A Study of an Investigational mRNA-1273.815 COVID-19 Vaccine in Previously Vaccinated Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of an Investigational mRNA-1273.815 COVID-19 Vaccine in Previously Vaccinated Adults (NCT06354998), a randomized phase 3 study. The primary outcome is Geometric Mean (GM) Value of Neutralizing Antibodies (nAbs) Against SARS-CoV-2-specific Strain at Day 15.

2. Clinical Question

The clinical question is about a measured immune response at a specified time point. Neutralizing antibodies are laboratory measures, and the primary endpoint is the geometric mean value in arbitrary units per milliliter. The record also reports a geometric mean ratio, which expresses the comparison between the groups on a relative scale. The endpoint is not a direct measure of clinical illness, infection, or protection.

The registry lists seroresponse rate as a secondary outcome, alongside safety outcomes. These provide additional information about the immune response and reported adverse events, but they do not change the primary question. The record does not report a clinical disease endpoint as the primary outcome.

3. Trial Design

This is a randomized, observer-blind, active-controlled, parallel-group Phase 3 clinical trial. Participants were assigned to investigational mRNA-1273.815 or a licensed Spikevax vaccine. Both interventions are described as intramuscular injections. The registry lists quadruple masking; the specific roles included in that masking designation are not reported in the registry record.

The record lists enrollment of 217 and gives a trial start date of 2024-04-08, primary completion on 2024-05-10, and a status of completed. These are registry-level trial details; they do not establish that every enrolled participant contributed to every outcome. For the primary immunogenicity outcome, the stated analysis population was the Per-protocol Immunogenicity Subset (PPIS), with 103 participants in the investigational group and 104 in the licensed-vaccine group. Safety figures use different at-risk counts, 106 and 109 respectively. The record does not describe a reconciliation of these populations.

The primary outcome was the geometric mean value of neutralizing antibodies against a SARS-CoV-2-specific strain at Day 15. Its reported unit is AU/mL, and the endpoint description specifies that values were log-transformed for confidence-interval calculation and then back-transformed for presentation. The registry also lists a Day 15 seroresponse rate and safety outcomes covering serious adverse events, adverse events of special interest, and adverse events leading to withdrawal.

The registry lists 3 outcome measures and 1 analysis. The full protocol, detailed allocation procedures, masking procedures, sample-size justification, and statistical analysis plan are not reported in the registry record. The planning illustration associated with the posted secondary comparison is not the trial’s original design justification.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Per-protocol Immunogenicity Subset (PPIS) included participants who received planned dose of study injection per schedule, complied with immunogenicity testing schedule and had no major protocol deviations that impacted key or critical data.

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: Safety Set included all enrolled participants who received study drug.

6. Primary Endpoint

The registry lists the primary outcome as Geometric Mean (GM) Value of Neutralizing Antibodies (nAbs) Against SARS-CoV-2-specific Strain at Day 15, measured over Day 15.

The primary endpoint is the geometric mean value of neutralizing antibodies against a SARS-CoV-2-specific strain at Day 15, measured in AU/mL. It summarizes antibody response on a multiplicative scale: geometric means are typically useful for measurements that are analyzed on a logarithmic scale and may vary proportionally rather than by equal absolute increments. This is a general statistical rationale, not an additional claim about the trial’s design.

The registry states that antibody values below the lower limit of quantification were replaced by 0.5 times the LLOQ. Values above the upper limit were replaced by the ULOQ when actual values were unavailable. The stated LLOQ was 38 AU/mL and the ULOQ was 6960 AU/mL. These rules make it possible to include censored assay results in the described analysis, but they also mean that some reported values may represent substitutions at assay limits rather than exact measured concentrations.

The confidence intervals for the geometric mean were calculated from log-transformed antibody values using a t-distribution, then transformed back to the original scale. A confidence interval describes the statistical uncertainty around an estimate under the analysis assumptions; it is not a range containing a fixed proportion of individual participants’ antibody values. The endpoint is an immunogenicity measure at a single stated time point, not a direct clinical outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Geometric means and ratios are natural summaries when measurements are handled on a logarithmic scale. In general, taking logarithms turns multiplicative relationships into additive ones, which can make statistical summaries and modeling more suitable for data whose variation is proportional to their level. A geometric mean is then obtained by transforming the mean on the log scale back to the original measurement scale. The registry describes this log-scale approach for the primary antibody endpoint.

What does the primary confidence interval represent?

The primary 95% confidence intervals were calculated from the log-transformed antibody values using a t-distribution and then back-transformed. In general, a confidence interval expresses the uncertainty in an estimated quantity under the method’s assumptions and the data used. It does not describe the range of individual values, nor does it give the probability that a fixed parameter lies inside the particular interval after the data have been observed. Back-transformation can make an interval asymmetric around the displayed geometric mean, which is expected for estimates on a multiplicative scale.

The assay limits are relevant to interpreting these summaries. The record states that values below LLOQ were replaced by 0.5 times LLOQ, and values above ULOQ were replaced by ULOQ when actual values were unavailable. Substitution is a way to handle results that the assay cannot quantify precisely within its stated range. In general, such substitutions can influence summaries, especially if many measurements lie beyond assay limits. The frequency of values below or above those limits is not reported in the registry record.

How should the geometric mean ratio be read?

The reported geometric mean ratio compares the two group geometric means. A ratio of 1 is the point of equality; values below or above 1 indicate a lower or higher geometric mean in the numerator group, respectively. The registry gives a ratio of 0.908 and a 95% confidence interval from 0.662 to 1.245. Because the interval includes 1, it does not rule out equality at the level represented by that interval. The record does not state the exact model, test, or construction method for the reported ratio interval. Those details are not reported in the registry record and should not be inferred from the separate description of the geometric-mean intervals.

What is the secondary risk-difference calculation?

The posted seroresponse summary includes a recalculated risk difference comparing licensed Spikevax with investigational mRNA-1273.815. A risk difference is the difference between the two observed proportions, expressed on the probability scale. The recalculated estimate is 0.032, and its 95% confidence interval is -0.095 to 0.160. In general, a risk-difference interval containing 0 is compatible with no difference as well as with differences in either direction. The associated p-value, 0.621, is unadjusted. This re-calculation uses posted summary statistics and is distinct from a sponsor-reported inferential analysis.

Other measures of binary association, such as a risk ratio or odds ratio, express group differences on different scales. They can be useful for different scientific questions, but their interpretation depends on the measure and its uncertainty. The registry record does not report a sponsor analysis for the seroresponse comparison. The posted re-calculation should therefore remain clearly distinguished from an analysis prespecified or conducted by the sponsor.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variability is greater than a statistical model expects. If a model assumes less variability than is present, standard errors can be too small and confidence intervals can be too narrow. The record does not report an over-dispersion assessment or identify a model for the primary comparison, so this is a general caution rather than a claim about the trial’s analysis.

How should the planning illustration be understood?

The planning illustration is calculated from the observed secondary effect, not from the trial’s own design. It assumes a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For planning for 100% of the observed effect, it gives 3,332 participants per arm for 80% power and 4,460 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 5,962 participants per arm for 80% power and 7,980 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 13,498 participants per arm for 80% power and 18,069 participants per arm for 90% power.

These figures are illustrative future-planning quantities, not observed power and not evidence that the original trial was designed around these assumptions. In general, planning calculations depend on the assumed effect, variability, significance level, allocation, and analysis method. The registry’s own sample-size justification and the assumptions used for its original design are not reported in the registry record.

10. Analyses Reported by the Sponsor

The registry reports a sponsor-associated primary comparison as a geometric mean ratio of 0.908, with a 95% confidence interval from 0.662 to 1.245. No p-value is reported for this comparison. The ratio is the direct relative-scale summary for the primary geometric-mean endpoint, and its interval includes 1, the value corresponding to equal group geometric means.

The separate recalculation concerns the secondary seroresponse outcome and uses posted summary statistics to estimate a risk difference. It is not a recalculation of the primary geometric mean ratio and does not provide an independent check of that ratio. The two comparisons also use different outcome scales: a relative ratio for the primary antibody measure and an absolute difference between proportions for seroresponse.

The registry’s discrepancy indicator is false, and the primary sponsor analysis is the relevant reported analysis for that endpoint. The secondary recalculation should be treated as supplementary, unadjusted statistical context rather than as a substitute for a sponsor analysis. No sponsor-reported inferential analysis for the secondary seroresponse comparison is listed in the registry record. Details of the primary ratio’s statistical method beyond its reported estimate and interval are not reported in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary immunogenicity outcome and secondary outcomes, but the statistical analysis plan and multiplicity procedure are not reported in the registry record. It is therefore not possible to determine from the record whether the endpoints were tested in a hierarchy, whether an adjustment was planned, or whether any particular secondary comparison was intended to support a confirmatory claim.

This matters because multiple testing changes how evidence should be interpreted. In general, if several outcomes or comparisons are tested and each uses an unadjusted threshold, the overall chance of at least one false-positive finding can be higher than the nominal level for a single test. The secondary seroresponse p-value is explicitly unadjusted, so it should not be treated as though it accounts for all outcomes examined. No adjustment should be assumed where none is reported.

The PPIS definition is stated for the primary endpoint: participants had to receive the planned injection per schedule, comply with immunogenicity testing, and have no major protocol deviations affecting key or critical data. This defines a selected analysis population. The registry does not report how many enrolled participants were excluded from the PPIS, the reasons for exclusion, or a corresponding intention-to-treat analysis. Those details are not reported in the registry record.

The record gives different group at-risk counts for safety and different group counts for immunogenicity. This is not necessarily inconsistent because the outcome populations and availability requirements can differ, but the registry does not provide a participant-flow account explaining the relationship. Missing outcome data, the extent of missingness, and any methods used to address it are not reported in the registry record.

The primary endpoint description specifies substitutions for antibody results beyond assay quantification limits, but does not report how often those substitutions were used. Interim analyses, stopping rules, and the sample-size justification are not reported in the registry record. These omissions limit assessment of the full analysis strategy; they do not establish that any particular procedure was or was not used.

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 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: small intestinal obstruction (0.9%).

The registry’s safety figures report serious adverse events for the safety at-risk groups: 1 affected participant among 106 at risk in the investigational group, and 0 among 109 at risk in the licensed Spikevax group. Deaths are reported as 0 in each group. The top serious term listed is Small intestinal obstruction, with 0.9% shown in the registry record.

These counts are descriptive. A count of zero in a group does not establish that an event is impossible, and a difference in counts does not by itself establish that the intervention caused or prevented an event. The record does not report a statistical comparison of serious adverse events, and the event counts are small. The safety at-risk counts also differ from the PPIS counts used for the primary immunogenicity outcome; the record does not explain participant flow between these analysis sets.

The registry lists adverse events of special interest and adverse events leading to withdrawal among the safety outcomes. Detailed results for those categories are not reported in the registry record. The serious adverse event figures should therefore be read as limited registry safety information, not as a comprehensive account of all adverse events or as a basis for a causal conclusion.

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

The posted results describe short-term immunogenicity at Day 15 in a randomized comparison of investigational mRNA-1273.815 and licensed Spikevax among previously vaccinated adults. They report geometric mean neutralizing-antibody values, a geometric mean ratio, and a secondary seroresponse comparison. The primary ratio interval includes the value representing equal geometric means, and the secondary recalculated risk-difference interval includes the value representing no difference. The intervals leave uncertainty about the magnitude and direction of group differences.

Those findings do not establish that the vaccines are equivalent or non-inferior. Such conclusions require a prespecified margin and an analysis designed to evaluate it; a margin and related testing plan are not reported in the registry record. Nor do the results establish that the groups are identical. An interval that includes a no-difference value can still encompass potentially meaningful differences in either direction.

The endpoint is an antibody measure rather than a clinical disease outcome. It cannot, by itself, determine whether participants became infected, developed illness, or experienced protection, and the registry record does not report such outcomes as the primary endpoint. The results also focus on Day 15; later antibody measurements and durability are not reported in the registry record.

Interpretation is further bounded by the stated PPIS population, the use of assay-limit substitutions, and the limited safety information. The posted re-calculation for seroresponse is unadjusted and should be considered secondary. The planning illustration describes hypothetical future sample sizes under stated assumptions; it is not observed power and does not describe the original design. Overall, the registry supports a careful description of measured responses and their uncertainty, not a medical recommendation or a conclusion about clinical effectiveness.

14. Why This Trial Matters Statistically

This trial illustrates why an immunogenicity result should be interpreted through both its estimate and its uncertainty. Reporting geometric means alone would show the observed response scale but not how precisely the relative comparison is estimated. The geometric mean ratio and its confidence interval add that context, while also making clear that the record does not establish a direction or magnitude with high precision.

It also demonstrates that endpoint choice shapes the comparison. A geometric mean uses the quantitative antibody values, whereas a seroresponse percentage reduces those measurements to whether participants meet a response criterion. These summaries answer related but distinct questions. Agreement or disagreement between them should not be expected to be exact, and neither alone provides a direct clinical outcome.

The PPIS definition and assay-limit substitutions matter because the analysis population and measurement rules affect what the reported estimate represents. The safety denominators differ from the immunogenicity denominators, which underscores the need to identify the population behind each result rather than assuming that all outcomes use the same participants.

Finally, the planning illustration shows why observed effect sizes should not automatically be treated as stable design targets. In general, a planning estimate based on an observed effect is uncertain and depends on the chosen assumptions. It is not a retrospective measure of whether the completed study had adequate power. The registry does not report its own sample-size rationale, so the illustration cannot answer that question.

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 registry record does not report the full protocol or statistical analysis plan, including the method used for the primary geometric mean ratio, the handling of missing outcome data, or any multiplicity strategy. This restricts independent assessment of whether the reported analyses follow a prespecified plan. It does not imply that these procedures were absent.

The primary result is limited to Day 15 and to the PPIS as defined in the registry. The record does not give participant flow into that subset, reasons for exclusion, or an intention-to-treat result. The frequency of antibody measurements replaced at the assay limits is also not reported, although the replacement rules are described.

The registry’s primary comparison has a confidence interval that includes 1, and no p-value is reported. No non-inferiority or equivalence margin is reported. As a result, the record does not support a formal equivalence or non-inferiority interpretation based solely on the reported ratio and interval.

The seroresponse calculation is an unadjusted re-calculation from posted summary statistics, and no sponsor-reported analysis for that outcome is listed. The planning illustration is based on the observed secondary effect rather than the trial’s original design assumptions. It should not be used to infer original power or design adequacy.

Safety reporting is limited in the record: detailed results for adverse events of special interest and events leading to withdrawal are not reported in the registry record. The serious-event counts are sparse and descriptive, and the safety analysis population differs from the stated immunogenicity population. The record does not report later immunogenicity measurements or clinical disease outcomes. These limits define the scope of interpretation; they do not establish what unreported analyses would have shown.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of an Investigational mRNA-1273.815 COVID-19 Vaccine in Previously Vaccinated Adults — NCT06354998.
• Registry record last updated 2025-05-25; status last verified 2025-05.
• Results first posted 2025-05-25.
• 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

The registry describes a completed randomized, observer-blind, active-controlled, parallel-group Phase 3 trial in previously vaccinated adults. It compares intramuscular investigational mRNA-1273.815 with a licensed Spikevax vaccine, with an immunogenicity focus on the XBB.1.5 Omicron subvariant strain. Enrollment is listed as 217, and the trial dates are 2024-04-08 to primary completion on 2024-05-10.

The primary outcome is the Day 15 geometric mean neutralizing-antibody value in the PPIS. The reported geometric mean ratio is 0.908, with a 95% confidence interval from 0.662 to 1.245. The registry also lists seroresponse and safety outcomes. The posted seroresponse re-calculation is unadjusted; the planning illustration is not the original trial design. Details of the statistical plan, missing-data handling, and multiplicity procedures are not reported in the registry record.