A Study on the Immune Response and Safety of the Shingles Vaccine and the Influenza Vaccine When Either is Given to Healthy Adults at the Same Time or Following a COVID-19 Booster Vaccine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study on the Immune Response and Safety of the Shingles Vaccine and the Influenza Vaccine When Either is Given to Healthy Adults at the Same Time or Following a COVID-19 Booster Vaccine (NCT05047770), a randomized phase 3 study. The primary outcome is Anti-glycoprotein E (gE) Antibody Concentrations Expressed as Geometric Mean Concentrations (GMCs) in HZ/suSeq and HZ/suCoAd Groups, and Between-group Ratios.

2. Clinical Question

The study also evaluated immune responses to the influenza vaccine and safety when the influenza or HZ/su vaccines were given with, or sequentially after, an mRNA-1273 booster. Those questions concern different vaccine groups and endpoints; they should not be conflated with the primary HZ/su antibody comparison. The registry lists 39 outcome measures and 11 analyses, and the total enrollment was 2013.

3. Trial Design

This completed Phase III study was randomized, open-label, controlled, and multicenter, with a parallel-group model. Enrollment was 2013. The study started on 2021-10-07, and primary completion was recorded as 2022-08-29. The number of centers is not reported in the registry record.

Four groups compared vaccine timing. In the HZ/suSeq Group, participants received mRNA-1273 at Day 1, followed by HZ/su at Week 2 and Week 10. In the HZ/suCoAd Group, the booster and first HZ/su dose were given together at Day 1, followed by the second HZ/su dose at Week 8. In the FluD-QIVSeq Group, participants received mRNA-1273 at Day 1 and Flu D-QIV at Week 2. In the FluD-QIVCoAd Group, the booster and Flu D-QIV were given together at Day 1.

The primary endpoint concerns only the HZ/su groups. Its analysis population was the HZ/su Per Protocol Set, with 228 participants in the sequential group and 230 in the coadministration group. The registry describes this set as including eligible participants who received all doses as assigned, had a known study-vaccine administration site, and did not receive prohibited concomitant intervention. The remainder of the population definition is incomplete in the registry record.

Masking was listed as none. This means participants and study personnel were not masked according to the recorded design; antibody concentrations are laboratory measurements, but the registry does not report whether laboratory personnel were masked. The protocol’s sample-size justification, detailed allocation procedures, and interim-analysis arrangements 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: Out of 2013 participants enrolled in the study, 468 were screen failures and 1545 were randomized to study groups. Out of 1545 randomized participants, only 1534 received at least 1 dose of study vaccine, were included in the Exposed Set and started the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: HZ/su Per Protocol Set included all participants who met all eligibility criteria, received all doses as per assignment, for whom administration site of study vaccine was known, who did not receive any other prohibited concomitant intervention, did not meet any of the criteria for elimination up to blood sample collection post-HZ/su Dose 2, and with immunogenicity data available for the specified analysis at the specified time point post-HZ/su Dose 2.

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as Anti-glycoprotein E (gE) Antibody Concentrations Expressed as Geometric Mean Concentrations (GMCs) in HZ/suSeq and HZ/suCoAd Groups, and Between-group Ratios, measured over At 1 month post-dose 2 of HZ/su vaccine administration (Week 14 for HZ/suSeq group and Week 12 for HZ/suCoAd group).

The primary endpoint is the concentration of antibodies against glycoprotein E, or anti-gE, measured by enzyme-linked immunosorbent assay and expressed as a geometric mean concentration in mIU/mL. Measurements were made one month after the second HZ/su dose: Week 14 for the HZ/suSeq Group and Week 12 for the HZ/suCoAd Group. The outcome therefore summarizes an immune response at a specified time after completion of the two-dose HZ/su schedule; it is not a measure of shingles cases or clinical protection.

A geometric mean is useful for antibody measurements that may be skewed, because it summarizes concentrations on a multiplicative rather than additive scale. The registry reports GMCs of 47430 mIU/mL for the sequential group and 47600 mIU/mL for the coadministration group, each with a 95% confidence interval. It also reports a between-group GMC ratio. The ratio expresses the relative concentration between groups, while its confidence interval conveys the range of values compatible with the analysis under its assumptions.

The outcome is relevant to the study’s immune-response question, but antibody concentration alone does not establish a difference in clinical disease outcomes. The registry record does not report a clinical efficacy endpoint for the primary comparison. It also does not state the non-inferiority margin used to judge the reported ratio.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary summary measure is a geometric mean concentration (GMC). In general, geometric means are suited to positive measurements that vary multiplicatively or have a right-skewed distribution. A geometric mean can be understood as averaging measurements on a logarithmic scale and transforming the average back to the original scale. That general explanation does not establish the exact transformations or model details used in this trial beyond the registry’s description of the endpoint and reported analysis.

What does the ratio represent?

A ratio compares the scale of one group’s GMC with the other’s. A ratio of 1 represents equality on the ratio scale; a value above 1 indicates a larger numerator GMC, and a value below 1 indicates a smaller numerator GMC. The registry reports a GMC ratio of 1.01 with a 95% confidence interval from 0.89 to 1.13. The registry does not specify the ratio’s numerator and denominator in the analysis description, so the direction should be interpreted with care. The arm-level GMCs make clear that the observed concentrations were close.

A confidence interval is a measure of statistical precision, not a range containing a fixed proportion of individual antibody measurements. In general, a 95% confidence interval describes uncertainty in an estimated group contrast under the model and sampling assumptions. A narrower interval indicates greater precision than a wider one, all else equal. The primary interval spans values both below and above 1, so it does not isolate a single relative effect.

What does ANCOVA contribute?

The registry identifies the primary comparison method as ANCOVA. In general, analysis of covariance estimates a group contrast while accounting for specified covariates. Adjustment can improve precision or address imbalances in measured covariates, depending on the model and design. The covariates, model specification, and any transformations used in the ANCOVA are not reported in the registry record. The reported sponsor analysis should therefore be read as the registered result, without assuming which covariates were included.

How does non-inferiority differ from a test of equality?

A non-inferiority analysis asks whether the result rules out an unacceptable loss relative to a comparator, according to a margin chosen before examining the results. It does not ask whether the two groups are exactly equal. A confidence interval can include 1 and still meet a non-inferiority criterion, depending on the margin and the direction of the comparison. Conversely, a point estimate near 1 does not on its own establish non-inferiority. Because the margin and its direction are not reported in the registry record, the label attached to the analysis cannot be independently evaluated against a stated threshold.

The registry’s primary analysis is a sponsor-reported ANCOVA comparison, rather than a recalculated contrast from the posted group summaries. The arm-level GMCs and their confidence intervals describe each group separately; they do not contain all the information used in an adjusted ANCOVA. This distinction matters because an adjusted model estimate need not be recoverable from separate group summaries alone.

What can unadjusted binary comparisons tell us?

Several posted secondary outcomes are binary, such as whether a participant had a vaccine response or reported a specified event. For these outcomes, an unadjusted risk difference compares the observed proportions between groups. A confidence interval around that difference describes uncertainty in the contrast. The recalculated comparisons use the posted counts and are unadjusted; they do not incorporate covariates or any multiplicity adjustment. These are descriptive analyses and should not be treated as equivalent to a prespecified sponsor model when such a model is reported.

When events are uncommon, a small number of participants can have a substantial influence on the estimated proportion and its uncertainty. In general, sparse event data can produce wide confidence intervals for relative measures and unstable estimates. A result near zero events in one group does not prove that the underlying event risk is zero. These considerations are particularly relevant to rare safety outcomes and to the posted clinically suspected HZ episode comparison.

For planning illustrations based on an observed binary effect, the number of participants required depends on assumptions about the effect to detect, significance level, allocation, and statistical approximation. The registry’s illustrations assume a two-sided significance level of 0.05, equal allocation, and a normal approximation; they scale the effect to detect as a stated fraction of the observed effect. They are illustrations, not the trial’s documented design justification and not observed power. The protocol’s own sample-size assumptions are not reported in the registry record.

10. Analyses Reported by the Sponsor

The registry reports the primary result as an ANCOVA-based GMC ratio of 1.01, with a 95% confidence interval from 0.89 to 1.13. This sponsor-reported analysis is the primary inferential result. It is distinct from a simple, unadjusted recalculation based only on the arm-level GMCs, because an adjusted model may use information not contained in those summaries. No p-value is reported for the primary comparison.

The recalculated binary comparisons among some secondary outcomes are unadjusted and are not substitutes for the primary ANCOVA. They use posted counts and do not reproduce an adjusted sponsor analysis. The registry does not report sponsor analyses for the three secondary comparisons that include recalculated contrasts. There is no discrepancy flagged in the posted results, but the absence of a discrepancy flag does not supply missing details about model specification or analysis populations.

The study identifies the primary comparison as non-inferiority, but the margin is not reported in the registry record. Thus, the numerical estimate and interval can be presented as the sponsor’s result, while a formal judgment against the non-inferiority criterion cannot be checked from the recorded information alone.

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises because the study records numerous outcome measures and analyses. When several endpoints or group contrasts are examined, interpreting every unadjusted result at the same nominal threshold can increase the chance of a false-positive finding across the family of tests. The registry record identifies a primary endpoint and lists secondary outcomes, but a comprehensive plan for controlling multiplicity is not reported in the registry record. The primary analysis is therefore distinct from the exploratory weight of unadjusted secondary comparisons.

The registry labels the primary comparison non-inferiority, but does not report the non-inferiority margin. It also does not report enough information to establish the planned hierarchy among endpoints, whether secondary outcomes were confirmatory or exploratory, or whether any adjustment method was used for secondary analyses. These details matter when interpreting claims that depend on formal hypothesis testing.

Missing-data handling is not reported in the registry record. The primary population is described as a Per Protocol Set and includes eligibility, dose receipt, known administration site, and restrictions on prohibited concomitant intervention, but the recorded definition is incomplete. The numbers of randomized participants excluded from this primary analysis, reasons for exclusion, handling of missing antibody measurements, and any sensitivity analyses are not reported in the registry record.

The available primary result is based on 228 and 230 participants in the two HZ/su groups. That analysis population should not be confused with total enrollment of 2013 or with the safety populations used for adverse-event reporting. The registry does not report an intention-to-treat primary result alongside the per-protocol result in the information.

Interim analyses and the statistical analysis plan are not reported in the registry record. The protocol’s sample-size justification is also not reported. Planning illustrations based on observed effects are not evidence of the study’s original design assumptions or of its observed power.

12. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: urosepsis (0.4%), cellulitis (0.4%), endometrial cancer (0.4%), intraductal proliferative breast lesion (0.4%), pancreatitis acute (0.4%).

For serious adverse events, the registry records 5 affected participants among 272 at risk in the HZ/suSeq Group and 6 among 267 in the HZ/suCoAd Group. The corresponding figures are 7 among 497 in the FluD-QIVSeq Group and 2 among 498 in the FluD-QIVCoAd Group. The recorded death count is 0 in each group. These are descriptive counts over the safety reporting period; they do not, by themselves, establish whether events were caused by a vaccine or whether groups differ reliably.

The listed serious-event terms each have a reported frequency of 0.4%: urosepsis, cellulitis, endometrial cancer, intraductal proliferative breast lesion, acute pancreatitis, and osteoarthritis. The registry record does not provide a basis for attributing these events to a specific vaccine or for determining whether an individual event was considered related to vaccination. Serious events are not necessarily vaccine-related events.

Safety comparisons also depend on definitions, observation periods, and the population at risk. The primary antibody analysis uses a different set of participants from the safety counts. The registry does not report further detail about event adjudication or the criteria used to classify an event as serious.

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

The primary result describes anti-gE antibody concentrations after two HZ/su doses in two schedules that differed in whether the first HZ/su dose was given with the mRNA-1273 booster. The reported ratio of 1.01 and its 95% confidence interval from 0.89 to 1.13 indicate that the estimated group contrast is close to equality, while retaining uncertainty on either side of 1. The result is an immune-response comparison at one month after dose two, not a comparison of clinical disease rates.

The non-inferiority label signals the type of question the sponsor intended to address, but the registry does not report the margin needed to assess that criterion. A near-one point estimate is not itself proof of non-inferiority, and a confidence interval that includes 1 is not a test of equivalence. The recorded result therefore supports a careful description of the estimate and precision, rather than an independent declaration about the formal criterion.

The result does not establish the duration of the antibody response beyond the stated measurement, the effect on shingles incidence, or the safety profile outside the recorded groups and follow-up. It also does not answer whether receiving mRNA-1273 changes the response compared with receiving no booster, because the described groups all received mRNA-1273. The influenza vaccine groups address different outcomes and are not part of the primary HZ/su comparison.

In general, laboratory immune measurements can inform understanding of vaccine responses, but a measured antibody concentration is not interchangeable with a clinical endpoint. Interpretation should remain tied to the specific assay, time point, population, and contrast reported in the registry.

14. Why This Trial Matters Statistically

This trial is statistically informative because it separates two scheduling strategies while keeping the mRNA-1273 booster in both HZ/su groups. The primary contrast is therefore about the timing of HZ/su relative to the booster and the resulting schedule, rather than a comparison of booster versus no booster. Clear definition of the contrast is essential to avoid attributing the result to a question the study did not test.

The endpoint also illustrates the difference between a group-level immune summary and a clinical outcome. GMCs provide a useful way to summarize antibody concentrations, and a ratio communicates their relative scale. The confidence interval adds information about precision that a point estimate alone cannot convey. At the same time, the recorded non-inferiority label cannot be fully assessed without the margin and relevant analysis details.

The trial’s multiple immune and safety outcomes demonstrate why an outcome hierarchy matters. A designated primary endpoint can anchor interpretation, while numerous secondary results can provide breadth but may be less conclusive when adjustment procedures and prespecified status are unclear. Reporting the population, time point, effect measure, and interval makes the evidence easier to interpret and compare responsibly.

Finally, the registry record distinguishes the primary per-protocol antibody population from the larger study enrollment and the safety populations. That distinction is statistically important: each result applies to the participants and endpoint used in its analysis, not automatically to every enrolled participant or to outcomes not measured in that analysis.

15. 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 study was open-label, with masking listed as none. Knowledge of assigned schedule can affect participant reporting and other aspects of study conduct, although the primary endpoint is a laboratory antibody measurement. Whether laboratory personnel were masked is not reported in the registry record.

The primary comparison is limited to anti-gE GMCs in the HZ/su Per Protocol Set. The population definition in the registry is truncated, and details about exclusions, missing measurements, and sensitivity analyses are not reported. This limits assessment of how representative the analyzed participants were of all randomized participants and how robust the result is to analysis-population choices.

The primary measurement occurred at different study weeks in the two schedules: Week 14 in the HZ/suSeq Group and Week 12 in the HZ/suCoAd Group. Both are recorded as one month after dose two, but the calendar timing relative to the Day 1 booster differs by schedule. The registry does not report further information to assess whether this timing difference affects interpretation.

The non-inferiority margin, covariates in the ANCOVA, detailed statistical analysis plan, and multiplicity procedures are not reported in the registry record. The primary estimate can be described, but its formal criterion and model details cannot be independently checked from the listed information. Secondary recalculated comparisons are unadjusted and should not be treated as confirmatory evidence without considering the many outcomes.

The registry record also does not report a clinical efficacy result for the primary comparison, or the number of study centers. Safety counts are descriptive, and causal attribution and further event-adjudication details are not reported. These limitations constrain conclusions to the stated immune measures, populations, follow-up, and recorded event counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study on the Immune Response and Safety of the Shingles Vaccine and the Influenza Vaccine When Either is Given to Healthy Adults at the Same Time or Following a COVID-19 Booster Vaccine — NCT05047770.
• Registry record last updated 2023-11-13; status last verified 2023-10.
• Results first posted 2023-11-13.
• 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.

19. Record Summary

This completed Phase III randomized, open-label, controlled, multicenter study enrolled 2013 participants. It compared sequential and coadministration schedules for HZ/su and Flu D-QIV when used with an mRNA-1273 booster. The primary endpoint was anti-gE GMC one month after the second HZ/su dose, analyzed in the HZ/su Per Protocol Set.

The registry reports GMCs of 47430 mIU/mL and 47600 mIU/mL in the sequential and coadministration groups, respectively. The sponsor-reported ANCOVA GMC ratio was 1.01, with a 95% confidence interval from 0.89 to 1.13, and the analysis was identified as non-inferiority. The margin needed to assess that criterion is not reported in the registry record. Secondary outcomes cover additional immune measures and reported events; safety counts include serious adverse events and no recorded deaths in the groups.