Long-Term Immunogenicity of the Norovirus GI.1/GII.4 Bivalent Virus-like Particle (VLP) Vaccine (NoV Vaccine) in Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Long-Term Immunogenicity of the Norovirus GI.1/GII.4 Bivalent Virus-like Particle (VLP) Vaccine (NoV Vaccine) in Adults (NCT03039790), a na phase 2 study. The primary outcome is Geometric Mean Blocking Titers 50 Percent (%) (GMBT50) of Anti-norovirus GI.1 VLP Antibodies as Measured by Histo-Blood Group Antigen HBGA Blocking Assay.

2. Clinical Question

3. Trial Design

This was a completed Phase 2, single-group long-term immunogenicity follow-up study. Its official title describes follow-up of adult and elderly participants who had previously received an intramuscular norovirus VLP vaccine. The registry lists an enrollment of 528. That enrollment figure describes the overall study record; it does not establish how many participants contributed endpoint data at any particular timepoint.

The extension brought together eligible participants from NOR-107, NOR-210, and NOR-204 after their participation in earlier vaccination studies. The prior regimens were not uniform: the arm descriptions include differences in GI.1 and GII.4 antigen amounts, use or amount of monophosphoryl lipid A, aluminium hydroxide composition, and one-dose or two-dose schedules. Some groups are described as having received hepatitis A vaccine before norovirus vaccine. These histories are relevant to interpreting the follow-up groups, but the registry does not describe the extension as a randomized comparison of those regimens.

Allocation is listed as not applicable, masking as none, and the model as single group. The registry also cautions that the arms are not a like-for-like control comparison. Consequently, differences between groups, if considered, would not by themselves estimate a causal effect of one regimen versus another. The extension’s stated purpose was descriptive evaluation of long-term immunogenicity after at least one vaccine administration.

The registry lists a study start date of 2017-02-21, primary completion on 2021-07-22, and completed status. Details of recruitment procedures, follow-up completeness, and the number of participants measured at each visit are not reported in the registry record. The trial’s planned sample-size justification and any interim analyses are also 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.

Only the first 6 of 20 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per Protocol Set (PPS) included all participants in the FAS who had no major or critical protocol violations that potentially confound the primary endpoint. Number analyzed is the number of participants with data available for analysis at specific timepoints.

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: Full Analysis Set (FAS) included all participants with data from at least 1 follow-up time point.

Only the first 6 of 21 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Geometric Mean Blocking Titers 50 Percent (%) (GMBT50) of Anti-norovirus GI.1 VLP Antibodies as Measured by Histo-Blood Group Antigen HBGA Blocking Assay, measured over Baseline up to Year 2 post-primary vaccination of initial study NOR-107, NOR-210 NOR-204 and up to Year 5 of this extension study.

The primary endpoint is the geometric mean blocking titer, or GMBT50, of antibodies to norovirus GI.1 VLP, measured with a histo-blood group antigen (HBGA) blocking assay. A titer summarizes the dilution at which a participant’s antibody sample meets the assay’s specified blocking criterion. The endpoint aggregates participant-level titers as a geometric mean, a common summary for measurements that are positive and can vary over a wide range.

The registry specifies a 95% confidence interval for this geometric mean. A confidence interval conveys the statistical precision of an estimate: a narrower interval indicates greater precision under the method’s assumptions, while a wider interval indicates more uncertainty. It does not show the range of individual participants’ titers, and it is not a guarantee that the true value lies within the particular interval.

Blocking assays assess antibody activity against a binding interaction relevant to the assay. They are used to characterize functional antibody responses, alongside binding-antibody assays such as the Pan-Ig ELISA listed among the secondary outcomes. The registry endpoint is an immunogenicity measure, not a direct clinical outcome such as norovirus illness. Numerical GMBT50 estimates and confidence intervals are not reported in the registry record, so the endpoint’s observed level, trajectory, and precision cannot be described from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a geometric mean endpoint and a 95% confidence interval, but it does not report the numerical outcome estimates or a detailed statistical analysis plan. The concepts below explain how such summaries are generally interpreted; they do not describe unreported methods used in this study.

What does a geometric mean summarize?

For positive measurements that can span a broad range, the geometric mean is commonly calculated by taking the arithmetic mean after logarithmic transformation and then converting the result back to the original scale. This gives a summary that reflects multiplicative rather than additive spacing. It can be more suitable than an arithmetic mean when values are right-skewed, although its interpretation depends on the assay and the data distribution. The registry names the geometric mean but does not report the exact calculation details, any handling of values below assay limits, or the transformation used.

What does the confidence interval communicate?

A confidence interval describes uncertainty around an estimated population quantity under the statistical method used. It is not an interval containing most individual participants’ results. Its width is influenced by the amount of information and variability in the data, as well as by the method of estimation. Because the endpoint’s estimates and intervals are not reported in the registry record, their precision cannot be evaluated. The confidence level alone does not reveal whether an estimate is clinically important or whether differences between timepoints are statistically persuasive.

Why does the single-group structure matter?

In a randomized controlled comparison, random assignment can help balance measured and unmeasured factors between groups. This extension is listed as single group, with allocation not applicable and masking none. Its participants had different prior study and regimen histories, but those histories are not randomized comparison arms within this extension. Any difference between their antibody summaries could reflect differences in participant characteristics, originating study, vaccine formulation, dose schedule, follow-up, or other factors. Without a suitable comparison design and an appropriate analysis, a difference should not be interpreted as the causal effect of a regimen.

How should repeated follow-up measurements be understood?

Longitudinal immunogenicity studies may collect measurements from the same participants at multiple visits. Repeated observations from one participant are related, rather than independent. A statistical analysis that compares timepoints should account for that dependence if it uses participant-level data. The primary outcome description identifies multiple collection times, but the registry does not report whether analyses used participant-level repeated-measures models, separate summaries at each visit, or another approach. The specific model and assumptions are not reported in the registry record.

The endpoint description states that the number analyzed at a timepoint is the number of participants with data available at that timepoint. That wording makes the available-case denominator potentially vary across visits. If participants miss follow-up, the observed summaries may represent different subsets over time. Whether missingness was described, modeled, or addressed through sensitivity analyses is not reported in the registry record.

What can be inferred from the analysis record?

The registry lists four outcome measures and zero analyses. This indicates that registered analysis entries are absent from the record; it does not explain why they are absent or establish which analyses were conducted elsewhere. The detailed statistical plan, treatment of outliers, assay-limit values, multiplicity procedures, and any interim analyses are not reported in the registry record. Those details should not be reconstructed from the endpoint label alone.

For multiple endpoints or timepoints, testing many hypotheses can increase the chance of at least one apparently unusual result. A prespecified hierarchy, adjustment procedure, or emphasis on estimation can help explain how such findings are interpreted. The registry does not identify a multiplicity strategy. In this descriptive extension, effect estimates and their uncertainty would be important, but the numerical results and analysis procedures needed to evaluate them are not reported in the registry record.

Why are planning calculations not observed power?

A sample-size illustration based on an observed effect is a planning exercise: it asks how many participants might be needed under stated assumptions to detect a chosen effect in a hypothetical design. It does not measure the probability that the completed study detected an effect, and it cannot repair limitations in the original design. The registry’s trial-specific sample-size justification is not reported in the registry record. Any planning illustration should therefore be read as hypothetical rather than as observed power or as evidence that the study was designed to answer a particular comparison.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures, including the primary GI.1 GMBT50 endpoint and secondary Pan-Ig ELISA geometric mean titers for GI.1 and GII.4 antibodies. The primary endpoint covers multiple collection times. Considering several outcomes and timepoints can create multiplicity: when many statistical tests are performed, the chance of at least one apparently notable result can increase. A prespecified testing hierarchy, adjustment, or descriptive emphasis on estimates can help define how results are interpreted. The registry’s approach to multiplicity is not reported in the registry record.

The endpoint population is the Per Protocol Set (PPS), defined as participants in the Full Analysis Set (FAS) without major or critical protocol violations that could potentially confound the primary endpoint. The number analyzed is described as those with data available at a particular timepoint. The registry does not give the numerical FAS or PPS counts by visit, explain the criteria used to define the FAS, or report how many participants were excluded from the PPS. Those details are not reported in the registry record.

When follow-up data are unavailable, estimates at later visits may be based on a different subset from estimates at earlier visits. Missingness can affect interpretation if availability of a measurement is related to antibody level or participant characteristics. The registry does not report the extent or reasons for missing endpoint data, the assumptions used to handle missingness, or any imputation or sensitivity analyses. These aspects are not reported in the registry record.

The registry lists no analysis entries. It does not state whether a statistical analysis plan specified primary comparisons, repeated-measures methods, multiplicity handling, or interim analyses. Conclusions about those procedures cannot be drawn from the outcome titles or population definition alone.

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

Serious events with the highest arm-level rate: colitis ulcerative (5.3%), episcleritis (4.2%), crohn's disease (3.7%), polymyalgia rheumatica (3.7%), amaurosis fugax (3.4%).

The safety listing gives group-level counts for participants at risk and participants affected by serious adverse events, other adverse events, and deaths. For example, the NOR-204 group labeled 15/50/500 µg with 1-Dose and MPL 15 µg lists 29 at risk and 2 affected by serious adverse events, with 0 affected by other adverse events and 1 death. The age-labeled NOR-204 1-Dose group for ages 60-94 Yrs lists 39 at risk, 5 affected by serious adverse events, and 3 deaths. These are descriptive counts in the registry record, not estimates of treatment effects.

The record’s list of serious adverse event terms includes Colitis ulcerative at 5.3%, Episcleritis at 4.2%, Crohn's disease at 3.7%, Polymyalgia rheumatica at 3.7%, Amaurosis fugax at 3.4%, and Metastases to lung at 3.4%. The registry listing does not make these terms evidence that vaccination caused the events. There is no concurrent randomized control group in this extension, and participants came from different originating studies and regimens.

Differences in counts across groups should not be interpreted as comparative risks without a suitable analysis and context on follow-up and participant characteristics. The record does not provide a causal attribution assessment or the details needed to infer why particular events occurred.

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

This trial record documents a long-term immunogenicity follow-up after prior norovirus VLP vaccination. It identifies the primary measure as geometric mean blocking titers of GI.1 antibodies in an HBGA blocking assay, with follow-up extending through Year 5 of the extension. That identifies what the study aimed to measure; it does not establish the size or direction of antibody changes. Numerical endpoint estimates and their confidence intervals are not reported in the registry record.

The design also determines what comparisons are supportable. This was a single-group extension, not a randomized trial comparing each prior regimen with a concurrent control. The participants came from prior studies and had different vaccine histories. Consequently, the record does not support a causal claim that one formulation, adjuvant amount, or dose schedule produced a different long-term antibody level from another. It also does not support attributing listed adverse events or deaths to the vaccine.

An antibody titer is an immunogenicity measure, not a direct measure of clinical protection. The registry’s primary outcome does not itself establish whether participants experienced norovirus infection, illness, or other clinical outcomes. The record’s listed secondary antibody assays are also laboratory measurements, and their numerical results are not reported in the registry record.

Likewise, a confidence interval, if reported, would communicate uncertainty about an estimated average under the analysis method; it would not describe the spread of individual responses or prove clinical importance. Here, without the numerical estimates, visit-specific analysis counts, and statistical procedures, the trajectory and precision of the antibody findings cannot be judged.

The most defensible interpretation is therefore limited: the registry describes the question, endpoint, follow-up framework, and group-level safety information, but does not report enough outcome analysis to conclude how antibody titers changed or what those changes mean clinically. The stated descriptive purpose should not be expanded into claims of efficacy, comparative superiority, or causation.

13. Why This Trial Matters Statistically

Long-term follow-up raises statistical questions that are different from those in a short-term trial. Antibody measurements over time can describe persistence or change, but interpretation depends on who returns for measurement, how repeated observations are analyzed, and whether the measurement remains comparable across visits. The registry’s endpoint description names an extended follow-up horizon, making these issues central to understanding the scientific question.

The extension also illustrates why a study’s design must shape the claims made from its data. Participants entered from different originating studies and had different vaccine histories. Although the registry lists multiple groups, it states that this is not a like-for-like control comparison. Treating those groups as if randomized would overlook possible differences in their source studies, participants, formulations, and follow-up.

Immunogenicity and clinical outcomes are related but distinct kinds of evidence. A blocking antibody assay can characterize an immune response, while the endpoint alone does not establish clinical protection. Keeping that distinction clear helps prevent a laboratory result from being interpreted as a direct estimate of disease prevention.

Finally, precision and completeness matter. The registry names a confidence interval and defines a timepoint-specific analysis population, but the numerical endpoint results and visit-specific analysis counts are not reported in the registry record. Without those quantities, readers cannot evaluate uncertainty or how the observed data may have changed across follow-up. The record is useful for identifying the intended measurement and design constraints, while its missing outcome details limit statistical conclusions.

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 interpreting this record is that numerical primary and secondary immunogenicity results are not reported in the registry record. Without estimates, confidence intervals, and participant counts by timepoint, it is not possible to describe the observed antibody trajectory or its precision. The registry names the PPS and explains that counts vary with data availability, but does not give those counts.

The single-group extension does not include a concurrent randomized control comparison. In addition, participants originated in NOR-107, NOR-210, and NOR-204 and had heterogeneous prior regimens. Differences across these histories cannot be read as causal effects of formulation, adjuvant, or dose schedule from this design alone. The registry explicitly notes that the arms are not a like-for-like control comparison.

The record does not describe the statistical analysis plan, missing-data methods, multiplicity strategy, or any interim analyses. The absence of registered analysis entries leaves those procedures unclear; it should not be taken as proof that no analyses were performed outside the registry record. The trial’s sample-size justification is also not reported in the registry record.

Further details that would aid interpretation, including participant characteristics at follow-up, reasons for missing measurements, and the handling of assay values outside measurable limits, are not reported in the registry record. Safety counts are descriptive and come without a concurrent randomized control group or causal attribution information. These constraints limit comparisons and causal conclusions even though the record reports group-specific safety counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Long-Term Immunogenicity of the Norovirus GI.1/GII.4 Bivalent Virus-like Particle (VLP) Vaccine (NoV Vaccine) in Adults — NCT03039790.
• Registry record last updated 2022-11-09; status last verified 2022-11.
• Results first posted 2022-10-06.
• 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

NCT03039790 is a completed Phase 2, single-group extension study sponsored by Takeda. Its stated purpose was descriptive evaluation of long-term immunogenicity after at least one norovirus vaccine administration. The registry lists enrollment of 528, a start date of 2017-02-21, and primary completion on 2021-07-22.

The primary endpoint is GI.1 geometric mean blocking antibody titer measured by HBGA blocking assay, with a 95% confidence interval and follow-up described through Year 5 of the extension. Participants came from NOR-107, NOR-210, and NOR-204 and had differing prior vaccine regimens. The registry says the arms are not a like-for-like control comparison.

Numerical immunogenicity results, timepoint analysis counts, detailed statistical methods, and missing-data procedures are not reported in the registry record. Safety information is listed descriptively by group and does not establish causation.