This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study of Yellow Fever Vaccine Administered With Tetravalent Dengue Vaccine in Healthy Toddlers (NCT01436396), a randomized phase 3 study. The primary outcome is Percentage of Flavi Virus (FV) Non-immune Participants With Seroconversion Against YF Antigen After Vaccination With Yellow Fever (YF) Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01436396 |
| Phase | Phase 3 |
| Condition | Dengue, Dengue Hemorrhagic Fever, Yellow Fever |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 792 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Sanofi Pasteur, a Sanofi Company |
| Results posted | Yes |
2. Clinical Question
Population
Healthy toddlers aged 12 to 13 months in Colombia and Peru were enrolled. The primary immune-response analysis focused on participants classified as flavivirus non-immune at baseline. The registry defines this group by antibody levels below 10 (1/dilution) for yellow fever virus and for each of the four parental dengue virus serotypes. The primary endpoint was assessed in the per-protocol set for Stamaril immune response, described as participants without protocol deviations.
Intervention
At enrolment, participants in the CYD Dengue Vaccine Group received Stamaril yellow fever vaccine and the first CYD dengue vaccine injection at separate administration sites during the same visit. The study question concerned whether giving these vaccines concomitantly met the planned non-inferiority objective for the yellow fever immune response.
Comparator
The Placebo Group received Stamaril at enrolment together with placebo matched to the CYD vaccine. The comparison therefore concerned the yellow fever response when Stamaril was administered with CYD dengue vaccine versus with placebo, rather than a comparison of yellow fever vaccination with no yellow fever vaccination.
Primary question
At 28 days after the first injection, did flavivirus non-immune participants given Stamaril with CYD dengue vaccine have a yellow fever seroconversion response that met the study’s non-inferiority objective relative to participants given Stamaril with placebo? Seroconversion was defined as yellow fever antibody levels of at least 10 (1/dilution). The non-inferiority margin and the detailed decision rule are not reported in the registry record.
This is an immune-response question, not a question about clinical yellow fever or dengue illness. The endpoint records whether an antibody threshold was reached after vaccination. It does not directly measure the duration of the antibody response, clinical protection, or the frequency of either disease. The registry also describes secondary aims concerning yellow fever responses in all participants, dengue antibody responses, and safety. Those aims provide context for the trial, but the primary question is specifically about yellow fever seroconversion in the baseline flavivirus non-immune population.
3. Trial Design
The registry describes a randomized, triple-masked, parallel-group phase 3 trial, with enrollment of 792 and completed status. The official title identifies healthy toddlers aged 12 to 13 months in Colombia and Peru. The study was designed to assess the immune response and safety of administering Stamaril yellow fever vaccine concomitantly with tetravalent CYD dengue vaccine. The two groups received their first injections at enrolment, at age 12 to 13 months, with the yellow fever and CYD or placebo injections given at different administration sites.
In the CYD Dengue Vaccine Group, Stamaril was given with the first CYD dengue injection. In the Placebo Group, Stamaril was given with placebo matched to CYD vaccine. The registry’s arm descriptions also list measles, mumps and rubella vaccine, pneumococcal conjugate vaccine, and hepatitis A vaccine at M1, and a later CYD injection at M6. The remaining schedule details are not reported in the registry record. These other vaccinations and later study injections are part of the trial context, but the primary comparison concerns the yellow fever response following the enrolment injections.
Random allocation supports a comparison between assigned groups, while masking is intended to limit the influence of knowledge of assignment on trial conduct or assessment. The registry identifies triple masking but does not report which parties were masked or how masking was maintained. It also does not report the randomization method, allocation ratio, stratification factors, or details of concealment. Those design particulars should not be inferred from the labels alone.
The primary immune-response outcome was assessed 28 days after Injection 1. The primary analysis population was the per-protocol set for Stamaril immune response, defined in the record as participants without protocol deviations. The record reports 296 in the CYD group and 299 in the placebo group for the primary outcome, with seroconversion percentages of 100.0 and 99.7, respectively. The safety summaries use different denominators, so the endpoint and safety populations should not be treated as interchangeable. The registry does not explain all reasons for differences between analysis populations.
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 792 participants who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomized; 787 participants were vaccinated.
Overall Study
| Stage | CYD Dengue Vaccine Group | Placebo Group |
|---|---|---|
| STARTED | 396 | 396 |
| Vaccinated | 394 | 393 |
| COMPLETED | 364 | 354 |
| NOT COMPLETED | 32 | 42 |
Reasons for not completing this period:
| Reason | CYD Dengue Vaccine Group | Placebo Group |
|---|---|---|
| Protocol Violation | 7 | 5 |
| Adverse Event | 1 | 2 |
| Withdrawal by Subject | 19 | 29 |
| Serious adverse event | 2 | 3 |
| Lost to Follow-up | 3 | 3 |
Analysis population for the primary outcome, as defined in the registry: Analysis was performed on Per-Protocol analysis set which included all participants who had no protocol deviations. Per-Protocol analysis set was defined for the Stamaril® vaccine immune response.
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 had received at least 1 dose of CYD dengue vaccine, stamaril® vaccine or placebo.
| Characteristic | Unit | CYD Dengue Vaccine Group | Placebo Group | Total |
|---|---|---|---|---|
| Participants analysed | 394 | 393 | 787 | |
| Age, Categorical: <=18 years | Participants | 394 | 393 | 787 |
| Age, Categorical: Between 18 and 65 years | Participants | 0 | 0 | 0 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Age, Continuous | Months | 12.2 (SD 0.25) | 12.2 (SD 0.25) | 12.2 (SD 0.25) |
| Sex: Female, Male: Female | Participants | 198 | 203 | 401 |
| Sex: Female, Male: Male | Participants | 196 | 190 | 386 |
6. Primary Endpoint
The registry lists the primary outcome as Percentage of Flavi Virus (FV) Non-immune Participants With Seroconversion Against YF Antigen After Vaccination With Yellow Fever (YF) Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo, measured over 28 days Post-Injection 1.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Percentage of participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the percentage of flavivirus non-immune participants who had seroconverted against yellow fever antigen 28 days after Injection 1. The registry says that yellow fever neutralizing antibodies were assessed using a yellow fever virus plaque reduction neutralization test, or YF PRNT50. Seroconversion was defined as a yellow fever antibody level of at least 10 (1/dilution) in participants below that threshold at baseline for yellow fever and each parental dengue virus serotype.
This binary endpoint reduces a laboratory measurement to whether each participant crossed a prespecified antibody threshold. Such a threshold can make an immune-response result easier to interpret as a proportion of participants achieving a defined response. It also discards information about how far above or below the threshold individual antibody measurements lie. The registry’s outcome is therefore a threshold-based immune response, not a direct measure of clinical disease prevention, symptom severity, or duration of immunity.
The baseline restriction is relevant to interpretation: the primary analysis concerns participants classified as flavivirus non-immune, rather than everyone enrolled. The all-participant seroconversion outcome is listed as a secondary outcome. The record states the measurement method and endpoint definition, but does not report the assay’s laboratory procedures, quality-control details, or the non-inferiority margin used for the primary objective.
7. Results Posted in the Registry
- CYD Dengue Vaccine Group: 100.0% (296/296) versus 99.7% (298/299) on control; risk difference 0.3 percentage points (95% CI -0.3 to 1.0), risk ratio 1.00 (1.00–1.01); unadjusted two-proportion z-test p = 0.319.
Risk difference: CYD Dengue Vaccine Group
95% CI: -0.3 to 1.0 percentage points
Recalculated from the posted summary statistics
8. Secondary Efficacy Endpoints
The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.
| Secondary outcome | Type | Effect measure | Estimate (95% CI) | Planning size, 80% power |
|---|---|---|---|---|
| Percentage of All Participants With Seroconversion Against YF Antigen After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo | Binary Endpoint | Risk difference | -1.1 pts (-2.3 to 0.2) | 1,107 per arm |
Percentage of All Participants With Seroconversion Against YF Antigen After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
- Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
- Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
- Result:
- CYD Dengue Vaccine Group: 98.7% (373/378) versus 99.7% (375/376) on control; risk difference -1.1 percentage points (95% CI -2.3 to 0.2), risk ratio 0.99 (0.98–1.00); unadjusted two-proportion z-test p = 0.102.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CYD Dengue Vaccine Group and the control. The interval gives the range of effects that remain compatible with the data.
The registry lists 13 secondary outcomes, including yellow fever seroconversion and antibody measures, dengue antibody measures, and safety outcomes. The posted all-participant yellow fever seroconversion result is 98.7% in the CYD Dengue Vaccine Group and 99.7% in the Placebo Group. The registry also reports a sponsor difference in percentage of -1.06, with a 95% confidence interval from -2.81 to 0.383, for that outcome. These secondary results address a broader population than the primary analysis, which is restricted to flavivirus non-immune participants.
The other secondary outcomes include geometric mean titers, geometric mean titer ratios, antibody-threshold summaries, and dengue antibody responses. The registry lists these outcomes, but the registry entries do not include numerical results for each one. A complete overall pattern across all secondary endpoints therefore cannot be characterized from the reported information. The secondary endpoint list indicates that the trial considered both yellow fever and dengue immune responses and safety, but does not by itself establish a consistent direction of effect across those outcomes.
In general, secondary outcomes help describe different dimensions of a trial, but they are usually less definitive than a prespecified primary outcome. Testing many outcomes creates more opportunities for apparently notable findings to arise by chance. Unless a multiplicity strategy is specified, individual unadjusted results should be interpreted cautiously and as supportive or exploratory rather than as independent confirmation. The registry does not report a multiplicity adjustment strategy. It also does not report a complete statistical analysis plan that would show how the secondary tests were prioritized or interpreted.
The secondary all-participant result is related to the primary result because both concern yellow fever seroconversion after Stamaril given with CYD or placebo. It is not the same estimand: the baseline population differs. A broader population result should not be substituted for the primary flavivirus non-immune analysis. Likewise, antibody titers and dengue responses measure different outcomes from crossing the yellow fever seroconversion threshold. Their relevance is complementary, but each requires its own estimate and uncertainty assessment.
Secondary outcomes registered for this trial, for reference (only those above were recalculated):
- Percentage of All Participants With Seroconversion Against YF Antigen After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
- Geometric Mean Titers (GMTs) of YF Antibodies in All Participants Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
- Geometric Mean Titer Ratios (GMTRs) of YF Antibodies in All Participants Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
- Percentage of All Participants With YF Antibody Titers of >=10 (1/Dil) Before and After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
- GMTs of Dengue Virus Antibodies Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
- GMTRs of Dengue Virus Antibodies Following Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
- Percentage of Participants With Antibody Titer >= 10 (1/Dil) Against Each Serotype With Parental Dengue Virus Strains After Vaccination With YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
- Percentage of Participants With Antibody Titer >= 10 (1/Dil) Against at Least 1, 2, 3, or 4 Serotypes With Parental Dengue Virus Strains After YF Vaccine (Stamaril®) Concomitantly With Either CYD Dengue Vaccine or a Placebo
9. Statistical Interpretation
In the primary per-protocol analysis, the registry reports seroconversion in 100.0% of the CYD Dengue Vaccine Group and 99.7% of the Placebo Group. The registry’s own analysis reports a difference in percentage of 0.334, with a 95% confidence interval from -0.976 to 1.87. The posted percentages are both close to the upper end of the possible range for this binary outcome. They indicate that nearly all participants in each analyzed group met the stated antibody threshold at the assessment.
The trial’s stated primary objective was non-inferiority, not superiority. A finding of non-inferiority depends on comparing the uncertainty around the estimated difference with a prespecified margin. The margin is not reported in the registry record, so the non-inferiority decision rule cannot be independently reconstructed from the posted result alone. The confidence interval describes the range of differences compatible with the reported data and analysis, but its relation to the missing margin is necessary to interpret the formal non-inferiority question.
A simple unadjusted recalculation from the posted summary statistics gives a risk-difference estimate close to zero, and its unadjusted p-value is 0.319. That p-value is not a test of non-inferiority: a conventional test for a difference and a non-inferiority test address different hypotheses. The primary comparison’s p-value should therefore not be used as a substitute for the registry’s own non-inferiority analysis. The record reports no p-value for the sponsor’s analysis.
The endpoint is seroconversion at one specified follow-up, not clinical infection or long-term protection. The result does not establish that the groups had identical immune responses, because observed percentages and estimates are subject to sampling uncertainty. Nor does it show that every participant in either group responded in the same way. It describes the proportion crossing a laboratory threshold in the stated analysis population.
The baseline flavivirus non-immune restriction matters. Results in that group cannot automatically be applied to participants with pre-existing flavivirus antibodies; the registry lists a separate all-participant analysis as secondary. The trial also included safety and dengue antibody aims, but those are distinct questions. Overall, the posted primary outcome is consistent with very high short-term seroconversion in both analyzed groups. The formal non-inferiority conclusion remains tied to the sponsor’s analysis and its decision criterion, which is not fully documented in the registry record.
10. Statistical Methods Explained
The primary outcome is binary: each participant either met the seroconversion threshold or did not. A percentage describes the share meeting that threshold within an analysis group. For a comparison between groups, a difference in percentages expresses how far apart the observed group response rates are on an absolute scale. A value near zero means the observed rates are close, but it does not by itself establish equivalence or non-inferiority. Those conclusions require a prespecified margin and an analysis that addresses the relevant hypothesis.
What does non-inferiority ask?
In general, a non-inferiority trial asks whether the response with an intervention is not unacceptably worse than the response with a comparator, according to a margin fixed in advance. The margin defines how much difference can be tolerated for the study’s purpose. The registry identifies non-inferiority as the primary objective and reports an analysis labelled non-inferiority, but the margin and the detailed statistical decision rule are not reported in the registry record. Without them, a reader cannot verify the formal decision by checking whether the confidence interval satisfies the planned criterion.
The registry reports the sponsor’s difference in percentage and its confidence interval. A confidence interval communicates statistical uncertainty around an estimate under the analysis assumptions. It is not a range containing a guaranteed proportion of individual participant responses, nor is it a probability statement that the true effect lies within its endpoints. For non-inferiority, the interval must be interpreted against the margin, not simply judged by whether it includes zero. The sponsor’s interval includes values on either side of zero, but zero is not the decision boundary for non-inferiority.
How should the recalculation be read?
A recalculated comparison based on posted group summaries is an unadjusted calculation. It is useful as a transparent check on the direction and broad scale of the posted percentages, but it may not reproduce an analysis that uses a specified model, population definition, or method for confidence intervals. The registry’s primary reported analysis is the sponsor’s non-inferiority analysis. The recalculated p-value is an unadjusted test and does not answer the non-inferiority question. Because the record does not identify the sponsor’s statistical method, the methodological source of any differences in estimates or intervals is not reported in the registry record.
For binary outcomes, different choices of effect measure can also communicate different aspects of the same data. A risk difference compares absolute percentages; a relative measure compares them in relation to one another. The registry’s sponsor analysis is expressed as a difference in percentage, while a simple recalculation is described as a risk difference. Estimates should be read on their stated scales rather than compared as though their units were necessarily identical. No extra transformation is needed to interpret the sponsor’s reported result.
Why do the analysis populations matter?
The primary endpoint population is the per-protocol set for Stamaril immune response, which the registry describes as participants without protocol deviations. This differs conceptually from an analysis that includes everyone according to assigned group, regardless of adherence or deviations. In general, per-protocol analyses focus on participants who followed specified study requirements, while intention-to-treat analyses preserve the randomized assignment comparison. Each can be informative, but non-inferiority assessments often depend particularly on understanding how the analysis population affects the result. The registry does not report an intention-to-treat primary analysis or provide enough information to compare alternative population definitions.
The baseline definition also determines who contributes to the primary result. Participants were classified as flavivirus non-immune using the stated antibody thresholds. The all-participant yellow fever seroconversion outcome is secondary and answers a broader population question. Results from these populations are not interchangeable, because prior antibody status can be relevant to the starting point for an immune-response assessment.
What do the secondary planning illustrations mean?
The registry includes a planning illustration based on the observed effect for the all-participant secondary seroconversion comparison. In general, a sample-size illustration estimates the number of participants per arm that would be needed under stated assumptions to detect a specified effect with a chosen power and significance level. The illustration lists planning for 100%, 75%, and 50% of the observed effect, with participants per arm for 80% power and participants per arm for 90% power. These are planning scenarios, not observed power and not the trial’s original sample-size justification. The registry explicitly identifies them as an illustration computed from the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. The trial’s own sample-size assumptions are not reported in the registry record.
The illustration is based on a secondary outcome and should not be taken as evidence that the trial was designed or powered according to those calculations. Planning estimates depend on assumptions about the effect to detect and the analysis. A smaller target effect generally requires more information to distinguish it from random variation, but the posted scenarios are not a substitute for a prospectively specified design. The record does not report an interim-analysis plan, stopping rules, or a detailed statistical analysis plan.
Finally, statistical significance and clinical or scientific importance are separate ideas. A p-value summarizes how unusual data would be under a specified null hypothesis and model; it does not quantify the probability that the null is true, the size of an effect, or the quality of the study. A confidence interval adds information about the range of estimates compatible with the data and method. For this trial, the primary question remains a margin-based non-inferiority question, while the unadjusted recalculation is descriptive and exploratory in relation to that objective.
11. Confidence Intervals and Precision
The primary sponsor-reported estimate is a difference in percentage of 0.334, with a 95% confidence interval from -0.976 to 1.87. The interval spans zero, so the registry result does not identify a precise direction of difference between the groups on this scale. Its endpoints also indicate that the data are compatible with values on either side of zero under the sponsor’s analysis. The upper and lower bounds should be interpreted relative to the non-inferiority margin, which is not reported in the registry record.
In general, a confidence interval is a measure of precision for an estimated effect under a particular analysis. A narrower interval indicates less statistical uncertainty than a wider interval, while the interval’s location indicates which effect values are compatible with the data and method. The interval does not show the range of responses among participants, and it does not account for limitations that are not represented in the statistical model, such as unreported analytic choices or potential sources of bias.
The displayed primary group percentages are 100.0% and 99.7%. Percentages near the top of a binary outcome’s scale leave limited room for a higher observed response, and the registry’s estimate should be read in that context. High observed rates do not remove sampling uncertainty or establish that responses are identical. The primary analysis uses 296 and 299 participants in the respective groups, according to the registry’s endpoint data.
The unadjusted recalculation is based on posted summary statistics and is not the sponsor’s non-inferiority analysis. Its confidence interval and p-value should not replace the sponsor-reported interval when interpreting the primary objective. In general, estimates and intervals can differ when the statistical method, population, or effect scale differs; the registry does not report enough method detail to explain any such difference fully. Precision is also specific to the endpoint, follow-up, and analysis set, rather than a statement about all outcomes in the trial.
12. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| not stated | Difference in percentage 0.334 | -0.976 to 1.87 | not reported |
The registry reports the sponsor’s primary non-inferiority analysis as a difference in percentage of 0.334, with a 95% confidence interval from -0.976 to 1.87. The simple recalculation from posted summary statistics is an unadjusted risk-difference analysis. Its estimate is close to zero, and its unadjusted p-value is 0.319. These results are broadly consistent with the posted group percentages being close, but the recalculation is not a replacement for the sponsor’s analysis or its non-inferiority decision.
The two analyses are not interchangeable merely because both concern the same endpoint. The sponsor’s result is explicitly labelled non-inferiority and is expressed as a difference in percentage. The recalculation is a simple unadjusted comparison from summary statistics and does not apply a documented non-inferiority margin. The registry does not report the sponsor’s detailed method or the margin, so the relationship between the methods cannot be fully audited from the record.
The registry’s discrepancy indicator is false. Accordingly, there is no flagged discrepancy that would require prioritizing one result because of a disagreement in the posted data. The sponsor’s own analysis remains the relevant result for the stated primary objective, while the recalculation serves as a limited numerical check. The registry does not report a sponsor p-value for the primary analysis.
13. Multiplicity, Missing Data and Analysis Populations
The registry identifies a primary endpoint and multiple secondary outcomes, but a multiplicity strategy is not reported in the registry record. Multiplicity concerns arise when a study evaluates more than one outcome or makes multiple comparisons. Without a reported strategy, it is not possible to determine whether the trial adjusted significance thresholds, followed a hierarchical testing sequence, or treated secondary analyses as descriptive. The absence of a reported strategy does not establish that no such plan existed; it means the registry record does not document it.
The primary result is labelled as a non-inferiority analysis, but the non-inferiority margin and detailed decision rule are not reported in the registry record. The statistical method used for the sponsor analysis is also not identified. The registry does not report an interim-analysis plan, stopping rules, or a complete statistical analysis plan. These omissions limit the ability to independently reproduce the primary analysis or establish how the trial’s planned hypotheses were organized.
The primary immune-response analysis is described as per-protocol and as including participants without protocol deviations. This population is distinct from a full randomized population analysis. The registry does not report a primary intention-to-treat analysis, a comparison of analysis populations, or a detailed account of missing endpoint data. It therefore does not allow a reader to assess how alternative missing-data assumptions or population definitions might affect the primary conclusion. The reasons for exclusions and the handling of missing antibody measurements are not reported in the registry record.
Analysis populations differ across the endpoint and safety summaries. The primary outcome reports 296 and 299 participants in the two groups, while the safety summaries report 394 and 393 at risk for the listed categories. These denominators should be interpreted in the context of their respective analyses; they should not be combined or treated as the same population. The registry does not explain the full derivation of each analysis set or the relationship between all denominators.
In general, transparent reporting of prespecified hypotheses, multiplicity handling, analysis populations, and missing-data methods helps readers separate confirmatory evidence from exploratory findings. The available record gives the endpoint definitions and selected results, but not all of those methods. Consequently, the primary result can be described as posted, while claims about unreported analysis choices or robustness to missing data cannot be made.
14. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| CYD Dengue Vaccine Group | 35 | 394 | 8.9% |
| Placebo Group | 38 | 393 | 9.7% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| CYD Dengue Vaccine Group | 0 of 394 |
| Placebo Group | 1 of 393 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| CYD Dengue Vaccine Group | 211 of 394 |
| Placebo Group | 193 of 393 |
Most frequent serious adverse event terms
| Event term | Organ system | CYD Dengue Vaccine Group | Placebo Group |
|---|---|---|---|
| Pneumonia | Infections and infestations | 12 of 394 | 11 of 393 |
| Febrile convulsion | Nervous system disorders | 6 of 394 | 4 of 393 |
| Urinary tract infection | Infections and infestations | 4 of 394 | 3 of 393 |
| Acute sinusitis | Infections and infestations | 2 of 394 | 1 of 393 |
| Cellulitis | Infections and infestations | 2 of 394 | 1 of 393 |
| Diarrhoea infectious | Infections and infestations | 1 of 394 | 1 of 393 |
| Gastroenteritis | Infections and infestations | 0 of 394 | 2 of 393 |
| Gastroenteritis viral | Infections and infestations | 1 of 394 | 1 of 393 |
| Accidental exposure | Injury, poisoning and procedural complications | 1 of 394 | 0 of 393 |
| Burns second degree | Injury, poisoning and procedural complications | 1 of 394 | 0 of 393 |
Most frequent non-serious adverse event terms
| Event term | Organ system | CYD Dengue Vaccine Group | Placebo Group |
|---|---|---|---|
| Appetite lost; Post-Any injection | Metabolism and nutrition disorders | 211 of 394 | 193 of 393 |
| Irritability; Post-Any injection | Psychiatric disorders | 179 of 394 | 179 of 393 |
| Crying abnormal; Post-Any injection | Psychiatric disorders | 182 of 394 | 170 of 393 |
| Fever; Post-Any Injection | General disorders | 185 of 385 | 155 of 385 |
| Drowsiness; Post-Any Injection | Nervous system disorders | 140 of 386 | 131 of 386 |
| Injection site Tenderness for CYD dengue vaccine; Post-Any Injection | General disorders | 141 of 386 | 105 of 363 |
| Nasopharyngitis | Infections and infestations | 118 of 394 | 120 of 393 |
| Vomiting; Post-Any injection | Gastrointestinal disorders | 118 of 386 | 105 of 386 |
| Injection site Tenderness for Stamaril® vaccine; Post-Any Injection | General disorders | 98 of 386 | 68 of 386 |
| Pharyngitis | Infections and infestations | 73 of 394 | 52 of 393 |
Serious events with the highest arm-level rate: pneumonia (3.0%), febrile convulsion (1.5%), urinary tract infection (1.0%), gastroenteritis (0.5%), acute sinusitis (0.5%).
The registry’s safety summary reports serious adverse events in the CYD Dengue Vaccine Group with 35 affected participants among 394 at risk, and in the Placebo Group with 38 among 393 at risk. It reports other adverse events in 211 among 394 at risk in the CYD group and 193 among 393 at risk in the placebo group. The record also reports 0 deaths in the CYD group and 1 in the placebo group. These are descriptive counts in the safety summaries, not estimates of causal effect.
The most frequently listed serious adverse event terms are pneumonia at 3.0%, febrile convulsion at 1.5%, urinary tract infection at 1.0%, gastroenteritis at 0.5%, acute sinusitis at 0.5%, and cellulitis at 0.5%. The registry excerpt does not give further details about event timing, severity beyond the serious-event classification, relatedness assessments, or the basis for the listed percentages. It also does not describe whether events were adjudicated or how serious-event reporting was defined beyond the summary label.
In general, adverse-event counts describe what was recorded in the trial, but a group difference alone does not establish that an intervention caused an event. The safety results should be read separately from the immune-response endpoint and with attention to the reported denominators. The registry’s safety data do not establish comparative safety beyond the specific reported summaries.
15. What the Result Does, and Does Not, Mean
The primary result describes short-term yellow fever seroconversion after Stamaril was given with either CYD dengue vaccine or placebo. The registry reports very high percentages in both primary analysis groups at 28 days after Injection 1. This is evidence about whether participants crossed a specified laboratory antibody threshold in the per-protocol flavivirus non-immune population. It is not a direct measure of clinical yellow fever cases, dengue cases, symptoms, or long-term protection.
The design’s central objective was non-inferiority. To decide whether that objective was met, the estimate and confidence interval must be assessed against the prespecified margin. The registry does not report that margin. The posted percentages and sponsor interval can be described, but the missing decision criterion limits an independent assessment of the formal non-inferiority conclusion. The unadjusted recalculation does not solve that limitation because it is not the sponsor’s margin-based analysis.
The result also does not show that the two groups had identical immune responses. A near-zero estimated difference and similar observed percentages are compatible with a range of underlying differences, as reflected by the confidence interval. Nor does a high percentage in the analyzed sample guarantee that every participant responds or that the response persists. The endpoint is binary and threshold-based; it does not describe the full distribution of antibody levels.
The primary analysis is restricted to participants classified as flavivirus non-immune at baseline and analyzed per protocol. It should not be generalized automatically to all trial participants or to people outside the enrolled population of healthy toddlers in Colombia and Peru. The all-participant analysis is secondary and uses a different population. Neither result alone answers every question about concurrent vaccination, later immune responses, or safety.
The secondary outcomes and safety summaries address other aspects of the study, but the registry does not provide complete numerical results for all listed secondary measures. Unadjusted secondary results also carry less evidential weight when no multiplicity strategy is documented. In sum, the record supports a careful description of the measured response at the specified follow-up. It does not, on its own, settle broader questions about clinical effectiveness, duration of response, or safety in other populations.
16. Why This Trial Matters Statistically
This trial illustrates why the wording of a clinical question matters. The main objective is not simply whether the response differed between groups; it is whether administering CYD dengue vaccine with Stamaril met a non-inferiority criterion for yellow fever immune response. That distinction determines which estimate, interval, and decision rule are relevant. A conventional unadjusted difference test does not answer the same question as a margin-based non-inferiority analysis.
It also illustrates the importance of defining the outcome and analysis population precisely. Seroconversion is defined by an antibody threshold, and the primary analysis is restricted to baseline flavivirus non-immune participants in the per-protocol set. The all-participant secondary outcome is not interchangeable with that primary estimand. Clear attention to population and endpoint prevents a result from being generalized beyond what was measured.
The record also shows why confidence intervals and design details need to be read together. The sponsor’s interval communicates uncertainty around the estimated difference, but interpretation for non-inferiority depends on the margin. Without that margin and the complete statistical plan, the estimate can be described but the formal decision cannot be independently checked. This is a reporting limitation, not a reason to replace the sponsor’s analysis with a different calculation.
Finally, the trial includes multiple immune and safety outcomes. Distinguishing the primary result from secondary analyses helps control overinterpretation. The record’s planning illustration is explicitly retrospective and based on an observed secondary effect; it is not evidence of observed power or the original design assumptions. These distinctions are central to responsible statistical reading of a vaccine trial.
17. 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.
- Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.
The registry record leaves important details of the primary non-inferiority analysis unavailable. The non-inferiority margin, sponsor statistical method, and detailed decision rule are not reported in the registry record. Without these, the formal criterion cannot be independently checked. The registry also does not report a complete statistical analysis plan, interim-analysis plan, or stopping rules.
The primary analysis is per protocol, defined as participants without protocol deviations, and is limited to flavivirus non-immune participants. The record does not provide a primary intention-to-treat result or enough information to compare conclusions across analysis populations. Details about exclusions, missing antibody measurements, and how missing data were handled are not reported in the registry record. This restricts assessment of how robust the result is to population and missing-data choices.
The available secondary results are incomplete relative to the outcomes listed. Numerical results are posted for all-participant seroconversion, but the registry entries do not include results for every listed antibody or safety outcome. A comprehensive assessment of the secondary immune-response pattern is therefore not possible from these data alone. The registry also does not report a multiplicity strategy, so individual secondary findings should not be treated as confirmatory without further context.
The trial’s primary outcome is a laboratory threshold at 28 days after Injection 1. It does not measure clinical disease outcomes or duration of response. The registry reports the assay name and response definition but not laboratory quality-control procedures or all assay details. The safety summaries provide counts and selected serious adverse event terms, but not the full event narratives, relatedness assessments, or timing. These reporting limits constrain what can be concluded beyond the posted short-term immune response and descriptive safety information.
18. Related Tutorials
19. Related Statistical Calculators
20. Sources
- ClinicalTrials.gov: Study of Yellow Fever Vaccine Administered With Tetravalent Dengue Vaccine in Healthy Toddlers — NCT01436396.
- Registry record last updated 2022-03-25; status last verified 2022-03.
- Results first posted 2019-07-29.
- 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.
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21. Record Summary
The registry describes a completed randomized, triple-masked, parallel-group phase 3 study of Stamaril yellow fever vaccine given with either CYD dengue vaccine or placebo in healthy toddlers aged 12 to 13 months in Colombia and Peru. Enrollment was 792. The primary outcome was yellow fever seroconversion 28 days after Injection 1 among baseline flavivirus non-immune participants in the per-protocol analysis set.
The registry reports seroconversion percentages of 100.0% for the CYD Dengue Vaccine Group and 99.7% for the Placebo Group. The sponsor’s non-inferiority analysis reports a difference in percentage of 0.334, with a 95% confidence interval from -0.976 to 1.87. The non-inferiority margin and detailed analysis method are not reported in the registry record, limiting independent assessment of the formal decision.
Secondary outcomes include additional yellow fever and dengue antibody measures and safety. The registry also provides descriptive safety counts and a planning illustration based on an observed secondary effect. These secondary and safety results address different questions from the primary endpoint and should be interpreted within their stated populations and reporting limits.