Immunologic Mechanisms of Immune Interference and/or Cross-Neutralizing Immunity After CYD Tetravalent Dengue Vaccine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Immunologic Mechanisms of Immune Interference and/or Cross-Neutralizing Immunity After CYD Tetravalent Dengue Vaccine (NCT01943825), a randomized phase 2 study. The primary outcome is Geometric Means Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype Strains.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group phase 2 study with enrollment of 90 participants. The registry record lists the study as completed, with a start date of 2013-11-05 and primary completion date of 2015-11-25. It does not report the allocation ratio or further details of the randomization procedure.

Four groups received different schedules. Group 1 received CYD dengue vaccine at 0, 2 and 6 months. Group 2 received CYD dengue vaccine at 0, 6 and 12 months. Group 3 received CYD dengue vaccine at 0, 2 and 6 months and Japanese encephalitis vaccine at 0 and 1 months. Group 4 received Japanese encephalitis vaccine at 0 and 1 months, followed by CYD dengue vaccine at 7, 9 and 13 months.

The schedules therefore varied both the spacing of the dengue vaccine doses and the timing of Japanese encephalitis vaccination relative to them. The study aim included evaluating a compressed dengue-vaccine schedule and describing immune responses when Japanese encephalitis vaccine was given with or before the dengue schedule. Because the trial was open-label, masking was not used.

The primary outcome was geometric mean titers of antibodies against each of the four parental dengue virus serotypes. The stated measurement times were before injections 1, 2 and 3; 28 days after each of those injections; and 6 months after injection 3. Secondary outcomes included antibody measurements in groups receiving Japanese encephalitis vaccine, vaccine viremia, and solicited injection-site and systemic reactions. The registry record does not report a single prespecified pairwise comparison that represents all four schedules.

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: A total of 90 participants were enrolled and randomized in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on full analysis set which included participants who received at least one injection of CYD dengue vaccine or JE vaccine and had at least one blood sample drawn and valid post-injection serology result. Here, 'Number analyzed' = participants with available data for each specified category.

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: Analysis was performed on safety analysis set which included all participants who received at least one dose of CYD dengue vaccine or JE vaccine.

6. Primary Endpoint

The registry lists the primary outcome as Geometric Means Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype Strains, measured over Pre-injection 1, 2 and 3; 28 days post-injection 1, 2 and 3; and 6 months post-injection 3.

The primary endpoint is the geometric mean titer (GMT) of antibodies against each of the four parental dengue virus serotypes, measured using a plaque reduction neutralization test (PRNT). The registry record expresses the measurement in titers (1/dilution) and gives the assay’s lower limit of quantitation as a titer of 10 (1/dilution). Measurements were planned before injections 1, 2 and 3, 28 days after each injection, and 6 months after injection 3.

A GMT summarizes antibody titers on a multiplicative scale. In general, this scale is appropriate when measurements vary across orders of magnitude: transforming titers to logarithms makes their central tendency easier to summarize, and transforming back gives a geometric mean. The registry record specifies a 95% confidence interval for the GMT. In general, a confidence interval describes uncertainty around an estimate under the analysis assumptions; it is not a range that contains every participant’s titer.

Measuring each serotype separately retains information that a single combined antibody measure could conceal. Measurements soon after doses describe the antibody response at specified times, while the later measurement addresses persistence after the third dose. These are distinct features of the response, not interchangeable outcomes. The registry record gives the endpoint definition and measurement schedule, but numerical GMT estimates and confidence intervals are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary outcome as geometric mean titers with 95% confidence intervals. It does not report the numerical estimates, the analysis model, or the specific methods used to construct those intervals. The following explains the statistical ideas relevant to the named outcome in general; it does not attribute an unreported method to this study.

What does a geometric mean summarize?

Antibody titers are dilution measurements and are often summarized on a logarithmic scale. In general, a geometric mean is found by taking the mean of the log-transformed observations and transforming that mean back to the original scale. This approach treats multiplicative changes symmetrically: a change by a given factor in one direction is handled comparably to a change by that factor in the other direction. It can be more suitable than an arithmetic mean when values are right-skewed or vary multiplicatively.

A GMT is a group summary, not a description of every individual. Participants can have different titers around the group estimate. The confidence interval reflects uncertainty in the estimated group-level GMT, subject to the assumptions of the analysis. It does not show the full spread of individual responses. The registry specifies a 95% confidence interval but does not report its bounds or explain the method used to calculate it.

Why retain the serotypes and time points?

The primary outcome concerns each of the four parental dengue virus serotypes separately. In general, keeping outcomes separate can reveal patterns that an overall summary would obscure. Responses might differ across serotypes or time points; a combined measure could hide those differences. The record’s measurement schedule includes baseline measurements before each of the three injections, measurements 28 days after each injection, and a later measurement 6 months after injection 3. The post-injection measurements describe responses at defined points, while the later measurement concerns persistence. They answer related but distinct questions.

Repeated measurements from the same participant are statistically dependent: measurements from one person tend to be more related to one another than to measurements from different people. In general, an analysis of repeated observations should account for that dependence if it estimates changes over time or compares trajectories. The registry record does not report whether the analysis used a repeated-measures model, a transformation-based method, or another approach.

What does the assay limit mean?

The stated lower limit of quantitation is a titer of 10 (1/dilution). In general, a result below an assay’s quantitation limit is not measured with the same precision as a result within the quantifiable range. The method used to handle values below the limit can affect summaries, especially if many observations fall below it. The registry record does not say how such values were handled in the statistical analysis. The limit is an assay property, not a clinical threshold, and the endpoint description does not assign it a clinical interpretation.

How do schedule comparisons need to be read?

There are four schedules, and they differ in dengue-dose timing and in whether Japanese encephalitis vaccine was administered alongside or before the dengue course. In general, comparisons among several groups can answer different questions depending on which schedules are contrasted and at what time. A comparison of two dengue schedules without Japanese encephalitis vaccine is not the same question as a comparison involving coadministration or prior Japanese encephalitis vaccination. The registry record does not report a single primary contrast or a model that accounts for all these differences.

Randomization can support comparisons between assigned groups by reducing systematic differences at baseline on average, but interpretation still depends on follow-up, analysis populations, missing data, and the prespecified comparison. The registry record states that allocation was randomized and that masking was none. It does not provide further randomization details or describe blinding of laboratory measurements.

The record also lists viremia and solicited reactions as secondary outcomes. In general, counts of participants with an event describe how many met an outcome definition, whereas an event rate would also require a defined time or exposure basis. The registry lists participant counts for adverse outcomes but does not provide an inferential analysis. No unreported statistical model, multiplicity adjustment, or sample-size rationale can be inferred from the endpoint descriptions alone.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome includes four serotypes and multiple scheduled measurement times. Secondary outcomes add antibody titers in particular groups, detectable vaccine viremia, Japanese encephalitis antibody titers, and solicited reactions. This creates many possible summaries and comparisons. In general, when many hypotheses are tested, the chance of at least one apparently unusual result can rise unless the analysis plan addresses multiplicity. The registry record does not report whether multiplicity was controlled, which comparisons were designated as confirmatory, or whether any outcome hierarchy was used.

The registry record describes a full analysis set as participants who received at least one injection of CYD dengue vaccine or Japanese encephalitis vaccine and had at least one blood sample drawn and a valid post-injection serology result. It also indicates that the number analyzed was based on participants with available data for each specified measure, but the corresponding description is incomplete in the registry record. The record does not report the number analyzed at each time point, the handling of missing observations, or the reasons for missing data.

In general, missing measurements can affect estimates if the likelihood of missingness is related to participants’ outcomes or characteristics. Repeated measurements also mean that the number with usable data can vary by time point. Without counts and a stated missing-data method, the degree to which incomplete follow-up affects each GMT estimate cannot be assessed.

The registry lists 0 analyses and does not report primary-outcome estimates or a statistical analysis plan. It therefore does not establish how multiplicity, missing data, or analysis populations were handled beyond the stated full analysis set definition. These omissions limit interpretation of any numerical claims that might otherwise be associated with the study.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: alcoholic pancreatitis (4.0%), cellulitis (4.0%), jaw fracture (4.0%), drug dependence (4.0%).

The registry lists serious adverse events by study group. The counts of participants affected are 3 in Group 1, 0 in Group 2, 0 in Group 3, and 1 in Group 4. Deaths are listed as 0 in every group. The registry separately lists other adverse events affecting 18 participants in Group 1, 15 in Group 2, 17 in Group 3, and 20 in Group 4. These are reported counts, not percentages or adjusted comparisons.

In general, adverse-event counts should be interpreted alongside the number at risk, the observation period, and the event definitions. The registry lists 25 participants at risk for serious events in Groups 1, 3 and 4, and 15 in Group 2; the same group-specific counts are listed for other events. Counts alone do not establish whether differences reflect risk, chance, follow-up, or other factors. The registry record does not report a statistical comparison of these safety counts.

The serious-event terms listed are Alcoholic pancreatitis, Cellulitis, Jaw fracture and Drug dependence, each with 4.0%. The record does not specify the denominator for those percentages in the listing or state that the events were caused by vaccination. A reported event during a trial is not, by itself, evidence of a causal relationship.

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

The study’s stated purpose was to examine immune responses under different CYD dengue vaccine schedules, including schedules involving Japanese encephalitis vaccine. The registry record defines a repeated antibody-titer outcome measured against each of the four dengue serotypes, with measurements after doses and during follow-up. It also identifies safety and other immune outcomes. This information establishes what the investigators intended to describe, not what the numerical results were.

The record does not report GMT estimates, confidence intervals, or other primary outcome results. It therefore does not show the observed size or direction of antibody responses, whether responses differed across schedules, or how precisely any such differences were estimated. It also does not report analysis results for the listed secondary outcomes. No conclusion about the relative immune response under the four schedules can be drawn from the endpoint definitions alone.

The safety listing records adverse events and deaths by group. Those counts provide a descriptive record, but without comparative analysis or additional context they do not establish that one schedule was safer or less safe. The event terms and percentages also do not establish that an event was caused by a vaccine.

In general, immunogenicity measures describe an immune response as assessed by a specified assay; they are not, by themselves, direct measures of clinical protection. This study’s posted primary endpoint is a laboratory antibody measure. The registry record does not report clinical efficacy outcomes that would show whether vaccination prevented dengue illness, nor does the endpoint description establish a clinical threshold for protection.

Thus, the registry record supports an account of the trial’s design, schedules, planned measurements, and listed safety counts. It does not support a conclusion about whether a particular schedule produced a larger or more persistent antibody response, whether any difference was statistically meaningful, or what the findings imply for clinical outcomes.

13. Why This Trial Matters Statistically

This trial raises several statistical issues that are common in clinical immunology studies. The outcome is measured repeatedly, separately for four serotypes, and across four different schedules. Those dimensions matter because an overall summary could conceal variation by serotype, time, or vaccination schedule. Describing the endpoint clearly is therefore essential to understanding what a reported estimate would represent.

The schedule groups also differ in more than one way. The timing of CYD dengue vaccine doses varies, and Japanese encephalitis vaccine is given alongside the dengue schedule in one group and before it in another. A comparison must be tied to a clearly stated question: the effect of dose spacing, the response when vaccines are given in a particular temporal relationship, or another contrast. The registry record does not identify one comparison as the sole analysis, so a single unqualified treatment-effect interpretation would not fit the design description.

The study also illustrates why outcome definitions and results must be distinguished. The record specifies PRNT, a lower limit of quantitation, measurement times, and a confidence-interval type. Those details help define how the primary outcome was intended to be assessed. However, without the estimates, intervals, and analysis methods, readers cannot judge precision or compare schedules statistically.

Finally, the listed safety counts require context about denominators, observation, and event attribution. Descriptive counts can be useful, but they are not substitutes for a stated comparative analysis. Taken together, the record is informative about the questions and measurements, while its lack of posted outcome analyses limits what can be learned about the observed responses.

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 principal limitation for interpreting this trial from its registry record is that numerical primary-outcome results are not reported. Although the outcome, assay, time points, and confidence-interval type are specified, no GMT estimates or interval bounds are available. The registry record lists 0 analyses, so the size, direction, and precision of schedule differences cannot be assessed from the record.

The trial includes four schedules that vary in dengue vaccine timing and in the timing of Japanese encephalitis vaccination. The registry record does not identify a single primary schedule contrast or report analyses that separate these features. This makes it difficult to attribute a potential difference to dose spacing rather than to the presence or timing of the other vaccine.

The analysis-population description is incomplete in the registry record. The record defines the full analysis set using receipt of at least one injection and availability of a valid post-injection serology result, but does not report the number analyzed for each time point, missing-data handling, or reasons for missing measurements. It also does not report how observations below the assay’s lower limit of quantitation were handled.

The record does not describe the statistical model, multiplicity strategy, or rationale for the planned enrollment. It does not report participant characteristics or detailed follow-up information in the outcome material described. Safety counts are listed without comparative analyses, and the relationship of the serious-event terms to vaccination is not specified. These limitations constrain both statistical interpretation and the conclusions that can be drawn from the posted information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Immunologic Mechanisms of Immune Interference and/or Cross-Neutralizing Immunity After CYD Tetravalent Dengue Vaccine — NCT01943825.
• Registry record last updated 2022-03-24; status last verified 2022-03.
• Results first posted 2020-02-05.
• 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

NCT01943825 is a completed randomized, open-label, parallel-group phase 2 study with enrollment of 90 participants. It examined four CYD dengue vaccine schedules, including schedules involving Japanese encephalitis vaccine. The registry lists a start date of 2013-11-05 and primary completion date of 2015-11-25.

The primary outcome was geometric mean antibody titers against each of the four parental dengue virus serotypes, measured by PRNT at baseline-related dose visits, 28 days after injections, and 6 months after injection 3. The assay lower limit of quantitation was a titer of 10 (1/dilution), and the outcome was specified with 95% confidence intervals.

The registry record describes secondary immune, viremia, and safety outcomes but does not report numerical primary results or analysis results. It lists serious adverse events, other adverse events, and deaths by group. The record supports description of the design and planned measurements, but does not establish comparative immune-response findings or causal safety conclusions.