Immunogenicity of Fluzone HD,A High Dose Influenza Vaccine, In Children With Cancer or HIV: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Immunogenicity of Fluzone HD,A High Dose Influenza Vaccine, In Children With Cancer or HIV (NCT01205581), a randomized phase 2 study. The primary outcome is Rate of Seroconversion After 1 Dose of Vaccine.

2. Clinical Question

The clinical question is therefore about immunogenicity in these diagnostic groups, rather than a reported clinical outcome such as influenza illness. Seroconversion is a laboratory-defined measure of an antibody response. The registry record also lists secondary questions about responses after one versus two doses, response by absolute lymphocyte count, and local or systemic reactogenicity. Those questions broaden the planned assessment, but their results are not included in the record. The trial’s stated endpoint and the missing arm-level results should be kept distinct: knowing what was measured does not establish what the observed response was.

3. Trial Design

The record describes a completed phase 2, randomized, open-label, parallel trial sponsored by St. Jude Children's Research Hospital. Enrollment was 85. The intervention was assignment to a high-dose or standard-dose formulation of Fluzone, with vaccination twice and evaluation of immune responses. Because masking was listed as none, treatment assignment was not blinded according to the registry record. Randomization is reported, but the sequence-generation and allocation-concealment procedures are not reported in the registry record.

Arm descriptions divide participants into six groups: leukemia receiving high-dose vaccine or standard-dose vaccine, solid tumor receiving either formulation, and HIV receiving either formulation. Thus, the comparison is organized within diagnosis as well as by vaccine dose. The record does not describe a single pooled comparison across all diagnoses, nor does it report the numbers randomized to each arm for the primary endpoint. The two participants excluded from that endpoint population were in the HIV-HD group and had baseline data only.

The primary endpoint timeframe was at least 21 days after the first dose and before the second dose. The record lists 14 outcome measures and six analyses. It identifies a primary endpoint and several secondary outcomes, including reactogenicity and seroconversion questions involving one versus two doses. The details of how those outcomes and analyses were prioritized or connected are not reported in the registry record.

The study is marked completed, with a start date of 2010-09 and primary completion date of 2013-08. These dates describe the registry record, not the timing of any particular analysis. The record does not report the rationale for the enrollment target, the statistical analysis plan, or whether any interim analyses were conducted. The design information establishes the broad structure of the comparison, but does not supply enough detail to assess all operational features of randomization, follow-up, or analysis.

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: Participants excluded if they had: pre-vaccination titer of ≥1:2560, severe hypersensitivity to egg proteins or any component of Fluzone, life-threatening reaction after prior influenza vaccine, history of Guillain-Barre syndrome in subject/subject's family, or unwilling to agree to acceptable birth control for 3 months after each dose.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Two patients in the HIV-HD group were excluded because data was only available at baseline. These 2 patients were lost for follow-up before evaluation for post-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: This was an open-label study where participants were randomized at a 1:1 ratio into Fluzone high-dose (HD) and Fluzone standard dose (SD) groups by disease group with the use of a computer-generated randomization schedule.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Rate of Seroconversion After 1 Dose of Vaccine, measured over at least 21 days after first dose, which is given at the time of baseline evaluation visit, and prior to second dose.

The primary endpoint is the rate of seroconversion after one dose of vaccine. It measures the proportion of participants meeting a laboratory-defined antibody-response criterion, rather than the occurrence of influenza infection or another clinical event. The hemagglutination-inhibition assay assessed response to each of the three vaccine antigens: H1, H3, and B.

Seroconversion was defined according to baseline HAI titer. If baseline was below 10, a post-vaccine titer of at least 40 met the definition. If baseline was at least 10, a fourfold rise in HAI titer met it. This baseline-dependent rule recognizes that the same final titer can represent different degrees of change for participants starting at different levels.

Seroconversion is used as an immunogenicity measure because it converts laboratory measurements into a response category that can be summarized as a rate. It can support a comparison of the proportions meeting the stated criterion in the vaccine groups. It does not, by itself, describe the full distribution of antibody titers, establish protection against illness, or quantify clinical benefit. The record does not report the endpoint rates by arm, antigen-specific results, or a statistical comparison. It also does not give enough information to determine how the three antigen-specific response measures were combined or presented in the primary analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design is described as randomized and parallel. In a randomized trial, assignment is intended to reduce systematic differences between treatment groups at the time of allocation. The registry record does not describe the randomization sequence or concealment procedures, so those implementation details cannot be evaluated. Parallel groups mean participants were assigned to a vaccine group for the comparison rather than being described as crossing between the two formulations. The record lists no masking, so the trial was open-label as recorded.

What a response rate represents

A binary response outcome classifies each participant as meeting or not meeting the seroconversion rule. A rate summarizes the share of participants who meet that rule among those included in the analysis. For this endpoint, the rule uses HAI titers against H1, H3, and B and depends on baseline titer. Such classification makes group response proportions understandable, but it discards some information about the magnitude of each participant’s titer and the pattern across antigens. The registry record does not report the resulting rates or explain how antigen-specific categories were summarized.

How comparisons and uncertainty are read

In general, a comparison of response rates estimates how the observed response frequency differs between groups. A confidence interval describes the range of values compatible with the data and the statistical method under its assumptions; it communicates precision as well as the estimate’s direction. A p-value addresses how compatible the observed data are with a specified null hypothesis, under the analysis assumptions. Neither a confidence interval nor a p-value is reported for the primary endpoint in the registry record. Without the estimate and its uncertainty, the observed magnitude and precision cannot be assessed.

The record’s sample-size assumptions describe a planning illustration based on an observed effect, two-sided significance level 0.05, equal allocation, and a normal approximation. The effect to detect is expressed as a fraction of the observed effect. These are planning assumptions, not observed power. The resulting participant counts for the planning illustration are not reported in the registry record, and the record does not state that these assumptions were the trial’s original design rationale. A sample-size illustration cannot substitute for the observed outcome estimate or its uncertainty.

Why event rates can be imprecise

In general, binary outcomes with few events or modest group sizes can yield estimates that are imprecise. An observed rate is a sample result, not a guarantee of the underlying rate in a broader population. The uncertainty around a rate depends on the number of participants and the event frequency, among other aspects of the analysis. Since arm-level primary outcome counts and uncertainty intervals are absent, precision cannot be reconstructed or described for this trial. No recalculated comparison is available in the registry record.

For count outcomes, over-dispersion is a general concern when variability in event counts exceeds what a simple model assumes. It can affect standard errors and the reliability of inferential conclusions if the analysis does not account for it. The registry record does not give enough detail about the statistical models for reactogenicity or other count outcomes to assess whether over-dispersion was considered. This is a general methodological point, not a claim that over-dispersion occurred in this trial.

Multiple outcomes and analyses

The record lists 14 outcome measures and six analyses. When a study examines multiple outcomes, antigens, groups, or time points, the chance of at least one apparently notable result can increase if each is tested separately without adjustment. In general, multiplicity can be addressed through prespecification, adjustment, a hierarchy of tests, or careful emphasis on estimation and uncertainty. The registry record does not report whether any multiplicity strategy was used. It also does not identify the full set of statistical tests, the primary analysis model, or which results were intended to be confirmatory.

The primary outcome is not reduced to one comparison in the available record because it involves several categories or time points. That structure makes it especially important to know how antigen-specific results and any one-versus-two-dose analyses were handled. The analysis procedures and any prespecified hierarchy are not reported in the registry record. Therefore, the number of listed outcomes alone cannot establish how many formal tests were conducted or whether particular comparisons were adjusted.

Interpretation and limits of inference

General statistical interpretation separates the observed estimate from its precision and from its clinical meaning. A rate difference may be estimated precisely or imprecisely; either way, the rate itself is a laboratory response measure. A statistically detectable difference would not by itself establish a difference in clinical outcomes, and a non-significant result would not prove equivalence. In this record, even that statistical distinction cannot be applied to the primary endpoint because the results and inferential statistics are not reported. The design and endpoint definition explain what was intended to be studied, but they do not supply the numerical evidence needed to estimate a comparative effect.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 14 outcome measures and six analyses, including the primary seroconversion endpoint and secondary outcomes involving one versus two doses, lymphocyte count, and reactogenicity. Multiple endpoints and comparisons create a multiplicity issue in general: when many hypotheses are tested, some results may appear notable by chance. A prespecified testing hierarchy or statistical adjustment can help control that issue, but whether either was used is not reported in the registry record. The analysis plan, test-level details, and any adjustment procedure are also not reported.

The primary endpoint description uses HAI response to three antigens and a baseline-dependent seroconversion definition. The registry record indicates that the primary outcome includes several categories or time points and is not reduced to one comparison. It does not report how the categories were combined, whether antigen-specific results were analyzed separately, or how the primary comparison was selected from the outcome structure. Consequently, the statistical interpretation cannot assume a single prespecified test.

For missing data, the record states that two participants in HIV-HD had baseline data only and were lost to follow-up before post-vaccine immune response evaluation. They were excluded from the primary endpoint population. The record does not report whether additional endpoint data were missing, or whether any imputation or sensitivity analysis was performed. The analysis populations for the remaining outcomes are not reported in the registry record. It is also not clear from the record whether the primary endpoint analysis followed an intention-to-treat, per-protocol, or another population definition.

These omissions matter because both multiplicity and missingness can affect how robustly an estimate should be interpreted. They do not establish that the analysis was inappropriate; they limit what can be evaluated from the registry information.

11. 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 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: somnolence (12.5%).

The registry record lists serious-event counts by diagnostic group and vaccine assignment. The affected-participant counts are zero for Leukemia-HD, Leukemia-SD, Solid Tumor-SD, HIV-HD, and HIV-SD; Solid Tumor-HD has one affected participant. The corresponding at-risk counts are listed for each group. These are descriptive counts, not comparative estimates, and the record does not provide uncertainty intervals or a statistical test for differences between groups.

The record also identifies somnolence at 12.5% among the serious terms. The denominator and additional event-level context for that percentage are not reported in the registry record. Death counts are not reported in the registry record. These limitations mean the serious-event entries should not be interpreted as a complete account of all adverse effects or as evidence that no other events occurred.

The secondary outcome list separately names grade 3 and grade 4 adverse events possibly, probably, or definitely attributable to either vaccine, as well as local and systemic reactogenicity. Those outcomes are not interchangeable with the serious-event counts. Seriousness, severity grade, and attribution are distinct classifications. The listed serious-event figures alone therefore do not describe the full safety profile or establish a comparative safety conclusion.

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

The record establishes that the trial was designed to compare immune responses after high-dose and standard-dose Fluzone in children with leukemia, solid tumors, or HIV. It defines seroconversion using HAI titers and specifies that the primary endpoint was assessed after the first dose and before the second. This is useful information about the scientific question and the measurement approach.

However, the primary endpoint results are not reported in the registry record. There are no response rates by arm, no effect estimate, and no confidence interval or p-value for the comparison. The registry entries therefore do not show whether one vaccine group had a higher seroconversion rate, whether the groups were similar, or how much uncertainty surrounded any difference. A lack of reported results is not evidence of no difference.

Even if an immune-response result were available, seroconversion is a laboratory endpoint. It measures whether participants meet a specified antibody-response criterion. It does not itself demonstrate prevention of influenza, quantify illness severity, or establish a clinical benefit. The registry record does not report clinical influenza outcomes as the primary endpoint.

The safety entries also have a limited meaning. They provide selected serious-event counts by group, but do not include uncertainty estimates, detailed context, or the full results of the separately listed severity and reactogenicity outcomes. The one affected participant listed for Solid Tumor-HD and the zero affected participants listed in the other groups cannot establish that the groups have equal safety profiles.

In general, a trial’s result is interpreted by considering the estimate, its precision, the analysis population, and the outcome’s relevance. Here, the endpoint definition and broad design can be described, but the missing comparative results prevent assessment of the observed immunogenicity effect. No conclusion about treatment effectiveness or lack of effectiveness follows from the information in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable for the structure of its immunogenicity question. It uses a binary seroconversion outcome based on HAI titers, with the criterion depending on baseline titer and responses considered for three vaccine antigens. A single response rate can make laboratory data easier to compare, while also compressing information about the size and antigen-specific pattern of antibody changes.

The design also separates participants by diagnosis and vaccine assignment. This gives the study a group structure relevant to the stated population, but it makes denominators and interpretation of any pooled result important. The registry record describes leukemia, solid tumor, and HIV groups; it does not report the primary outcome estimates needed to assess the within-diagnosis comparisons or any overall comparison.

Multiple outcomes are listed, including dose-response timing, lymphocyte-count associations, and several kinds of reactogenicity. That breadth illustrates why prespecified priorities and multiplicity handling matter in clinical research. The record does not report the analysis plan or multiplicity approach, so the confirmatory status of particular comparisons cannot be judged.

Finally, the record identifies two participants lost before the post-vaccine response evaluation and excluded from the primary endpoint population. This highlights the value of reporting analysis denominators and missing-data handling alongside outcome rates. The trial offers a clear example of how design and endpoint definitions can be documented while the results needed for statistical interpretation remain unavailable in the registry record.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for statistical interpretation is that the primary endpoint results are not reported in the registry record. Arm-specific seroconversion rates, antigen-specific findings, effect estimates, confidence intervals, and p-values are absent. This prevents assessment of the observed direction, magnitude, and precision of the comparison.

The record does not report group-specific primary endpoint denominators or the analysis population definitions beyond noting the exclusion of two HIV-HD participants who had baseline data only and were lost before post-vaccine evaluation. The extent of missing data in other groups and any methods used to address missingness are not reported. These gaps limit assessment of possible bias related to follow-up or analysis inclusion.

Although randomization is stated, the sequence-generation and allocation-concealment procedures are not reported. The trial was open-label, and the record does not explain whether any outcome assessment was blinded. This is especially relevant to subjective outcomes such as reactogenicity, while the HAI assay outcome is laboratory-based. The record does not describe laboratory procedures or safeguards against knowledge of treatment assignment.

The outcome structure includes multiple antigens, dose-related questions, and secondary outcomes. The statistical analysis plan, multiplicity strategy, and detailed model specifications are not reported. Enrollment was 85, but the rationale for the enrollment target and the trial’s original power assumptions are not reported in the registry record. The planning assumptions listed for a sample-size illustration do not establish the original design rationale.

For safety, event counts are available by group, but detailed event descriptions, uncertainty estimates, and death counts are not reported. These limitations restrict conclusions to the recorded descriptive information and do not support a complete evaluation of efficacy or safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Immunogenicity of Fluzone HD,A High Dose Influenza Vaccine, In Children With Cancer or HIV — NCT01205581.
• Registry record last updated 2016-09-23; status last verified 2016-07.
• Results first posted 2014-09-12.
• 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

NCT01205581 is a completed, randomized, open-label, parallel phase 2 trial sponsored by St. Jude Children's Research Hospital. It enrolled 85 participants with leukemia, solid tumors, or HIV and compared twice-administered high-dose Fluzone with standard-dose Fluzone. The primary endpoint was seroconversion after one dose, assessed by HAI response to H1, H3, and B antigens.

The record defines seroconversion using post-vaccine titer and baseline titer criteria, and notes that two participants in HIV-HD had baseline data only and were lost before post-vaccine evaluation. It lists 14 outcome measures and six analyses. Selected serious-event counts are reported by group, but the primary endpoint rates and comparative statistical results are not reported in the registry record. The statistical analysis plan, multiplicity approach, and most missing-data details are also not reported. Consequently, the record describes the trial question and methods but does not permit interpretation of the observed comparative immunogenicity result.