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 Immunogenicity Trial of Recombinant Influenza Vaccine Among HCP in Israel (NCT04523324), a randomized phase 4 study. The primary outcome is Post-vaccination Geometric Mean Titer Against Influenza Virus A/H1N1.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04523324 |
| Phase | Phase 4 |
| Condition | Influenza |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Single |
| Enrollment | 577 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Centers for Disease Control and Prevention |
| Results posted | Yes |
2. Clinical Question
Population
Healthcare personnel in Israel who had received an egg-based quadrivalent influenza vaccine during the previous 2018-19 season and were enrolled in SHIRI. The trial summary describes recruitment at two hospital sites during the 2019-20 influenza season.
Intervention
A single dose of recombinant quadrivalent influenza vaccine, RIV4 (Flublok Quadrivalent), described as containing 45µg of hemagglutinin per strain.
Comparator
A single dose of egg-based quadrivalent influenza vaccine, IIV4 (Vaxigrip Quadrivalent), described as containing 15µg of hemagglutinin per strain.
Primary question
What were the post-vaccination geometric mean hemagglutination inhibition antibody titers against influenza virus A/H1N1 in each randomized group, measured 28 days after vaccination?
The registry record describes a randomized comparison of immune responses, not a comparison of clinical influenza illness. The primary endpoint is a laboratory measurement of antibody titers after vaccination. The posted results give a geometric mean titer and a 95% confidence interval for each vaccine group.
The target population is specific: healthcare personnel who had received IIV4 in the previous season and were enrolled in the named Israeli study. The results therefore describe the recorded antibody response in this study population. They should not automatically be taken to describe other populations, other vaccine formulations, or outcomes that were not measured by this primary endpoint.
3. Trial Design
The registry identifies this as a phase 4, randomized, parallel-group trial with an enrollment of 577. The trial compared recombinant RIV4 (Flublok Quadrivalent) with egg-based IIV4 (Vaxigrip Quadrivalent) in healthcare personnel in Israel. Both are described as quadrivalent influenza vaccines, and the trial summary states that participants received a single dose during the 2019-20 influenza season.
The study dates recorded are 2019-10-31 for the start and 2020-01-30 for primary completion. The record lists the status as completed. The trial summary describes two hospital sites and a population enrolled in SHIRI, with previous-season IIV4 vaccination as an eligibility characteristic.
The record's masking descriptions are not fully aligned: its masking classification is “single,” while the brief summary describes the trial as open-label. Who, if anyone, was masked is not reported in the registry record. This matters because readers should not assume that participants, staff, laboratory personnel, or outcome assessors were masked based only on the classification.
The posted results list 203 participants in the RIV4 group and 334 in the IIV4 group for the primary endpoint. These are the group sizes attached to the reported endpoint results; the registry record does not explain the difference in group sizes or provide a participant-flow account. The randomization method, allocation concealment procedures, and the statistical plan 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: 577 HCP were randomly allocated to receive either IIV4 or RIV4. Due to a delay in the delivery of RIV4 vaccines, 67 participants randomized to receive RIV4 had already been vaccinated in the community with IIV4 before the study started. Because they received the same IIV4 brand (Vaxigrip) as the study control vaccine, we allowed them to continue in the study as controls.
Overall Study
| Stage | RIV4 (Flublok Quadrivalent) | IIV4 (Vaxigrip Quadrivalent) |
|---|---|---|
| STARTED | 211 | 366 |
| COMPLETED | 203 | 334 |
| NOT COMPLETED | 8 | 32 |
Analysis population for the primary outcome, as defined in the registry: Influenza A(H1N1)pdm09 Hemagglutination Inhibition Assay Outcome
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.
| Characteristic | Unit | RIV4 (Flublok Quadrivalent) | IIV4 (Vaxigrip Quadrivalent) | Total |
|---|---|---|---|---|
| Participants analysed | 203 | 334 | 537 | |
| Age, Continuous | years | 47 (37 to 53) | 44 (38 to 57) | 45 (38 to 57) |
| Sex: Female, Male: Female | Participants | 133 | 229 | 362 |
| Sex: Female, Male: Male | Participants | 70 | 105 | 175 |
| Race/Ethnicity, Customized: Ethnicity – Arab | Participants | 16 | 22 | 38 |
| Race/Ethnicity, Customized: Ethnicity – Jewish, not Ultra-Orthodox | Participants | 181 | 305 | 486 |
| Race/Ethnicity, Customized: Ethnicity – Jewish, Ultra-Orthodox | Participants | 6 | 7 | 13 |
| Region of Enrollment: Israel | participants | 203 | 334 | 537 |
6. Primary Endpoint
The registry lists the primary outcome as Post-vaccination Geometric Mean Titer Against Influenza Virus A/H1N1, measured over Day 28 days after vaccination.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | titers |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the post-vaccination geometric mean titer of antibodies against influenza virus A/H1N1. The registry specifies that titers were measured using a hemagglutination inhibition (HI) assay and reports the endpoint at 28 days after vaccination. The population description identifies the assay outcome as influenza A(H1N1)pdm09 hemagglutination inhibition.
Antibody titers are laboratory measurements of the antibody response. A geometric mean is used when measurements are naturally interpreted on a multiplicative scale or are unevenly distributed, so that very high values do not influence the mean in the same way they would on an ordinary additive scale. This is a general statistical rationale; the registry does not describe the distribution of titers or the calculation details used for this analysis.
The HI assay is used to quantify a particular antibody response to influenza virus. It is therefore an immunogenicity endpoint, not a direct count of influenza infections, severe illness, or other clinical outcomes. A result on this endpoint addresses the measured antibody titers in the defined population and at the stated follow-up time. The registry record does not report a primary clinical disease endpoint in the results.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The reported geometric mean titer against influenza A/H1N1 was 173.1 in the RIV4 group, with a 95% confidence interval from 148.5 to 201.7. In the IIV4 group, the reported geometric mean titer was 83.9, with a 95% confidence interval from 74.5 to 94.5. These are the group-level estimates at the recorded post-vaccination time point.
The RIV4 group has the higher posted geometric mean titer. That descriptive comparison does not, by itself, give a confidence interval or test for the difference between groups. The confidence intervals reported alongside the two means describe uncertainty around each group estimate separately; they are not a confidence interval for a treatment contrast. The registry record does not post a comparative estimate, a p-value, or a test result for this primary outcome.
A confidence interval conveys uncertainty associated with an estimate under the analysis used. It is not a range containing most individual participants' titers, nor does it account automatically for every possible source of bias or uncertainty. Interpreting the intervals also requires information about the statistical model and analysis population, and those details are not reported in the registry record.
The result should be read as an antibody-response comparison in the enrolled healthcare personnel who had received IIV4 in the previous season. It does not establish the size of any effect on infection or other clinical outcomes, because those outcomes are not represented by this primary measure. Nor does the record establish whether any observed difference is statistically significant: a direct comparison and its uncertainty are not posted.
The record lists no analyses and no secondary results. It does list 10 outcome measures, but the posted primary result alone cannot answer questions about other outcomes. The record also reports zero serious adverse events and zero other adverse events in each group; those counts are addressed separately and should not be used to infer that adverse events are impossible or that the vaccines have identical safety profiles.
Overall, the posted result is a pair of group-level geometric mean estimates with confidence intervals. It supports a descriptive account of the measured antibody titers at the specified follow-up time. Additional conclusions about comparative precision, statistical significance, clinical outcomes, or generalizability require information that is not reported in the registry record.
9. Statistical Methods Explained
The primary result is a geometric mean, rather than an arithmetic mean. In general, geometric means are suited to measurements that vary multiplicatively: multiplying all observations by a constant changes the geometric mean by that same factor. The transformation used to calculate a geometric mean can make skewed measurements easier to summarize, but the registry record does not state the exact calculation procedure or any transformation used.
What does the confidence interval describe?
The 95% confidence interval gives a range of values compatible with the group estimate under the assumptions of the statistical method used. In repeated applications of a valid method, intervals constructed in this way would cover the underlying quantity at the stated rate. It is not a probability statement about the particular interval after it has been calculated, and it is not a description of the spread of individual titers. The record reports a 95% confidence interval for each group mean, but does not identify how those intervals were calculated.
For RIV4, the posted geometric mean is 173.1 and the confidence interval is 148.5 to 201.7. For IIV4, the posted geometric mean is 83.9 and the confidence interval is 74.5 to 94.5. A comparison of those separate intervals is not a substitute for estimating the difference or ratio between groups. A direct contrast would require its own estimate and uncertainty, and the registry record does not report one for this endpoint.
Why does the endpoint scale matter?
HI titers are laboratory measurements, and their values can differ substantially across observations. As a general statistical point, analyses of positively skewed measurements may use a logarithmic scale, with results then expressed as geometric means on the original scale. The registry identifies a geometric mean and an HI assay, but does not report whether a logarithmic transformation was used, how values at assay limits were handled, or what model was fitted. Those choices can affect estimation and uncertainty.
Over-dispersion is a general concern when observed variability is greater than a statistical model expects. If a model assumes less variability than the data contain, its uncertainty estimates may be too narrow. Conversely, methods that account for extra variability can produce more appropriate uncertainty. The registry record does not report a model, variance assumptions, or an assessment of over-dispersion, so no claim can be made about whether these issues arose or how they were handled in this analysis.
What can be inferred from the posted group estimates?
Randomization is intended to make comparison groups comparable on average, reducing the role of confounding at assignment. The record identifies the allocation as randomized, but does not describe the sequence generation or concealment method. Randomization does not guarantee that every group characteristic is balanced in a particular study, and the record does not provide baseline characteristics for assessing balance.
The reported group sizes are 203 for RIV4 and 334 for IIV4. The record does not explain how those counts relate to all randomized participants, whether all randomized participants contributed an endpoint measurement, or whether any exclusions occurred. It also does not state whether the analysis followed intention-to-treat, per-protocol, or another population definition. These details affect the interpretation of both the group estimates and the uncertainty around them.
The statistical plan, including the planned comparative measure and test, is not reported in the registry record. No p-value or between-group confidence interval is posted. The displayed group estimates therefore support descriptive comparison, but do not supply a formal test of a difference.
How should planning illustrations be understood?
The record describes planning illustrations based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. The effect to detect is expressed as a stated fraction of the observed effect. Such calculations are hypothetical planning exercises: they indicate participant counts per arm under specified assumptions, not an estimate of the trial's achieved power. Sample sizes derived after observing an effect do not establish that the original study was adequately powered, and the registry record does not report its original sample-size justification.
Planning calculations inherit uncertainty from the observed effect and depend on the assumptions used. If the observed effect is imprecise, a plan based on it is also uncertain. These illustrations should not be confused with the actual allocation in the trial, which was unequal according to the posted group sizes, or with a statistical analysis of the randomized comparison.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 10 outcome measures, but reports no secondary results and no analyses. It does not state whether the primary endpoint was the sole confirmatory outcome, whether multiple endpoints were tested, or whether any adjustment for multiple comparisons was planned or applied. A multiplicity strategy is therefore not reported in the registry record.
Multiplicity matters when several outcomes, time points, subgroups, or comparisons are tested. Repeated testing can increase the chance of finding an apparently unusual result by chance. Adjustments or a prespecified testing hierarchy can address that issue, but the record does not provide enough information to determine whether such procedures were used. No unreported p-values or significance claims can be inferred from the group-level means and confidence intervals.
The record does not report how missing endpoint measurements were handled, the amount or pattern of missing data, or whether any imputation was used. It also does not define the primary analysis population or explain whether analyses included all randomized participants. The posted group counts alone cannot resolve these questions.
For these reasons, the reported estimates can be described as posted group-level results, but the completeness of the outcome data and the population represented by the analysis are unclear. Details about prespecification, missingness, analysis populations, and multiplicity are not reported in the registry record.
11. 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 |
|---|---|---|---|
| RIV4 (Flublok Quadrivalent) | 0 | 203 | 0.0% |
| IIV4 (Vaxigrip Quadrivalent) | 0 | 334 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| RIV4 (Flublok Quadrivalent) | 0 of 203 |
| IIV4 (Vaxigrip Quadrivalent) | 0 of 334 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| RIV4 (Flublok Quadrivalent) | 0 of 203 |
| IIV4 (Vaxigrip Quadrivalent) | 0 of 334 |
The registry reports zero serious adverse events among 203 participants at risk in the RIV4 group and zero among 334 participants at risk in the IIV4 group. It also reports zero other adverse events in each group, with the same respective at-risk counts. The reported number of deaths is zero in each group, and no top serious-event terms are listed.
These entries describe what was recorded in the registry for the stated groups. A reported zero is not proof that an event cannot occur, nor does it show that two groups have identical safety profiles. The registry record does not provide event definitions, the period used for safety follow-up, details of collection or adjudication, or information about participants who may not have contributed safety data.
The adverse-event figures are counts, not a complete characterization of every possible safety outcome. They should be read alongside the record's limited reporting detail and should not be extended to populations or follow-up periods not described in the registry.
12. What the Result Does, and Does Not, Mean
The central result is a higher posted geometric mean HI titer against influenza A/H1N1 in the RIV4 group than in the IIV4 group at 28 days after vaccination. The group estimates are accompanied by separate 95% confidence intervals. Together, these figures describe the recorded antibody response in the trial population at that time point.
The result does not provide a direct estimate of the between-group difference or ratio, and the registry record does not post a comparative test or p-value. The two group confidence intervals should not be treated as if they were the interval for a contrast. Without the comparative estimate and analysis details, the precision of the group difference cannot be read directly from the posted values.
This is an immunogenicity result, not a clinical outcome result. It does not establish how many participants developed influenza, whether illness severity differed, or whether transmission changed. Those conclusions are outside the primary endpoint described in the registry record. The result also does not establish what response would be observed in people outside the defined healthcare personnel population or in a different season.
The registry describes randomized allocation, but does not report enough detail about the analysis population, missing data, or statistical methods to assess those features fully. Its masking descriptions are also not aligned: the classification says single, while the summary calls the trial open-label. These limitations should be kept in mind when interpreting the posted estimates.
Accordingly, the most defensible reading is descriptive: the record reports these group-level antibody titers and confidence intervals for the specified assay and follow-up. It does not, on its own, support a claim about comparative clinical benefit, a definitive statistical difference, or safety beyond the reported event counts.
13. Why This Trial Matters Statistically
This trial is statistically informative because it makes the distinction between a biomarker result and a clinical outcome important. The primary measure is a geometric mean of HI antibody titers, which captures a laboratory response on a scale suited to multiplicative measurements. It answers a focused question about immunogenicity rather than directly measuring influenza illness.
The reporting also illustrates why group estimates and comparative estimates are not interchangeable. A mean and confidence interval for each arm describe each group separately. A direct treatment comparison requires an estimate of the contrast and its uncertainty, together with the analysis method. That comparative result is not reported in the registry record, so the posted numbers allow a descriptive comparison but not a complete inferential one.
The different group sizes make transparent reporting of allocation, analysis populations, and missing data especially useful. The record provides group counts for the outcome but does not explain the participant flow or analysis population. Clear reporting of those details would help readers understand exactly which observations contribute to the endpoint estimates.
The record also highlights the importance of distinguishing planned statistical procedures from retrospective planning illustrations. A sample-size illustration based on an observed effect is not observed power and cannot substitute for the original design rationale or a prespecified statistical plan. Those elements are not reported in the registry record.
Finally, the mismatch between the masking classification and the summary description cautions against treating registry labels as complete methodological accounts. Clear descriptions of who was masked, how outcomes were handled, and how comparisons were tested are central to interpreting trial results.
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 registry record leaves important methodological details unspecified. It does not describe the randomization sequence, allocation concealment, or the people masked, despite listing a single-masking classification and describing the trial as open-label in the summary. The record also does not provide baseline characteristics with which to assess the groups or a participant-flow account explaining the posted endpoint group counts.
The statistical analysis plan and analysis population are not reported. There is no posted comparative estimate, confidence interval for a between-group contrast, or p-value for the primary endpoint. Methods for calculating the geometric means and confidence intervals are also not described. These omissions prevent a full assessment of the precision and inferential basis of the group comparison.
Missing-data handling, assay-limit procedures, multiplicity control, and prespecification of analyses are not reported in the registry record. The record lists 10 outcome measures but no secondary results or analyses, limiting assessment of the broader outcome set. The safety entries do not specify definitions or follow-up details for adverse events.
The trial population is specific to healthcare personnel in Israel who had received IIV4 during the previous season and were enrolled in SHIRI. The primary endpoint is an antibody measurement at a specified post-vaccination time, not a clinical influenza outcome. Generalization beyond this population, setting, season, or endpoint therefore requires evidence not included in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Immunogenicity Trial of Recombinant Influenza Vaccine Among HCP in Israel — NCT04523324.
- Registry record last updated 2023-11-15; status last verified 2023-11.
- Results first posted 2023-11-15.
- 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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18. Record Summary
The registry record describes a completed phase 4 randomized parallel-group trial of RIV4 (Flublok Quadrivalent) versus egg-based IIV4 (Vaxigrip Quadrivalent) among healthcare personnel in Israel. Its primary endpoint is the geometric mean HI antibody titer against influenza A/H1N1 28 days after vaccination.
The posted geometric mean titer is 173.1 for RIV4, with a 95% confidence interval of 148.5 to 201.7, and 83.9 for IIV4, with a 95% confidence interval of 74.5 to 94.5. A direct comparative estimate and its statistical test are not reported. The record also reports zero serious adverse events, zero other adverse events, and zero deaths in each group.
The sponsor is the Centers for Disease Control and Prevention. The record does not report the statistical analysis plan, handling of missing data, analysis populations, or multiplicity procedures.