A Study to Evaluate the Safety and Immune Response of mRNA-1345, a Vaccine Targeting Respiratory Syncytial Virus (RSV), When Co-administered With a Fluzone HD, in Adults ≥65 Years of Age: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety and Immune Response of mRNA-1345, a Vaccine Targeting Respiratory Syncytial Virus (RSV), When Co-administered With a Fluzone HD, in Adults ≥65 Years of Age (NCT06060457), a randomized phase 3 study. The primary outcome is Number of Participants With Solicited Local and Systemic Adverse Reactions (ARs) Within 7 Days After Day 1 Injection.

2. Clinical Question

3. Trial Design

This was a randomized Phase 3 study with a sequential model and quadruple masking. The registry lists an enrollment of 1900 and a completed status. The recorded study start was 2023-09-25, and primary completion was 2024-06-07. The trial focused on adults aged 65 years and older and evaluated mRNA-1345, an RSV-targeting vaccine, with Fluzone HD, a high-dose quadrivalent seasonal influenza vaccine.

The two arm schedules differed on Day 1 and Day 22. Participants in the coadministration arm received Fluzone HD and mRNA-1345 together on Day 1, then placebo on Day 22. Participants in the sequential arm received Fluzone HD and placebo together on Day 1, then mRNA-1345 on Day 22. The primary safety endpoint captured solicited reactions during the 7 days after Day 1, so it principally compares the experience after the different Day 1 injections. The primary endpoint does not compare post-injection reactions after the Day 22 injections.

The registry describes the study's broader purpose as evaluating safety and immunogenicity, including immune responses to RSV-A and RSV-B and responses to four vaccine-matched influenza strains. Five secondary outcomes are posted, including seroresponse, fold-rise, and seroconversion measures. The study record lists 13 outcome measures and 2 analyses. Those details establish that the trial addressed more than the primary safety question, but the primary result is a count of participants reporting solicited local or systemic reactions.

The reported primary analysis groups included 947 participants in the coadministration arm and 945 in the sequential arm. The primary safety-set description requires Day 1 intervention and solicited-reaction data. Randomization and masking describe the trial design; the registry record does not report further details of sequence generation, allocation concealment, masking procedures, or the original sample-size 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: Day 1 Solicited Safety Set included all randomized participants who received any study intervention on Day 1 and contributed any solicited ARs data from the time of study injection on Day 1 through the following 6 days. Participants were included in the treatment arm corresponding to the study drug they actually received.

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: The Randomized Set included all participants who were randomized in the study, regardless of the participant's treatment status in the study.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Solicited Local and Systemic Adverse Reactions (ARs) Within 7 Days After Day 1 Injection, measured over Within 7 days after Day 1 injection.

The primary endpoint counts participants with solicited local or systemic adverse reactions during the 7 days after the Day 1 injection. Participants could contribute a reaction if they reported one or more of the listed symptoms. Local reactions included injection-site pain, redness, swelling or hardness, and underarm swelling or tenderness on the injection side. Systemic reactions included fever, headache, fatigue, muscle or joint pain, nausea or vomiting, and chills. Reactions were collected in an electronic diary.

This is a participant-level count: it indicates how many participants had a solicited reaction, not how many reaction episodes occurred or how severe each reaction was. The registry notes that not every solicited reaction was considered an adverse event. Investigators reviewed whether a solicited reaction also needed to be recorded as an adverse event. Serious and nonserious adverse events are described separately in the registry.

Solicited reactions are used in vaccine safety assessment because a prespecified list and short observation window provide a structured way to collect commonly monitored symptoms after an injection. They can support a comparison of the proportion of participants who report at least one listed reaction under different schedules. They do not, by themselves, establish a cause for each symptom, describe the full safety profile, or answer whether a vaccine produces an immune response. The endpoint is limited to the specified Day 1 reporting period and the participants included in the Day 1 Solicited Safety Set.

7. Results Posted in the Registry

• Fluzone HD + Placebo Followed by mRNA-1345: 57.9% (547/945) versus 72.8% (689/947) on control; risk difference -14.9 percentage points (95% CI -19.1 to -10.6), risk ratio 0.80 (0.74–0.85); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either had at least one solicited reaction in the specified period or did not. The registry reports counts of participants with reactions by arm and a risk-difference comparison. A risk difference expresses the difference between the two arms' event risks on an absolute scale. In this analysis, the comparison is sequential schedule minus coadministration schedule, so a negative estimate indicates fewer participants with a reaction in the sequential arm. No new calculation is needed to interpret that direction.

What does a risk difference describe?

A risk difference compares the proportion of participants experiencing the endpoint in one group with the corresponding proportion in another group. Unlike a relative measure, it stays on an absolute scale: it describes how far apart the event risks are, rather than how many times one risk is another. The estimate is specific to the outcome definition and the groups being compared. Here the outcome is having any listed solicited reaction within 7 days after the Day 1 injection, and the groups differ in whether mRNA-1345 was given with Fluzone HD on Day 1 or later.

The direction of the estimate matters. Because the registry defines the posted comparison as the sequential arm against the coadministration arm, a negative risk difference corresponds to a lower observed reaction risk in the sequential arm. The interval around the estimate describes uncertainty about the underlying difference under the analysis assumptions. Since the reported interval excludes zero, the data are inconsistent with no difference at the conventional level used by the reported unadjusted test. That statistical statement does not, by itself, decide whether the magnitude matters clinically.

What does the p-value contribute?

The reported p-value is <0.001. In general, a p-value describes how incompatible the observed data, or data more extreme, would be with a specified null hypothesis if that hypothesis and the statistical model were correct. It is not the probability that the null hypothesis is true, and it does not quantify the size or importance of the difference. The estimate and its confidence interval are needed to describe direction and precision; the p-value alone cannot do that.

The p-value is labeled unadjusted. The registry record does not report whether the primary test was part of a broader multiplicity-control procedure or how any testing hierarchy was defined. Therefore, the posted p-value should be described as an unadjusted result, not as a multiplicity-adjusted claim across all outcomes or comparisons.

Why is the endpoint a count rather than a severity score?

The primary measure counts participants with any solicited reaction. It therefore gives each participant a binary endpoint status regardless of whether that participant reported one listed symptom or several. This can make the result straightforward to compare between arms, but it discards information about the number, duration, and severity of symptoms. Separate outcomes or detailed event-level summaries would be needed to address those dimensions. The registry record does not report a primary severity scale for this endpoint.

The registry says solicited reactions were collected through an electronic diary and that investigators reviewed whether a solicited reaction should also be recorded as an adverse event. This distinction matters because a solicited symptom and an adverse event are not interchangeable labels in the record. The primary endpoint captures the solicited-reaction definition, while the reported adverse-event summaries have separate definitions and populations.

What does randomization contribute?

Random assignment is intended to make the comparison groups similar, on average, with respect to factors that could otherwise influence outcomes. That rationale supports interpreting an arm difference as associated with the assigned schedule, subject to trial conduct, missing observations, and the analysis population. The registry identifies the study as randomized and quadruple-masked, but does not report the detailed randomization method, masking implementation, or the analysis model used for the primary comparison. Those specifics are not reported in the registry record.

The trial is described as sequential, and the schedules explicitly place the vaccines on different days in the two arms. The primary endpoint's Day 1 window thus evaluates a schedule contrast at the time of the first injection. It does not estimate a general effect of receiving both products across all time points, and it cannot be interpreted as a comparison of reactions after Day 22 based on this endpoint.

How should the assumptions be understood?

General statistical interpretation assumes that the outcome is defined consistently across arms and that the analysis uses the participants and observations described. The primary population is the Day 1 Solicited Safety Set, consisting of randomized participants who received a Day 1 intervention and contributed solicited-reaction data through the following 6 days. The registry record does not report details of missing-data handling, any covariate adjustment, or additional sensitivity analyses. Those omissions limit how fully the analysis can be reproduced or its robustness assessed from the record alone.

Over-dispersion is a concern mainly for count models when observed variability in counts exceeds what the selected model assumes. The primary endpoint is a count of participants with an event by arm, not a count of repeated event episodes modeled as a rate. The posted comparison is a risk difference; a concern about over-dispersion in a recurrent-event count model should not be imported into this binary endpoint without evidence that such a model was used. The model details are not reported in the registry record.

10. Confidence Intervals and Precision

A confidence interval gives a range of values compatible with the observed data under the statistical method and its assumptions. It communicates the uncertainty around an estimate, rather than guaranteeing that the true effect lies within the interval. For a risk difference, zero represents no difference between the compared risks. The posted interval lies below zero, supporting the direction that the recorded reaction risk was lower in the sequential arm than in the coadministration arm.

The interval also conveys precision: a narrower interval indicates less statistical uncertainty than a wider interval on the same scale. Precision depends on factors such as the number of participants, the frequency of the endpoint, and the analysis method. The primary analysis included 947 participants in the coadministration arm and 945 in the sequential arm. Those group sizes provide context for the estimate, but do not remove uncertainty or address possible limitations in endpoint recording.

The registry's reported comparison includes a risk-difference estimate and confidence limits. The estimate is not a forecast for every participant, and its interval does not describe the range of individual reactions. It concerns the group-level difference in the chance of meeting the binary endpoint. The interval also does not capture uncertainty from aspects not represented in the statistical model, such as unreported missing-data procedures or possible differences in how outcomes were recorded.

The p-value is <0.001, but a small p-value is not a substitute for examining the estimate and its interval. Statistical evidence against a zero difference and precision are related but distinct ideas: the p-value addresses compatibility with a null hypothesis, while the confidence interval shows the range of effect sizes supported by the analysis. The interpretation should therefore combine the direction of the risk difference, the interval's exclusion of zero, the participant counts, and the limitations of the registry's methodological detail.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations based on the observed effect, not the original trial design assumptions. The stated calculation uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For each planning scenario, the effect to detect is a stated fraction of the observed effect. The original trial's own sample-size justification and design assumptions are not reported in the registry record.

The 80% power column gives the estimated number of participants per arm for a hypothetical study to have an 80% chance of detecting the selected effect under those assumptions, if that effect were real and the assumptions held. The 90% power column describes the corresponding hypothetical number for a 90% chance. These are planning quantities, not guarantees that a future study will reach a particular conclusion. They also do not describe the probability that the observed result is true.

The planning scenarios use 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. The corresponding participants-per-arm figures are 160 and 214 for 80% and 90% power at 100% of the observed effect; 278 and 371 at 75%; and 606 and 811 at 50%. As the effect to be detected becomes smaller, more participants are needed under the same calculation assumptions. This is not observed power: it is a prospective planning illustration derived from the observed effect, not a measure of the trial's probability of detecting an effect after the results are known.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.728; treatment proportion p₁ = 0.579; average p̄ = 0.653.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6731 = 1.3192.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6648 = 0.5595.
4. n = (1.3192 + 0.5595)² / (-0.1487)² = 159.6, rounded up to 160 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.727560718057022                          # control proportion
p1 <- 0.578835978835979                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(6060457)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 160 (80% power), 214 (90% power)
 75% of observed effect: n per arm = 278 (80% power), 371 (90% power)
 50% of observed effect: n per arm = 606 (80% power), 811 (90% power)
power.prop.test: 159.6 
Simulated power at n = 160 per arm: 0.809 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures, including the primary solicited-reaction endpoint and five posted secondary outcomes. The secondary outcomes cover immune-response measures, including seroresponse, fold-rise, and seroconversion. The record also lists two analyses. These multiple measures create the general possibility of multiplicity: when many hypotheses are tested, the chance of at least one apparently unusual result can increase if each is judged separately.

The primary comparison is reported with an unadjusted p-value of <0.001. The registry record does not report whether the trial used a prespecified hierarchy, a family-wise error adjustment, a false-discovery procedure, or another method to address multiplicity. It also does not report which analyses were designated confirmatory or exploratory, beyond identifying the primary outcome. Consequently, the unadjusted p-value should not be treated as evidence that every secondary result has been protected against multiplicity.

The endpoint population is defined as randomized participants who received an intervention on Day 1 and contributed solicited-reaction data from the injection through the following 6 days. This gives a stated inclusion rule for the primary safety set. However, the registry record does not report how incomplete diaries, partial reporting, or other missing observations were handled. It does not describe imputation, exclusion rules beyond the stated population definition, or sensitivity analyses for missing data. The effect of missing information on the estimate therefore cannot be evaluated from the record.

The record identifies randomization and quadruple masking, but does not report the detailed analysis populations used for every secondary outcome, the primary statistical model, or any covariate adjustments. These details are relevant when interpreting a family of outcomes and assessing whether analyses followed a prespecified plan. Their absence does not change the reported primary counts, but it limits a full appraisal of analysis choices and multiplicity control.

14. 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: pneumonia (0.3%), angina unstable (0.2%), atrial fibrillation (0.2%), coronary artery disease (0.2%), bradycardia (0.2%).

The serious adverse-event summary lists 23 participants among 947 at risk in the Fluzone HD plus mRNA-1345 followed by placebo group, and 33 among 946 at risk in the Fluzone HD plus placebo followed by mRNA-1345 group. The registry lists 0 participants with other, nonserious adverse events in each group in the displayed summary. Deaths are listed as 2 in each group. The at-risk denominators for this summary are the denominators recorded for these adverse-event groups; they are not identical to every denominator reported for the primary solicited-reaction endpoint.

The registry lists serious-event terms including pneumonia at 0.3%, and unstable angina, atrial fibrillation, coronary artery disease, bradycardia, and acute respiratory failure at 0.2% each. These percentages are reported term summaries, not estimates of comparative risk for those events. They should not be interpreted as evidence that an event was caused by a particular intervention; the displayed figures alone do not establish causality or a difference between groups.

Serious adverse events are distinct from solicited reactions. The primary endpoint captures specified symptoms reported within 7 days after Day 1, whereas the serious-event summary is a separate safety listing. These figures describe what the registry records, but do not supply event-level timing, investigator causality assessments, or a complete account of clinical context. A zero in the displayed other-event count means none were recorded in that summary, not that no other health events occurred under every possible definition.

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

The primary result shows a difference between the two Day 1 schedules in the number of participants recorded with at least one solicited local or systemic reaction during the following 7 days. The count was 689 of 947 after Day 1 coadministration and 547 of 945 after Fluzone HD with placebo on Day 1 in the schedule that placed mRNA-1345 on Day 22. The posted risk-difference comparison is negative for the sequential arm, its confidence interval excludes zero, and the unadjusted p-value is <0.001.

This finding is about a defined, short-term safety endpoint. It does not show which individual symptoms account for the difference, how severe or persistent reactions were, or whether an individual participant would have reported a reaction. The count combines local and systemic symptoms and treats participants as having or not having the endpoint. It also does not establish that a particular reaction was caused by a vaccine, since the registry notes that solicited reactions were reviewed separately for adverse-event recording.

The comparison is tied to the treatment sequence and observation window. On Day 1, one group received both vaccines and the other received Fluzone HD with placebo. The primary window followed that injection. The result therefore does not directly compare responses after Day 22, nor does it estimate the impact of receiving both products at the same time across all possible schedules.

The primary result does not establish immune response or protection against RSV or influenza. The registry's stated purpose includes immunogenicity and lists secondary immune-response outcomes, but their detailed results are not reported in the registry record. Nor do the primary counts answer questions about disease incidence or effectiveness in routine use. Those are different outcomes requiring their own evidence.

Finally, the result is an estimate for the analyzed Day 1 Solicited Safety Set, not a prediction for every adult aged 65 years and older. The randomized design supports a schedule comparison, while unreported details about missing-data handling, model specification, and multiplicity control limit independent assessment of the full analysis plan. The result should be interpreted within those boundaries rather than extended to outcomes the primary endpoint did not measure.

16. Why This Trial Matters Statistically

This trial presents a useful statistical distinction between a schedule comparison and a simple comparison of vaccine ingredients. Both arms were scheduled to receive mRNA-1345 and Fluzone HD, but the timing differed: the coadministration group received both on Day 1, while the sequential group received Fluzone HD with placebo on Day 1 and mRNA-1345 on Day 22. Because the primary safety window followed Day 1, the comparison specifically concerns reactions after coadministration versus the Day 1 control injection schedule.

The endpoint is a participant-level binary outcome, which makes the central comparison understandable: how many people reported at least one solicited reaction in the defined window. At the same time, a binary summary compresses detail. It does not show symptom counts, severity, or duration. A statistically clear difference in this combined measure should therefore be read alongside the endpoint definition and separate safety information, rather than as a complete description of tolerability.

The risk difference adds an absolute-scale summary, while the confidence interval indicates uncertainty around that contrast. The reported interval excludes zero and the unadjusted p-value is <0.001, but neither statistic answers questions about immune response or protection. Keeping safety and immunogenicity distinct is particularly important in a study whose stated purpose includes both.

The registry record also illustrates why analysis transparency matters. It identifies randomization, masking, the primary safety population, and the reported endpoint, but does not report the original sample-size justification, missing-data procedures, detailed statistical model, or multiplicity approach. Those omissions do not erase the posted result, but they constrain how fully readers can reconstruct the analysis and assess its robustness. The planning illustrations are useful for thinking about future designs, but are not the trial's own design rationale and are not observed power.

17. 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 original sample-size justification or the assumptions used to plan the completed trial. The planning illustrations based on the observed effect are not a substitute for that information. The detailed statistical model, any covariate adjustment, and the handling of missing solicited-reaction data are also not reported in the registry record. These omissions limit assessment of reproducibility and robustness.

The primary endpoint summarizes whether participants had any solicited local or systemic reaction during the specified period. It does not, by itself, describe the frequency of multiple symptoms in one participant, symptom severity, duration, or impact. The registry also distinguishes solicited reactions from adverse events, so the endpoint should not be treated as a complete adverse-event measure.

The observation window is limited to the 7 days after the Day 1 injection. The result does not directly describe reactions after the Day 22 injection or across a longer follow-up period. The schedule contrast also means the arms received different Day 1 injections; interpretation should remain specific to the comparison of those schedules.

The record lists several outcomes and analyses, but does not report a multiplicity strategy or detailed analysis hierarchy. Secondary immune-response results are not reported in the registry record. The serious-event summary includes group counts and selected terms, but the displayed information does not provide detailed event-level timing or causality assessments. These limits call for a focused reading of the primary safety finding, without extending it to outcomes or methodological details that are not reported.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety and Immune Response of mRNA-1345, a Vaccine Targeting Respiratory Syncytial Virus (RSV), When Co-administered With a Fluzone HD, in Adults ≥65 Years of Age — NCT06060457.
• Registry record last updated 2025-07-30; status last verified 2025-07.
• Results first posted 2025-07-30.
• 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.

21. Record Summary

NCT06060457 is a completed randomized Phase 3 study sponsored by ModernaTX, Inc., evaluating mRNA-1345 with a high-dose quadrivalent seasonal influenza vaccine in adults aged 65 years and older. The trial used a sequential model and quadruple masking. Its two schedules compared Day 1 coadministration of mRNA-1345 and Fluzone HD with Fluzone HD plus placebo on Day 1 followed by mRNA-1345 on Day 22.

The primary endpoint counted participants with solicited local or systemic reactions within 7 days after the Day 1 injection. The recorded counts were 689 of 947 in the coadministration arm and 547 of 945 in the sequential arm. The registry reports a negative risk difference for the sequential arm, a confidence interval excluding zero, and an unadjusted p-value of <0.001. This result concerns short-term solicited reactions after the specified Day 1 schedules, not immune response, disease protection, or the full safety profile.