Immunogenicity, Safety and Interchangeability of Two Tbe Vaccines Administered According to a Conventional Schedule in Children: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Immunogenicity, Safety and Interchangeability of Two Tbe Vaccines Administered According to a Conventional Schedule in Children (NCT00840801), a randomized phase 3 study. The primary outcome is Seropositivity Rate as Determined by Neutralization Test (NT) 28 Days After the Second Vaccination.

2. Clinical Question

3. Trial Design

This was a randomized, single-blind, Phase III B study of two tick-borne encephalitis vaccines in children aged 1–11 years. The study is recorded as completed, with enrollment of 302. The registry record lists Pfizer as sponsor. The study objective was to examine immunogenicity, safety and interchangeability under a conventional schedule.

The schedule consisted of vaccinations on days 0, 28 and 360. The objective describes FSME-IMMUN 0.25 ml Junior or Encepur 0.25 ml Children for the first and second vaccinations, and FSME-IMMUN 0.25 ml Junior for the third. The arm descriptions themselves state that participants received three vaccinations with a paediatric vaccine according to the conventional schedule, without differentiating the sequences in those descriptions. The allocation ratio and the precise masking procedures are not reported in the registry record.

The primary endpoint was measured 28 days after the second vaccination, before the scheduled third vaccination. The primary population was per protocol and required baseline and follow-up immunogenicity measurements, negative baseline neutralization-test values, receipt of the first two vaccinations, eligibility, and absence of major protocol violations. This population definition matters: the primary percentages do not necessarily describe every randomized participant.

Additional outcomes covered seropositivity and antibody response by neutralization test and ELISA at several time points, fold increases, and systemic reactions after the first and second vaccinations. The record lists 15 outcome measures and 14 posted secondary outcomes. Detailed protocol procedures, the planned analysis hierarchy and the reasons for any exclusions from the per-protocol set 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: The study was conducted from 06 February 2009 to 20 May 2010 in Austria and Czech Republic.

Part A: Screening- Day 28 Postdose 2

Reasons for not completing this period:

Part B:Day 28 Postdose2-Day 28 Postdose3

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per-protocol analysis set included eligible participants who received first and second vaccination; had negative baseline values in NT; had immunogenicity measurements available at baseline; 28 days after second vaccination and no major protocol violations.

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: The safety analysis set included all participants who received the third vaccination of FSME-IMMUN, after first 2 doses of FSME-IMMUN or Encepur and had documented adverse event information at least immediately afterwards.

6. Primary Endpoint

The registry lists the primary outcome as Seropositivity Rate as Determined by Neutralization Test (NT) 28 Days After the Second Vaccination, measured over 28 days after Vaccination 2.

The primary endpoint is the percentage of participants with a neutralization-test titer of at least 10, measured 28 days after the second vaccination. A neutralization test assesses whether antibodies in a sample can inhibit the virus in the test system. The endpoint converts that laboratory measurement into a binary outcome: each participant either meets the stated titer threshold or does not.

Reporting the percentage meeting a threshold makes the result interpretable as a seropositivity rate under the study’s definition. It does not describe the full distribution of antibody titers: participants just above the threshold and participants with much higher titers both count as meeting it. The registry also lists antibody-response outcomes, including neutralization-test and ELISA measures, at other time points, but those are distinct from the primary endpoint.

The measurement was taken 28 days after the second vaccination, which is the stated primary time point. The result applies to the per-protocol analysis set, not automatically to all randomized participants. The registry record does not report further detail on the threshold’s validation, the assay’s laboratory procedures, or how values at the threshold were handled beyond the description that titers of at least 10 qualified.

Immunogenicity is a laboratory outcome. By itself, this endpoint does not measure clinical tick-borne encephalitis cases, duration of protection, or comparative safety. It also cannot establish interchangeability without considering the planned comparison criteria and the sponsor’s analysis.

7. Results Posted in the Registry

• Encepur: 97.8% (131/134) versus 100.0% (127/127) on control; risk difference -2.2 percentage points (95% CI -4.7 to 0.3), risk ratio 0.98 (0.95–1.00); unadjusted two-proportion z-test p = 0.090.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the percentage measure?

The primary outcome is binary at the participant level. A participant is counted as meeting the endpoint if the neutralization-test titer is at least 10 at the specified visit; otherwise, the participant does not meet it. The reported percentage is the proportion meeting that definition within the analysis population. This approach is straightforward to interpret, but it compresses the underlying laboratory values into two categories and does not show how far titers lie above or below the threshold.

Why report confidence intervals?

A confidence interval describes the uncertainty around an estimate under the statistical method used. It is not a guarantee that the true value falls within the interval, and it does not represent the range of individual participants’ titers. The intervals attached to the arm-specific percentages indicate that the estimated seropositivity rates have sampling uncertainty, even when an observed percentage is at or near the scale’s upper boundary. Comparing two separate arm intervals is not, by itself, the same as conducting a formal test of the difference between groups.

What is the group comparison?

The posted results include a sponsor analysis described as a stratified score test and classified as a legacy non-inferiority or equivalence analysis. A score test assesses a group comparison using a test statistic derived under a specified null hypothesis. Stratification generally means that the comparison accounts for categories defined in the analysis, rather than treating all observations as an undifferentiated set. The strata and full test specification are not reported in the registry record, so the exact calculation cannot be reconstructed from the description alone.

Non-inferiority and equivalence questions require a margin chosen before interpreting results. In a non-inferiority analysis, the question is whether the result excludes an unacceptable loss relative to a comparator; equivalence asks whether the difference lies within prespecified bounds. The relevant margin, its direction, and its rationale are not reported in the registry record. A small p-value from a test labelled non-inferiority or equivalence should therefore not be interpreted without knowing the hypothesis, margin, and analysis plan.

Why is the recalculation different?

A simple unadjusted recalculation based on posted summary statistics does not necessarily reproduce an analysis that uses stratification or other planned features. The registry marks a discrepancy between the recalculation and the sponsor’s result. The recalculation is not a replacement for the sponsor’s analysis; the sponsor’s own analysis takes precedence. The available record does not provide sufficient detail to identify every reason for the difference or independently reproduce the sponsor’s test.

What does the analysis population imply?

The primary endpoint uses a per-protocol population with specified eligibility, vaccination, baseline, follow-up and protocol-compliance conditions. Such a population focuses on participants who met the stated analysis requirements. It is not automatically equivalent to an analysis of everyone randomized. The number excluded for each reason, the handling of missing measurements, and any complementary analysis population results are not reported in the registry record.

How should the safety outcomes be understood?

The primary endpoint is not a safety outcome. Safety summaries require attention to the event definition, observation period, population at risk and whether the event is serious or non-serious. The registry lists systemic reactions after vaccinations and serious adverse event terms, but the full details needed to interpret event attribution and comparative risk are not reported in the registry record. In general, an event reported after vaccination is not necessarily caused by vaccination; causal attribution requires more information than temporal occurrence alone.

These methods describe different questions: a threshold-based immune response, a formal group comparison, and safety event reporting. They should not be collapsed into a single claim about overall clinical benefit or interchangeability. The primary estimates describe the specified laboratory outcome and population; the sponsor’s test addresses its stated comparison framework, whose full specifications are not available in the registry record.

10. Confidence Intervals and Precision

The 95% confidence interval for FSME-IMMUN is 97.1% to 100.0%, around a reported seropositivity estimate of 100.0%. For Encepur, the estimate is 97.8%, with a 95% confidence interval from 93.6% to 99.5%. These intervals convey uncertainty in each group’s estimated percentage under the interval method used. The registry record does not name the method used to calculate these arm-specific intervals.

An observed estimate of 100.0% does not mean that the underlying rate is known without uncertainty. Its interval extends below 100.0%, illustrating that a sample in which every analyzed participant meets the criterion can still be compatible with a lower population rate. The Encepur interval also reflects uncertainty; its lower and upper limits are not a range of individual responses.

Separate confidence intervals are not a direct confidence interval for the between-group difference. The registry gives an unadjusted recalculation of the comparison, but the record flags a discrepancy with the sponsor analysis. The sponsor’s own analysis takes precedence. The sponsor result is reported as p < 0.001 for a stratified score test, while the recalculation reports p=0.09. The margin and full analysis specification needed to interpret the sponsor’s non-inferiority or equivalence result are not reported in the registry record.

Precision also depends on the analysis population and available measurements. The primary population is per protocol, and the registry record does not report the number of missing outcome measurements or the reasons participants were omitted. The interval estimates therefore should be read alongside that population definition, rather than as uncertainty statements for every randomized participant.

11. Analyses Reported by the Sponsor

The registry reports a sponsor analysis using a stratified score test, with p < 0.001, classified as a legacy non-inferiority or equivalence analysis. A simple unadjusted recalculation from the posted summaries gives a different result, including p=0.09. The record explicitly flags this discrepancy. Accordingly, the sponsor’s own analysis takes precedence over the recalculation for describing the trial’s reported inferential result.

This precedence does not make the sponsor result independently reproducible from the registry entries. The strata, full test specification, non-inferiority or equivalence margin, and rationale for that margin are not reported in the registry record. Those details are needed to assess exactly what hypothesis was tested and how the test supports the intended conclusion. The sponsor’s p-value should therefore be presented as reported, while recognizing the limits of the available methodological detail.

The arm-specific estimates remain useful descriptive results: 100.0% for FSME-IMMUN and 97.8% for Encepur, with their respective confidence intervals. They do not resolve why the analyses differ, and they do not independently establish equivalence or interchangeability. The record’s classification and p-value should not be expanded into a broader claim than the reported endpoint and analysis support.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures, including the primary neutralization-test seropositivity rate and secondary outcomes involving seropositivity, antibody response, fold increase, and systemic reactions at different time points. The record also lists 14 posted secondary outcomes. Evaluating several outcomes or time points can increase the chance that at least one result appears notable by chance if each is tested separately without an appropriate plan for multiplicity.

The statistical plan for handling multiple outcomes, time points, or comparisons is not reported in the registry record. It is therefore unclear which outcomes were confirmatory, whether any testing hierarchy or adjustment was planned, or how the reported sponsor test fits into a broader analysis strategy. No adjustment method should be assumed from the outcome list alone.

The primary endpoint population is defined as per protocol, with eligibility, vaccination, baseline and follow-up measurement requirements, and no major protocol violations. The registry record does not report an intention-to-treat analysis result or provide a full account of missing data, exclusions, or methods used to handle missing measurements. This limits assessment of how robust the primary finding is to different population definitions or missing-data assumptions.

Interim analyses, stopping rules, and sample-size justification are not reported in the registry record. The available planning illustrations are not observed power calculations and should not be read as the trial’s original design justification. Without the prespecified analysis plan and its rationale, the registry results can be described but cannot fully establish how all analyses were planned or prioritized.

These omissions matter particularly when interpreting a non-inferiority or equivalence result. The comparison margin, its rationale, multiplicity procedures, and analysis population strategy are important to the strength of such a conclusion; they are not reported in the registry record. Consequently, the reported test should be distinguished from a complete independent evaluation of the trial’s confirmatory statistical framework.

13. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: bronchitis (4.0%), concussion (2.1%), acquired phimosis (2.1%), hypospadias (2.0%), eustachian tube disorder (2.0%).

The registry lists serious adverse event terms including bronchitis at 4.0%, concussion at 2.1%, acquired phimosis at 2.1%, hypospadias at 2.0%, eustachian tube disorder at 2.0%, and herpangina at 2.0%. These are posted term-specific percentages, not a single overall serious-event rate. The registry record does not provide the context needed to determine whether these terms represent unique events or participants across the listed categories, so they should not be added or treated as mutually exclusive.

The adverse-event summaries also show counts at risk and affected for systemic and other events across age groups, vaccine groups, and time periods. Those entries distinguish events by seriousness and timing. They are not the primary immunogenicity endpoint, and comparisons need to account for the specific group and observation period rather than treating all entries as one pooled result.

The registry record does not report deaths in these entries, and the causal relationship between listed events and vaccination is not established by their appearance in a safety summary. Seriousness, timing, frequency, and attribution are distinct aspects of safety reporting. The listed percentages alone do not support a causal conclusion or a complete comparative safety assessment.

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

The primary result describes the percentage of participants in the per-protocol analysis set who met a neutralization-test threshold 28 days after the second vaccination. The observed estimates were 100.0% for FSME-IMMUN and 97.8% for Encepur. Their confidence intervals indicate uncertainty around the group estimates. This is evidence about a defined laboratory response at a defined time point, not a direct count of clinical tick-borne encephalitis cases.

The finding does not by itself show how long the response lasts, whether it prevents disease, or whether every participant will respond similarly. It also does not summarize the full distribution of antibody titers, because the endpoint classifies participants according to a threshold. Other immunogenicity outcomes are listed, but their numerical results are not reported in the registry record.

The trial objective includes interchangeability, but interchangeability is broader than observing high seropositivity percentages in two groups. A formal conclusion depends on the intended comparison, prespecified margin, statistical method, and analysis populations. The registry reports a stratified score test labelled as a legacy non-inferiority or equivalence analysis, but the margin and its rationale are not reported. The discrepancy between that sponsor analysis and a simple recalculation is also relevant; the sponsor’s analysis takes precedence, but the available details do not permit full independent assessment.

The primary result does not establish comparative safety. Safety summaries include event reports by group and time point, while the serious adverse event list gives selected terms and percentages. Those reports do not alone establish whether vaccination caused an event, and the registry information is not a complete clinical safety evaluation.

In short, the posted primary data show high measured seropositivity in both analysis groups at the specified visit. They do not, without the fuller protocol and statistical details, settle questions of clinical protection, duration, equivalence, interchangeability, or comparative safety.

15. Why This Trial Matters Statistically

This trial illustrates why a high response percentage and a formal comparison answer different statistical questions. The arm-specific percentages describe how often the threshold was reached in each analyzed group. A comparison test evaluates a stated hypothesis using a particular method and, for non-inferiority or equivalence, depends on a margin. Readers need both the outcome estimates and the framework used to compare them.

It also shows why the analysis population matters. The primary result is per protocol, with defined requirements for vaccination, baseline and follow-up measurements, eligibility, and protocol compliance. That is a specific subset of the trial population, not automatically a result for everyone randomized. Missingness and exclusions can affect how broadly the estimate applies.

The discrepancy between the sponsor’s stratified score test and a simple unadjusted recalculation is a practical reminder that a posted summary may not contain enough detail to reproduce a planned analysis. Here, the registry marks the discrepancy, so the sponsor’s result takes precedence. At the same time, the absence of the comparison margin and full analysis specifications limits independent interpretation.

Finally, immunogenicity and safety are separate evidence streams. A threshold-based antibody measure is not a clinical disease outcome, and listed adverse-event terms do not establish causation. Clear interpretation requires keeping each result connected to its population, measurement, time point, and statistical purpose rather than treating one result as a complete account of vaccine performance.

16. 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 principal limitation in interpreting the primary comparison is the absence of the prespecified non-inferiority or equivalence margin and its rationale in the registry record. Although the sponsor reports a stratified score test with p < 0.001, the record does not provide enough information to assess the margin-based conclusion in full. A simple unadjusted recalculation differs, and the record flags that discrepancy; the sponsor’s analysis takes precedence.

The primary analysis is per protocol. The registry defines eligibility and measurement requirements but does not report the number excluded for each reason, the handling of missing measurements, or a corresponding intention-to-treat result. The effect of those choices cannot be evaluated from the record.

The endpoint is a laboratory threshold measured 28 days after the second vaccination. It does not directly measure clinical disease, duration of protection, or the distribution of antibody titers. The registry lists additional outcomes, but their complete numerical results are not reported in the registry record. It also does not report the multiple-outcome strategy or identify a testing hierarchy.

The arm descriptions do not give detailed distinctions between the vaccine sequences, while the study objective describes the first two vaccinations with either vaccine and the third with FSME-IMMUN. The allocation ratio, full masking procedures, protocol details, sample-size justification, interim analyses, and full statistical plan are not reported in the registry record.

Safety entries are separated by age, vaccination timing, and event category. The serious-event term percentages do not provide enough information to establish causation or form a complete comparative safety assessment. These limitations call for a narrow reading of the reported immunogenicity percentages and sponsor test.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Immunogenicity, Safety and Interchangeability of Two Tbe Vaccines Administered According to a Conventional Schedule in Children — NCT00840801.
• Registry record last updated 2024-01-19; status last verified 2023-04.
• Results first posted 2024-01-19.
• 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.

20. Record Summary

This completed, randomized, single-blind Phase III B study examined two paediatric tick-borne encephalitis vaccines in children aged 1–11 years. Its objective covered immunogenicity, safety, and interchangeability on a conventional vaccination schedule of days 0, 28 and 360. Enrollment was 302.

The primary endpoint was the percentage with a neutralization-test titer of at least 10, measured 28 days after the second vaccination in a per-protocol analysis set. The posted estimates were 100.0% for FSME-IMMUN and 97.8% for Encepur. The sponsor’s stratified score test is reported as p < 0.001 under a legacy non-inferiority or equivalence classification. A simple recalculation differs, and the registry flags the discrepancy; the sponsor’s analysis takes precedence.

The comparison margin, full statistical plan, multiplicity handling, and detailed missing-data accounting are not reported in the registry record. The endpoint measures a laboratory response, not clinical disease, and the safety summaries do not by themselves establish causation.