Safety and Immunogenicity With Two Different Serotype 2 Potencies of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Adults in Singapore: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Immunogenicity With Two Different Serotype 2 Potencies of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Adults in Singapore (NCT02425098), a randomized phase 2 study. The primary outcome is Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 15.

2. Clinical Question

The study’s stated purpose was to assess post-vaccination neutralizing antibody response by vaccine group. Its focus was immunogenicity—measured antibody response—not a clinical endpoint such as dengue illness. The randomized, controlled comparison was designed to examine responses associated with the two vaccine formulations in the enrolled adult population. No conclusion about the relative antibody response can be drawn from the endpoint description alone: the registry record does not report the observed estimates or a statistical comparison.

3. Trial Design

This was a Phase II, randomized, controlled, double-blind trial with a parallel-group model and quadruple masking. It enrolled 351 adults in Singapore and is listed as completed. The recorded study dates are 2015-06-03 for the start and 2017-09-18 for primary completion. The interventions were HD-TDV and TDV, both described as tetravalent dengue vaccine candidates.

Each arm description specifies a 0.5 mL subcutaneous injection on Day 1. The descriptions identify live attenuated vaccine strains for DENV-1, DENV-2, DENV-3, and DENV-4. The study title identifies the contrast as two different serotype 2 potencies, but the specific potency values are not reported in the registry record. The available arm-description text does not provide a complete quantitative description of the high-dose formulation, so the precise potency contrast cannot be reconstructed from that text.

Random allocation and a parallel-group design support a between-group comparison: participants were assigned to a vaccine group, and the groups were followed under the trial’s masking arrangement. The registry identifies masking as quadruple but does not report which roles were masked or how masking was maintained. It also does not report the randomization sequence method, allocation concealment procedure, or details of any stratification.

The primary endpoint was geometric mean neutralizing antibody titer for each dengue serotype at Day 15, measured by microneutralization test. The stated primary population was the per-protocol set. The record also lists safety outcomes, antibody measures by baseline seropositivity status, and vaccine-viremia outcomes. Although the record lists 19 outcome measures, it does not provide analysis records. The primary endpoint’s observed results and the detailed statistical analysis plan 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: Healthy volunteers were enrolled and randomized in 1:1 ratio to receive single injection of either high-dose tetravalent dengue vaccine (HD-TDV) or tetravalent dengue vaccine (TDV).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per-protocol set (PPS) included all randomized participants who received study vaccine and for whom valid pre-dosing and at least one valid post-dosing MNT result was available, and who had no major protocol violations. Here 'number analyzed' refers to participants with valid MNT results available at given time-point.

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 set included all randomized participants who received the study vaccine.

6. Primary Endpoint

The registry lists the primary outcome as Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 15, measured over Day 15.

The primary endpoint was the geometric mean neutralizing antibody titer (GMT) for each of the four dengue serotypes at Day 15. Titers were assessed by microneutralization test (MNT). This laboratory test measures the capacity of antibodies in a sample to neutralize virus under the test conditions. The endpoint therefore describes an immune response measured in blood, rather than the occurrence of dengue disease.

A geometric mean is a summary suited to measurements that vary multiplicatively and may have a skewed distribution. In general, such a mean is obtained by working with logarithms of the measurements, averaging on that scale, and transforming the result back. The registry specifies a 95% confidence interval as the dispersion measure. In general, a confidence interval describes the statistical uncertainty around an estimate under the analysis assumptions; it is not a guarantee that the true value lies within the interval.

Measuring each serotype separately matters because a tetravalent vaccine is intended to address four dengue serotypes, and the antibody response may differ by serotype. The endpoint description does not establish that a particular GMT is a validated threshold for protection, nor does it demonstrate prevention of infection or clinical illness. The registry record does not report the Day 15 GMT estimates, confidence intervals, or comparative tests. Thus, it identifies what was measured and when, but not the observed magnitude or precision of the antibody responses.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a GMT represent?

A geometric mean titer summarizes antibody measurements when values are better understood as varying by multiplicative rather than additive amounts. In general, the analysis uses logarithms of the titers, calculates an average on that scale, and transforms the average back to the original titer scale. This makes the summary less sensitive to the right-skew that can occur with titer measurements than an arithmetic mean may be. The registry identifies GMT as the primary endpoint summary, but does not report the calculation details, any treatment of values below assay limits, or the resulting estimates.

The GMT is a group-level summary. It does not show the full distribution of individual titers, the proportion of participants with a particular level, or how much individual responses varied. Different distributions can share the same geometric mean. For that reason, the estimate is most informative when read alongside its uncertainty interval and the measurement methods. The registry lists MNT as the assay and a 95% confidence interval as the dispersion measure; assay details beyond that are not reported in the registry record.

How should a confidence interval be read?

In general, a confidence interval communicates the uncertainty associated with an estimated quantity under the statistical model and sampling process. It is not a measure of the spread of individual participant values. For a GMT, it gives a range of values compatible with the data and the method used to calculate the interval. The registry specifies 95% confidence intervals for the primary endpoint, but does not report their limits. Therefore, neither the precision of the titers nor the uncertainty around any between-group contrast can be judged from the registry record.

A confidence interval should be interpreted in relation to the quantity being estimated. An interval for a group GMT describes uncertainty in that group’s summary. To assess a comparison, the relevant interval would be for a defined contrast between groups, or the two group estimates would need to be compared using a suitable method. Separate group intervals alone do not necessarily provide a complete test of a group difference. The registry record does not report a comparative effect estimate or its interval.

Why assess four serotypes separately?

The endpoint is defined separately for DENV-1, DENV-2, DENV-3, and DENV-4. Separate estimates preserve information about responses to each serotype rather than combining them into a single summary that could obscure variation among them. In general, immune responses can differ across components of a multivalent vaccine. The trial’s focus on two serotype 2 potencies makes serotype-specific reporting particularly relevant, but the registry record does not report the potency values or the observed GMT results for any serotype.

Multiple serotype-specific outcomes also create an interpretation issue: looking across several estimates can increase the chance of emphasizing a result that appears unusual by chance. Statistical methods can address multiplicity through prespecified testing sequences, adjusted significance thresholds, or other approaches. Which approach, if any, was used is not reported in the registry record. The existence of multiple endpoint components does not by itself establish that an adjustment was or was not required; that depends on the prespecified objectives and inferential claims.

What does randomization contribute?

In general, random assignment helps make treatment groups comparable at the time of assignment, including with respect to factors that are not measured. That supports a causal interpretation of a between-group contrast when the trial is conducted and analyzed appropriately. Randomization does not ensure that every characteristic is exactly balanced, and it cannot correct problems such as outcome data that are missing for reasons related to response. The record identifies the study as randomized but does not report the sequence-generation method, allocation concealment, or procedures used to address missing outcome data.

The parallel-group design means the comparison is between participants assigned to different vaccine groups. Double-blind and quadruple-masked labels indicate masking was part of the design, but the registry does not identify the specific roles masked or the procedures used to preserve masking. Masking can reduce the influence of expectations on participant reporting and outcome assessment, but its effect depends on implementation. The relevant implementation details are not reported in the registry record.

How should planning illustrations be interpreted?

The registry’s planning illustration is explicitly not the trial’s own design calculation. It is described as using the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. For time-to-event outcomes it gives total events; for other outcomes it gives participants per arm. Such illustrations concern hypothetical planning under stated assumptions. They are not observed power, do not show the probability that the completed trial detected an effect, and do not substitute for the trial’s analysis. The numerical illustration values are not reported in the registry record, and the trial’s own sample-size justification is not reported.

Finally, the listed primary analysis population is per protocol. In general, a per-protocol analysis can exclude randomized participants who did not satisfy specified eligibility or adherence conditions, or who lacked required measurements. Its interpretation therefore depends on the criteria and on how exclusions relate to outcomes and assigned treatment. The registry provides the broad definition—vaccinated randomized participants with valid pre-dosing and at least one valid post-dosing MNT result and no major protocol violations—but does not report participant flow by reason, analysis counts for each serotype, or sensitivity analyses comparing analysis populations.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 19 outcome measures, including the primary Day 15 GMT endpoint, safety outcomes, antibody outcomes assessed by baseline seropositivity status, and vaccine-viremia measures. The primary endpoint itself has separate results for four dengue serotypes. When several outcomes or contrasts are examined, there can be more opportunities for chance findings. In general, a statistical plan may specify a hierarchy of outcomes, adjust testing thresholds, or treat some analyses as descriptive. The registry record does not report whether a multiplicity strategy was specified or applied.

The record lists no analysis records. It does not report the primary endpoint estimates, comparative tests, or the analysis plan details needed to assess which comparisons were confirmatory. It is therefore not possible to determine how multiplicity was handled or how the reported results, if any, were prioritized.

The primary analysis population is described as the per-protocol set. It included randomized participants who received vaccine and had valid pre-dosing and at least one valid post-dosing MNT result, with no major protocol violations. This description identifies criteria for inclusion but does not explain how missing titers were handled, whether any imputation was used, or whether additional sensitivity analyses were conducted. The number analyzed for each serotype is not reported in the registry record.

The registry record also does not report the analysis population definitions for each secondary outcome or how missing safety and laboratory measurements were handled. These omissions limit assessment of whether conclusions might depend on exclusions or incomplete follow-up. They do not demonstrate that the analyses were inappropriate; they mean the information needed to evaluate those methods is not reported in the registry record.

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: retinal tear (0.6%), gastroenteritis (0.6%), barotrauma (0.6%), endometriosis (0.6%), urinary tract infection (0.6%).

The registry reports serious adverse event figures for the two vaccine groups. In the HD-TDV group, 3 serious adverse events were reported among 176 participants at risk. In the TDV group, 3 were reported among 175 participants at risk. Deaths were recorded as 0 in each group. These figures describe the recorded counts; they do not by themselves establish whether events were caused by vaccination or whether the groups differ in risk.

The registry also lists serious-event terms including retinal tear, gastroenteritis, barotrauma, endometriosis, urinary tract infection, and hypokalaemia, each reported as 0.6%. The record does not specify the group attribution for these terms in the listed summary. The percentages and terms should therefore not be used to infer a group-specific pattern from this record alone.

In general, safety comparisons depend on event definitions, follow-up duration, completeness of reporting, and the numbers of participants observed for each outcome. The registry gives serious-event counts and at-risk denominators, but does not provide enough detail to assess timing, relatedness, recurrent events, or comparative uncertainty. The listed counts are descriptive summaries, not proof of equivalence or of a causal relationship.

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

The registry record establishes that a randomized Phase II trial compared HD-TDV with TDV in adults in Singapore, and that the primary immunogenicity endpoint was serotype-specific neutralizing antibody GMT at Day 15. It also describes the MNT assay, the 95% confidence interval as the dispersion measure, and the per-protocol analysis population. These details clarify the intended measurement and the population used for the primary analysis.

The record does not report the GMT estimates, confidence intervals, or statistical comparisons. It therefore does not show the magnitude, direction, or precision of the antibody responses in either group. Without those results, it is not possible to say whether the observed responses were higher in one group or whether the data supported a difference. The vaccine-specific serotype 2 potency values are also not reported in the registry record, which limits description of the exact formulation contrast.

Even if numerical GMT results were available, an antibody endpoint would need to be interpreted as an immune-response measure. In general, a laboratory antibody response does not by itself establish prevention of infection, dengue illness, or other clinical outcomes. The primary endpoint is not a clinical efficacy endpoint, and the registry record does not report clinical outcomes that would resolve those questions.

The safety summary reports serious adverse event counts of 3 in each group and no deaths in either group. These are descriptive figures. They do not establish that the vaccine groups have equal safety profiles, nor do they identify whether an event was caused by vaccination. The record does not report comparative uncertainty or the detailed information needed to assess event timing and relatedness.

Accordingly, the supported conclusion is about the trial’s design and intended outcomes, not the direction or clinical importance of its primary result. The numerical immunogenicity findings and detailed analysis methods are not reported in the registry record. That absence should not be read as evidence of no effect; it means the record does not permit a result-based conclusion.

13. Why This Trial Matters Statistically

This trial is statistically notable for comparing two formulations that the title distinguishes by serotype 2 potency while measuring responses to all four dengue serotypes. That design frames a focused immunogenicity question: whether the formulation contrast is reflected in serotype-specific neutralizing antibody measurements. Separate GMT estimates can preserve differences across serotypes that a combined summary could conceal. The registry record, however, does not report the estimates or the potency values needed to quantify that contrast.

The choice of a per-protocol population also matters for interpretation. The record specifies that participants needed to receive study vaccine, have valid pre-dosing and at least one valid post-dosing MNT result, and have no major protocol violations. That definition makes the analysis population explicit at a broad level. The absence of analysis counts and participant-flow details makes it difficult to assess how many randomized participants contributed to each serotype estimate or how exclusions might affect interpretation.

The trial also illustrates the difference between a laboratory immunogenicity endpoint and a clinical outcome. GMTs summarize neutralizing antibody titers, whereas clinical benefit would require evidence about outcomes such as dengue illness. The endpoint can characterize an immune response, but it does not by itself answer a clinical efficacy question.

Finally, the registry lists multiple outcomes and no analysis records. This highlights why prespecified analysis methods and transparent reporting matter: readers need to see the estimates, uncertainty, analysis populations, and multiplicity approach to judge how securely an observed pattern supports a claim. Those details are not reported in the registry record. The trial design identifies a meaningful statistical comparison, while the available registry information is insufficient to assess its numerical findings.

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.

The main limitation for interpreting this trial from the registry record is that the primary endpoint results are not reported. There are no group-specific Day 15 GMT estimates, confidence intervals, comparative effect estimates, or tests. As a result, the direction, size, and precision of the antibody responses cannot be evaluated.

The exact serotype 2 potency values for the two vaccines are not reported in the registry record. Although the title identifies the comparison as two different serotype 2 potencies, the available formulation description does not permit a precise quantitative account of the contrast. The specific roles included in quadruple masking, the randomization procedure, and allocation concealment are also not reported.

The per-protocol definition is given, but analysis counts by serotype and participant flow are not reported. The record does not describe missing-data methods, sensitivity analyses, or whether additional analysis populations were used. These details matter because the primary analysis required valid post-dosing MNT data and excluded participants with major protocol violations.

The registry lists 19 outcome measures but no analysis records. The multiplicity approach, detailed statistical plan, and sample-size justification for the trial are not reported in the registry record. The safety summary gives serious adverse event counts and deaths, but does not provide detailed timing, relatedness, or comparative uncertainty. These reporting limitations restrict assessment of the results; they do not establish that the trial’s conduct or analyses were deficient.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Immunogenicity With Two Different Serotype 2 Potencies of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Adults in Singapore — NCT02425098.
• Registry record last updated 2019-08-28; status last verified 2019-07.
• Results first posted 2019-08-28.
• 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

NCT02425098 is a completed Phase II, randomized, controlled, double-blind, quadruple-masked, parallel-group trial of HD-TDV versus TDV in adults in Singapore. Enrollment was 351. Both vaccine descriptions specify a 0.5 mL subcutaneous injection on Day 1. The primary endpoint was MNT-based neutralizing antibody GMT for each dengue serotype at Day 15, with a 95% confidence interval specified as the dispersion measure and the per-protocol set identified as the primary analysis population.

The record lists 19 outcome measures, including safety, serotype-specific antibody, and vaccine-viremia outcomes, but lists no analysis records. Primary GMT estimates, comparative results, and their confidence intervals are not reported in the registry record. Serious adverse events were recorded in 3 participants in each group; deaths were recorded as 0 in each group. The record does not provide the detailed analysis methods needed to evaluate missing data or multiplicity.