for the listed seropositivity outcome and most other secondary outcomes are also not reported in the registry record.

The primary endpoint was defined for a Per Protocol Set within the immunogenicity subset, rather than all enrolled participants. Although the eligibility criteria for this set are described, the number analyzed by group and visit is not reported. The record does not describe exclusions in detail, missing immunogenicity measurements, or the approach to missing data. These details matter when interpreting a subset that is assessed repeatedly over time.

The record does not report the planned primary comparison, analysis model, baseline adjustment, handling of assay limits, multiplicity strategy, or sensitivity analyses. It also does not provide the rationale for the sample size or details of any interim analyses. These methods are not reported in the registry record and should not be inferred from the study’s phase or enrollment.

For safety, serious adverse-event counts and selected event terms are available, but attribution and comparative analyses are not reported. The figures should not be treated as evidence of causation or as a complete account of every safety outcome in the trial. The limits of the registry summary constrain what can be concluded; they do not establish that the trial did not collect additional information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Immunogenicity of Different Schedules of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Healthy Participants — NCT02302066.
• Registry record last updated 2020-02-24; status last verified 2020-02.
• Results first posted 2020-02-24.
• 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.

18. Record Summary

The registry record describes a completed Phase II, randomized, quadruple-masked, parallel-group trial of TDV schedules and placebo in healthy participants aged 2 and <18 years living in dengue-endemic countries in Asia and Latin America. The listed enrollment is 1800. The study began on 2014-12-05 and reached primary completion on 2019-02-18.

The primary outcome was geometric mean neutralizing-antibody titers for DENV-1, DENV-2, DENV-3 and DENV-4, measured by MNT50 through Month 48 in the Per Protocol Set within the immunogenicity subset. Numerical primary endpoint results and direct comparisons are not reported in the registry record. Serious adverse-event counts and deaths are listed by group, but attribution and comparative safety analyses are not reported.