Safety and Immunogenicity of RSVpreF Coadministered With SIIV in Adults ≥65 Years of Age: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Immunogenicity of RSVpreF Coadministered With SIIV in Adults ≥65 Years of Age (NCT05301322), a randomized phase 3 study. The primary outcome is Percentage of Participants Reporting Local Reactions Within 7 Days After Vaccination With RSVpreF or Placebo.

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, double-blind, placebo-controlled, parallel study. The registry record describes masking as quadruple. Its stated purpose was to assess the safety and immunogenicity of RSVpreF when coadministered with SIIV, compared with giving the vaccines sequentially, with SIIV followed by RSVpreF a month later. Enrollment was 1471. The study started on 2022-04-13, had primary completion on 2022-10-12, and is listed as completed.

In the coadministration group, RSVpreF and SIIV were given together, followed by placebo a month later. In the sequential-administration group, placebo and SIIV were given first, followed by RSVpreF a month later. The schedules therefore compare coadministration with a sequence in which RSVpreF is given after the SIIV visit. The record does not give further details about allocation procedures, concealment, or the operational meaning of quadruple masking; these are not reported in the registry record.

The listed secondary outcomes concern neutralizing titers for RSV A and RSV B before vaccination and at 1 month and 2 months after RSVpreF, and geometric mean fold rise in those titers. Other secondary outcomes concern HAI geometric mean titers before SIIV and 1 month after SIIV, and strain-specific HAI geometric mean fold rise. These outcomes describe immune responses rather than clinical RSV illness. The registry record does not report the numerical results for these secondary outcomes in the registry record.

The study also recorded safety outcomes, including local reactions and adverse events. The registry record gives adverse-event counts by study group, but the primary local-reaction outcome is not reduced to a single comparison in the posted results. Further details of the statistical analysis plan are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 1471 participants signed the informed consent and were enrolled in the study, of which 68 were screen failures and 1403 participants were randomized to a vaccine group.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population was analyzed. 'Overall Number of Participants (Par) Analyzed' (N)= par with at least 1 e-diary (within 7 days through Vaccination \[vax\]) transmitted. 1 par randomized in Sequential-Administration Group (SAG) incorrectly received RSVpreF + SIIV at Vax 1; hence, par was included in (RSVpreF + SIIV)/Placebo. 1 par randomized in SAG incorrectly received placebo at Vax 2; hence, par was included in vaccine group administered at Vax 1 and excluded from safety analysis at Vax 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.

Population: Safety population included all enrolled participants who received the study intervention (RSVpreF, placebo, or SIIV). The safety population was based on study intervention actually received. One participant randomized in the Sequential-Administration Group incorrectly received RSVpreF + SIIV at Vaccination 1; hence, the participant was included in the vaccine group as administered i.e., (RSVpreF + SIIV)/Placebo: Coadministration Group.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Reporting Local Reactions Within 7 Days After Vaccination With RSVpreF or Placebo, measured over Within 7 days after Vaccination 1 or Vaccination 2.

The primary endpoint is the percentage of participants reporting local reactions at the RSVpreF or placebo injection site within 7 days after Vaccination 1 or Vaccination 2. Reactions were recorded by participants in an electronic diary. The specified reactions were redness, swelling, and pain. Redness and swelling were measured in device units, with 1 measuring device unit =0.5 centimeter (cm); severity grades were mild, moderate, or severe. Pain was graded according to whether it interfered with or prevented daily activity.

A percentage is useful for describing how common a recorded reaction was in the analyzed safety population. The accompanying 2-sided 95% confidence interval, calculated by the Clopper and Pearson method, is intended to show uncertainty around that percentage. It does not by itself establish whether a difference between groups is meaningful or whether reactions were caused by a particular intervention.

The record specifies that local reactions were collected after the RSVpreF or placebo injection at both vaccination visits. This makes the endpoint relevant to the timing and injection context of the study, but a single overall percentage would not convey every reaction type, severity grade, visit, or group. The registry record does not report the primary endpoint values in the results, so the magnitude and precision of the observed local-reaction percentages are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record names methods and outcome measures, but does not report a complete statistical analysis plan. The explanations below describe what the stated methods mean in general; they do not imply that unreported analyses were performed.

What does a percentage describe?

For a binary outcome such as whether a participant reported a local reaction, a percentage expresses the share of the analyzed group with the event. The denominator matters: it defines which participants contribute to the estimate. For the primary outcome, the record defines the analyzed number as participants with at least one electronic diary transmitted within 7 days through the relevant vaccination. This is a diary-based analysis population, so it is not necessarily identical to every person randomized or enrolled.

A percentage is a descriptive estimate. It does not alone quantify the uncertainty in that estimate, establish a difference between groups, or indicate whether an event was caused by an intervention. Those interpretations require the relevant comparison, uncertainty measure, and analysis context.

What does a confidence interval add?

A confidence interval describes uncertainty around an estimate under the assumptions of the statistical method. The primary outcome specifies a 2-sided 95% confidence interval using the Clopper and Pearson method. In general, this method is used for a proportion and is based on the binomial model for event counts. A 2-sided interval allows uncertainty to extend in either direction around the estimate. It is not a guarantee that the true value falls within the particular interval, and it does not substitute for a direct comparison between groups.

The registry record does not report the primary percentages or their intervals in the results. Consequently, their widths and the precision of the primary estimates cannot be assessed. Nor does the record provide a reported test or interval for a difference between the schedules in the registry record.

How should the immune-response measures be understood?

Geometric mean titers summarize antibody measurements on a multiplicative scale. In general, this approach is useful when measurements are positive and vary over a wide range: the values are transformed to a logarithmic scale, averaged there, and expressed back on the original scale. A geometric mean fold rise describes a relative change in titers between measurement times, rather than an absolute change in the original units. These measures can characterize immune responses, but they are not direct measures of clinical protection.

The listed secondary outcomes include neutralizing titers for RSV A and RSV B before vaccination and at 1 month and 2 months after RSVpreF, along with geometric mean fold rise. The SIIV outcomes include HAI geometric mean titers before vaccination and 1 month after SIIV, and strain-specific HAI geometric mean fold rise. The numerical results, confidence intervals, and statistical comparisons for these measures are not reported in the registry record.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variability is greater than a statistical model expects. If an analysis assumes less variability than the data contain, its uncertainty estimates can be too small. This concern can arise in grouped or repeated measurements, but the registry record does not identify an over-dispersion model or report a method addressing it. It would therefore be inappropriate to claim that such a model was used in this trial.

What can be learned from the adverse-event counts?

Counts and denominators provide a basic descriptive account of events in each group. A formal comparison would need to specify the outcome definition, analysis population, statistical model or test, and treatment of uncertainty. The reported adverse-event counts do not themselves identify whether a comparison was adjusted or unadjusted, and no such analysis is reported in the registry record. Rare events, including serious events, can be especially difficult to compare precisely when only a small number are observed; uncertainty should be considered alongside the count.

The registry record lists 12 outcome measures and 6 analyses. It does not explain how those analyses were assigned to outcomes, which tests or models were used for each, whether estimates were adjusted, or whether any interim analyses occurred. Those details are not reported in the registry record. Any planning illustration based on an observed effect is a hypothetical design calculation, not observed power and not evidence that the original study was designed using that calculation.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 12 outcome measures and 6 analyses, including a primary local-reaction outcome and secondary immunogenicity outcomes. It does not report how statistical testing across outcomes, time points, vaccine strains, reaction types, or severity grades was handled. A multiplicity adjustment, testing hierarchy, or prespecified strategy for interpreting several results is not reported in the registry record. Without that information, a reader cannot determine whether reported findings were treated as confirmatory or exploratory across the family of outcomes.

The primary outcome description says that participants recorded reactions in an electronic diary and defines the analyzed number as participants with at least one diary transmitted within the specified period. This clarifies the diary-based denominator, but the record does not describe how missing diary entries were handled, whether diary completion differed between groups, or how missing data affected the outcome estimates. Those details are not reported in the registry record.

The population description also contains an incomplete note about a participant randomized to the sequential-administration group who incorrectly received RSVpreF + SIIV at Vaccination 1. The note ends before fully stating how the participant was included in the analysis. The exact analysis handling is therefore not reported in the registry record. This matters because randomized-group assignment and treatment actually received can lead to different analysis populations.

The registry record identifies a safety population for the primary outcome, but does not give a complete account of analysis populations for every outcome. It does not report a full intention-to-treat definition, a per-protocol definition, or outcome-specific rules for exclusions in the registry record. These omissions limit assessment of how closely each analysis follows randomization and how sensitive results may be to missing or misclassified observations.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cerebral infarction (0.1%), hypertension (0.1%), atrial fibrillation (0.1%), amaurosis fugax (0.1%), cholangitis (0.1%).

The adverse-event figures are counts with the number at risk shown for each group. For serious adverse events, the reported counts are 8 of 703 in the RSVpreF + SIIV coadministration group, 2 of 689 in the placebo coadministration group, 6 of 695 in the placebo + SIIV sequential-administration group, and 5 of 691 in the RSVpreF sequential-administration group. The listed counts for other adverse events are 418 of 703, 300 of 689, 370 of 695, and 330 of 691, in the same group order.

These figures are descriptive. They should not be read as proof that an intervention caused an event or as a formal test of differences between groups. The registry record does not report comparative estimates or confidence intervals for these adverse-event counts in the registry record. It lists one death in the placebo + SIIV sequential-administration group and zero in each other group, but does not establish whether the death was related to study intervention.

The serious-event terms are each reported as 0.1%: cerebral infarction, hypertension, atrial fibrillation, amaurosis fugax, cholangitis, and hand fracture. The record does not specify a group for each term in the registry record. These terms therefore cannot support group-specific conclusions.

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

The design addresses a specific question about timing: RSVpreF and SIIV administered together versus a sequence in which SIIV is given with placebo and RSVpreF follows a month later. The trial also collected safety and immunogenicity information. Its randomized, double-blind, placebo-controlled, parallel design describes how the comparison was structured, but design labels do not supply the missing numerical results.

The primary outcome is the percentage reporting local reactions within 7 days after the RSVpreF or placebo injection. The registry record gives definitions for the reactions and specifies a confidence-interval method, but the outcome values are not reported in the registry record. It is therefore not possible to say from these registry entries how often reactions were reported in either schedule, how large any difference was, or how precise the estimates were.

The adverse-event counts describe events recorded in the listed groups. They do not establish causation, and the registry record does not report a formal comparative analysis of these counts in the registry record. The death count is likewise a descriptive observation, not an attribution of cause. The listed serious-event terms are not mapped to groups in the registry record.

The secondary outcome descriptions identify antibody measures for RSV A, RSV B, and influenza strains. Such measures can help characterize immune responses, but they are not themselves direct evidence of fewer clinical cases of disease. Numerical immune-response results are not reported in the registry record, and the record does not report clinical disease outcomes in the registry record.

Accordingly, the available record supports a description of the trial question, schedules, outcome definitions, and selected safety counts. It does not support a quantitative conclusion about the primary local-reaction comparison or the immune-response results. These limits are about what is reported in the registry record, not evidence that an unreported result was favorable or unfavorable.

13. Why This Trial Matters Statistically

This trial is statistically relevant because it compares two vaccination schedules rather than simply comparing an active intervention with no vaccination. The coadministration and sequential groups differ in the timing of RSVpreF relative to SIIV, while placebo is part of each schedule. The design therefore raises a question about how to define the contrast of interest and how to interpret outcomes recorded at more than one vaccination visit.

The primary outcome is a participant-reported safety measure collected through an electronic diary. Its interpretation depends on the reporting window, diary transmission, the reaction definitions, and the analyzed denominator. The registry record specifies a window within 7 days and an analysis population requiring at least one transmitted diary, while leaving further missing-data details unreported in the registry record. Those features illustrate why outcome definitions and analysis populations matter as much as the headline event count.

The study also includes immunogenicity outcomes measured at multiple times and for multiple antigens or strains. Geometric mean titers and fold rises answer different descriptive questions: one summarizes antibody levels, while the other describes relative change. Interpreting multiple such measures requires attention to uncertainty and multiplicity, but the registry record does not report its multiplicity strategy or numerical immune-response findings.

Finally, the adverse-event counts show why safety descriptions should distinguish counts, denominators, uncertainty, and causal attribution. The listed counts can describe what was recorded in each group, but without reported comparative estimates they do not establish the size or precision of between-group differences. Statistical reporting is most informative when these elements are available together.

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 most consequential limitation for interpreting this record is that the primary local-reaction results are not reported in the registry record. The outcome definition and confidence-interval method are described, but the percentages and intervals needed to judge the observed pattern are absent in the registry record. The numerical results for the listed immunogenicity outcomes are also not reported in the registry record.

The primary outcome is based on electronic diary reporting, and the analyzed number depends on at least one diary being transmitted within the stated period. The registry record does not report diary completion by group, the handling of incomplete diaries, or sensitivity analyses for missing observations. This leaves uncertainty about how the analyzed population relates to all participants who received study intervention.

The note about a participant assigned to the sequential group who received RSVpreF + SIIV at Vaccination 1 is incomplete. The registry record does not fully state the participant’s analysis classification in the registry record. This limits assessment of the precise population used for that outcome.

The registry record does not report a full statistical analysis plan, including testing strategy across the 12 outcome measures and 6 analyses, any adjustment for multiplicity, or the statistical methods used for each secondary outcome. It also does not report comparative estimates for the adverse-event counts in the registry record. The listed serious-event terms are not connected to particular groups in those details.

Finally, the record’s stated purpose includes safety and immunogenicity, while the registry entries do not include numerical immune-response results or clinical RSV disease outcomes. The available information therefore does not permit a full assessment of the study’s immunogenicity findings or clinical implications.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Immunogenicity of RSVpreF Coadministered With SIIV in Adults ≥65 Years of Age — NCT05301322.
• Registry record last updated 2023-10-27; status last verified 2023-10.
• Results first posted 2023-10-27.
• 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

NCT05301322 is a completed phase 3 randomized, double-blind, placebo-controlled, parallel study of RSVpreF with SIIV in adults ≥65 years of age. Enrollment was 1471. The study started on 2022-04-13 and had primary completion on 2022-10-12.

The coadministration group received RSVpreF and SIIV followed by placebo a month later. The sequential-administration group received placebo and SIIV followed by RSVpreF a month later. The primary outcome concerns local reactions within 7 days after RSVpreF or placebo vaccination, with percentages and 2-sided 95% confidence intervals specified in its description.

The registry record reports serious and other adverse-event counts by group and lists serious-event terms. However, the primary outcome values and numerical immunogenicity results are not reported in the registry record in the registry record. The record also does not report a complete statistical analysis plan, missing-data approach, or multiplicity strategy.