Safety and Immunogenicity of the Live Attenuated Zika Vaccine rZIKV/D4Δ30-713 in Flavivirus-naïve Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Immunogenicity of the Live Attenuated Zika Vaccine rZIKV/D4Δ30-713 in Flavivirus-naïve Adults (NCT03611946), a randomized phase 1 study. The primary outcome is Number of Participants With Solicited Local and General Adverse Events (AEs).

2. Clinical Question

3. Trial Design

This was a randomized, quadruple-masked, parallel-group phase 1 trial of a live attenuated Zika vaccine. The registry lists enrollment of 56 participants and describes the intended population as adults without a history of previous flavivirus infection. The brief study description identifies a double-blind, placebo-controlled evaluation; the formal masking designation in the record is quadruple.

There were two vaccine cohorts and two corresponding placebo groups. Cohort 1 received a single dose of rZIKV/D4Δ30-713 at 10^3 PFU, while Cohort 2 received a single dose at 10^4 PFU. Both vaccine doses were administered by subcutaneous injection in 0.5ml. Participants in each placebo group received a single 0.5ml subcutaneous injection. The registry does not describe the allocation ratio or explain how participants were assigned among the cohorts.

The study was designed to evaluate safety, reactogenicity and immunogenicity. The primary outcome was the number of participants with solicited local and general adverse events, assessed at every visit through Day 28. Listed secondary outcomes include detectable vaccine-induced viremia, infection with the vaccine, immunogenicity, durability of antibody response and the quantity and duration of Zika virus presence.

The record gives a start date of 2018-07-06, a primary completion date of 2022-03-18 and a completed status. The available information does not report the protocol’s detailed conduct, the number enrolled in each cohort at the outset, or whether the final allocation matched any planned allocation.

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.

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Solicited Local and General Adverse Events (AEs), measured over Solicited AE's assessed every visit through Day 28.

The primary endpoint is a count of participants who experienced solicited local or general adverse events. The registry says these events were assessed at every visit through Day 28 and evaluated using the Adverse Event Grading Table in the study protocol. The endpoint is therefore a participant count, rather than a measure of event severity averaged across participants or a time-to-event outcome.

Counting participants can describe how many people experienced at least one event, while avoiding a higher count simply because one person reported several events. In general, solicited event collection uses specified questions or categories to seek reports consistently across participants. This can make the observation process more systematic than relying only on spontaneous reports. The registry record does not provide the protocol’s event categories, grading thresholds, or rules for counting multiple events for this endpoint.

In an early-phase vaccine study, safety and reactogenicity observations help characterize events after administration and can inform later evaluation. However, the primary outcome as registered covers solicited local and general adverse events through Day 28; it does not, by itself, summarize all possible safety outcomes or establish a vaccine’s effect on Zika infection. Although the record defines the endpoint, it does not report a single overall result for it. The posted adverse-event group summaries should not be treated as a substitute for that missing endpoint result unless their definitions and follow-up match the primary endpoint, which is not established in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help distinguish the study design, its endpoint definition and the results actually reported. The registry record describes a randomized parallel-group trial, defines a participant-count endpoint and lists adverse-event counts. It reports no analyses, so statistical methods beyond those explicitly described should not be attributed to the investigators.

What does randomization contribute?

In general, randomization assigns participants to study groups using a chance process. Its purpose is to reduce systematic differences between groups at the time of assignment, including differences that might otherwise influence the outcomes. Randomization does not guarantee that groups will be identical, especially in a modest-sized study, and it does not correct problems that arise after assignment, such as missing outcome measurements or differences in how events are recorded. The registry says the study was randomized, but the method used to generate or conceal assignments is not reported in the registry record.

Why does masking matter?

Masking is intended to limit the influence of group knowledge on study conduct or outcome assessment. This can matter when outcomes depend on participants noticing or reporting symptoms, or when assessors apply judgment. The registry identifies the study as quadruple masked, while the brief description calls it double blind. The information available does not identify which people were masked or explain the masking procedures. It is therefore possible to describe the recorded design label, but not to assess how masking was implemented or maintained.

How should a participant count be read?

A count of participants with an event is a binary-outcome summary at the participant level: each person either meets the event definition or does not. The accompanying denominator indicates the group at risk in the summary. This differs from counting every event occurrence, because an individual participant may have more than one event. The registry’s primary endpoint is a count of participants with solicited local and general adverse events, but the record does not give the single combined result or clarify how its categories and visit-specific observations are combined. The separate adverse-event summary should therefore be read according to its own labels and not assumed to reproduce the primary endpoint.

What would an uncertainty interval mean?

In general, a confidence interval describes a range of values reasonably compatible with the observed data under a specified statistical method. It communicates precision as well as the direction and scale of an estimate. Wider intervals indicate greater uncertainty; narrower intervals indicate greater precision, conditional on the model and assumptions. A confidence interval is not a guarantee that the true value lies in the interval, and it does not remedy limitations in study design or outcome measurement. No confidence intervals for the adverse-event summaries are reported in the registry record, so the precision of group comparisons cannot be assessed from those counts alone.

Why can sparse events be difficult to compare?

General statistical reasoning: when few participants experience an event, estimates of between-group differences can be unstable. A group with no observed events may still have a nonzero underlying event probability. Standard methods can also behave poorly when counts are sparse, depending on the analysis and its assumptions. The registry record does not state a method for comparing the serious adverse-event counts, and no such analysis is listed. It would be inappropriate to infer a significance test, adjusted estimate or confidence interval.

What does the planning illustration represent?

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. It specifies that the effect to detect is a stated fraction of the observed effect. Such calculations are planning scenarios: they ask what sample size would be associated with a chosen effect and assumptions. They are not evidence that the trial was designed that way, and they are not “observed power.” The record does not report the trial’s own sample-size justification. It also does not provide a single primary-endpoint effect in the available results, so the planning assumptions should not be mistaken for a reported treatment comparison.

For general context, over-dispersion refers to variation greater than a model assumes. It is relevant when the outcome and statistical model involve counts whose variability is larger than expected under that model. The primary endpoint is a participant count for a binary event status, not a reported repeated-event count model; the registry does not state that over-dispersion was assessed or that a model requiring such an assessment was used. This general concept should not be read as a description of the investigators’ analysis.

Finally, a statistical analysis plan would ordinarily clarify the analysis population, outcome definitions, treatment contrasts, handling of missing observations and any multiplicity adjustments. These details are not reported in the registry record. Without them, a reader cannot determine whether the observed group summaries were intended as exploratory descriptions, how the primary endpoint was operationalized in analysis, or which inferential claims were planned.

10. Multiplicity, Missing Data and Analysis Populations

The record lists one primary outcome and several secondary outcomes, but it does not describe a multiplicity strategy. Multiplicity arises when several outcomes, comparisons, time points or analyses are evaluated: the more opportunities there are to identify a seemingly notable result, the more important it is to understand whether and how the analysis accounted for that. No adjustment method, hierarchy among secondary outcomes, or prespecified testing sequence is reported in the registry record. It would not be justified to assume that an adjustment was or was not used in an analysis outside the information recorded.

The primary outcome itself is described as having several categories or time points and is not reduced to one comparison in the posted results. The record provides the assessment window through Day 28, but not the event-level results needed to understand those categories or visits. It does not report a single primary-endpoint estimate, confidence interval or p-value. The registry lists no analyses.

Missing-data procedures are also not reported in the registry record. The available information does not explain whether all enrolled participants contributed to each outcome, how missed visits or incomplete event reports were handled, or whether any imputation or sensitivity analyses were planned. The analysis populations are not reported either; the record does not specify an intention-to-treat, per-protocol, safety or other population for each endpoint.

These omissions affect interpretation because estimates can depend on who is included and how incomplete observations are treated. They also limit assessment of whether reported outcomes correspond to the original analysis plan. No inference about the investigators’ procedures should be made in the absence of those details.

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: breast cancer female (5.0%).

The serious adverse-event summary lists the number at risk and the number affected in each group. The affected counts are 0 of 20 for Cohort 1 - Vaccine, 0 of 8 for Cohort 1 - Placebo, 1 of 20 for Cohort 2 - Vaccine, and 0 of 8 for Cohort 2 - Placebo. The record also lists zero deaths in each group. These are descriptive registry counts; they do not, on their own, establish a comparative safety effect or identify whether an event was caused by an intervention.

The record names “Breast cancer female” as the top serious adverse-event term and gives 5.0%. It does not provide enough contextual detail to explain the term’s coding, timing, relationship to treatment or the denominator used for that percentage. That entry should not be interpreted as evidence of causation.

The other-adverse-event summary lists 14 of 20, 6 of 8, 11 of 20 and 6 of 8 for the four groups in registry order. These figures should not automatically be read as the primary endpoint: that endpoint is specifically solicited local and general events assessed through Day 28, and the record does not establish that the separate summary uses the same event definitions and observation period. Counts without uncertainty estimates also leave the precision of comparisons unclear.

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

The results establish that the registry record contains adverse-event summaries for two vaccine dose cohorts and two placebo groups, as well as a defined primary endpoint focused on solicited local and general adverse events through Day 28. They also establish that the registry marks the study as completed and lists safety, reactogenicity and immunogenicity among its aims. These registry entries describe the study and its reported summaries; they are not a complete account of the trial’s findings.

The record does not provide a single result for the primary endpoint or a statistical comparison of vaccine and placebo groups. It does not report confidence intervals, p-values or analysis methods for the displayed adverse-event counts. Accordingly, the numbers cannot support a precise estimate of a comparative effect or a judgment about statistical compatibility with no difference. The one serious adverse event listed in Cohort 2 - Vaccine and the zero counts in the other groups are observations, not proof that an event is or is not associated with a vaccine dose.

The listed outcomes include viremia, infection with the vaccine and antibody responses, but their numerical results are not reported in the information available for this analysis. Outcome names indicate what investigators planned to assess; they do not show what was observed. The record therefore cannot establish an immune response, its durability, or a virologic effect based on those labels alone.

More generally, a phase 1 study with enrollment of 56 is an early evaluation, and the registry’s group summaries are descriptive. The record does not report the sample-size justification, analysis populations, missing-data procedures, or multiplicity approach. Those absences limit the strength and precision of conclusions that can be drawn from the posted data. The findings should be understood as the information recorded in this trial registry, not as a stand-alone determination of safety or effectiveness.

13. Why This Trial Matters Statistically

This trial illustrates a basic distinction in clinical-trial reporting: an endpoint can be clearly defined without its result being available as a single interpretable comparison. The registry specifies a participant-count endpoint for solicited local and general adverse events, its assessment period through Day 28, and the protocol grading framework. Yet the available record does not reduce that endpoint’s categories or time points to one result. For statistical interpretation, the definition and the numerical estimate are both necessary.

The four-group structure also matters. Two vaccine doses were evaluated in separate cohorts, each with a placebo group. A pooled vaccine-versus-placebo comparison could obscure differences between dose cohorts, while separate comparisons would require attention to the number of analyses and the precision of each. The registry record does not report which contrasts were planned or how multiplicity was addressed. A reader should not infer a pooled or dose-specific analysis from the group labels alone.

The serious adverse-event counts show why uncertainty is important in early-phase studies. Sparse outcomes, including zero counts in several groups, can be difficult to compare precisely. Descriptive counts are useful for reporting what was observed, but they do not substitute for uncertainty intervals or a prespecified analysis. The record lists no analyses and does not report the methods that would support inferential interpretation.

Finally, the planning assumptions described in the record are not the same as the trial’s own design justification or an observed measure of statistical power. Separating planning illustrations from observed results prevents a hypothetical calculation from being mistaken for evidence. This case therefore highlights the value of complete reporting: clear outcome definitions, group-level results, analysis methods, uncertainty and handling of missing data are all needed to connect trial observations to a careful statistical interpretation.

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 information available has important trial-specific limitations. The registry defines the primary outcome but does not report a single result for it. It also does not provide numerical results for the listed secondary outcomes on viremia, infection, immunogenicity, antibody durability, or the quantity and duration of Zika virus presence. The adverse-event summaries cannot fill those gaps because the record does not establish that their categories and observation periods match the solicited primary endpoint.

Although the study is described as randomized and quadruple masked, the method of randomization, allocation concealment and masking procedures are not reported in the registry record. The brief description uses the term double-blind, and the available information does not reconcile that wording with the formal masking designation. Baseline participant characteristics and detailed eligibility criteria are also not reported, limiting assessment of the enrolled population.

The record does not report an analysis plan, analysis populations, missing-data procedures, multiplicity handling or a method for comparing adverse-event groups. It gives no confidence intervals or p-values for the posted summaries. Consequently, the precision and inferential interpretation of the group counts cannot be assessed from this record alone. The study’s sample-size justification is not reported, and the planning assumptions are not evidence of the original design rationale.

Finally, the serious adverse-event term and percentage are listed without enough context to evaluate coding, attribution or timing. These limitations do not mean that the study lacked procedures or analyses; they mean those details are not reported in the registry record available for interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Immunogenicity of the Live Attenuated Zika Vaccine rZIKV/D4Δ30-713 in Flavivirus-naïve Adults — NCT03611946.
• Registry record last updated 2025-08-05; status last verified 2025-07.
• Results first posted 2025-08-05.
• 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

NCT03611946 is a completed, randomized, quadruple-masked, parallel-group phase 1 study of live attenuated Zika vaccine rZIKV/D4Δ30-713 in flavivirus-naïve adults. The registry lists enrollment of 56 and two vaccine-dose cohorts, each with a placebo group. The primary outcome counts participants with solicited local and general adverse events assessed at every visit through Day 28.

The record lists serious and other adverse-event counts by group, but does not report a single primary-endpoint comparison or analyses. Numerical results for the listed virologic and immunogenicity outcomes are not available in the information assessed. Analysis populations, missing-data methods, multiplicity procedures and the trial’s sample-size justification are not reported in the registry record. The summaries therefore support descriptive reading of the recorded counts, but not a precise comparative conclusion.