A Study of an Adenovirus Serotype 26 Pre-fusion Conformation-stabilized F Protein (Ad26. RSV. preF) Based Respiratory Syncytial Virus (RSV) Vaccine in the Prevention of Lower Respiratory Tract Disease in Adults Aged 60 Years and Older: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of an Adenovirus Serotype 26 Pre-fusion Conformation-stabilized F Protein (Ad26. RSV. preF) Based Respiratory Syncytial Virus (RSV) Vaccine in the Prevention of Lower Respiratory Tract Disease in Adults Aged 60 Years and Older (NCT04908683), a randomized phase 3 study. The primary outcome is Number of Participants With First Occurrence of Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)-Confirmed Respiratory Syncytial Virus (RSV) Mediated Lower Respiratory Tract Disease (LRTD).

2. Clinical Question

The outcome is a count of participants meeting the protocol-defined disease criteria, rather than a measure of symptom severity averaged across all participants. The posted comparison expresses the difference in event risk between the groups and also reports relative measures. Those measures describe the observed trial data; they do not establish how the result would apply to people or circumstances outside the study population and follow-up period.

3. Trial Design

This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group efficacy study sponsored by Janssen Vaccines & Prevention B.V. It enrolled 25236 participants. The registry title identifies the intended population as adults aged 60 years and older, and the brief summary describes the aim as evaluating prevention of RT-PCR-confirmed RSV-mediated lower respiratory tract disease compared with placebo.

The study began on 2021-07-21, reached primary completion on 2023-07-21, and has a registry status of completed. The active group received a single intramuscular injection on Day 1; the placebo group received a single matching intramuscular injection on Day 1. Random allocation is intended to make treatment groups comparable on average at the start of a trial, while double masking is intended to reduce the influence of treatment knowledge on participant reporting and outcome assessment. These are general purposes of the design features; the registry record does not describe the procedures used to implement them.

The primary outcome period ran from Baseline (Day 1) up to 12 months. The primary efficacy analysis population is described as the per-protocol efficacy population, including randomized and vaccinated participants but excluding major protocol deviations expected to affect efficacy outcomes. The record also names timing-related exclusions, but the complete population definition is not reported in the registry record.

The registry reports enrollment of 25236, while the brief summary says the study would enroll up to 27,200 participants. These are different record entries and should not be treated as interchangeable measures of the number analyzed for the primary endpoint. The analysis denominators posted for that endpoint are 16260 in the vaccine group and 8152 in the placebo group. The registry record does not report the trial's original sample-size justification or detailed statistical analysis plan.

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: Per-protocol efficacy (PPE) population included all randomized and vaccinated participants, excluding those with major protocol deviations (MPDs) expecting to impact the efficacy outcomes. Participants with an RSV onset within 14 days after vaccination and participants who discontinued within 14 days after vaccination were excluded from the PPE population.

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: Baseline characteristics data were analyzed on full analysis set (FAS) which included all participants with a documented vaccine administration, regardless of the occurrence of protocol deviations.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With First Occurrence of Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)-Confirmed Respiratory Syncytial Virus (RSV) Mediated Lower Respiratory Tract Disease (LRTD), measured over From Baseline (Day 1) up to 12 months.

The primary endpoint counts participants with a first occurrence of RT-PCR-confirmed RSV-mediated lower respiratory tract disease (LRTD) from Baseline (Day 1) up to 12 months. A participant met the stated case definition if there was new onset or worsening from baseline of 3 or more specified symptoms at the same assessment time point, together with RSV confirmation by RT-PCR in one or more nasal swabs or a sputum sample. The listed symptoms were cough, shortness of breath, coughing up phlegm (sputum), and wheezing.

Symptoms were captured using the respiratory infection intensity and impact questionnaire, version 2. Its symptom scale ran from 0 for none to 3 for severe, with higher scores indicating greater severity. The record says the total LRTD symptom score was calculated as the mean of the four lower respiratory scores. That score contributes to how symptoms are described, while the primary endpoint itself is the number of participants meeting the case definition.

A first-occurrence endpoint gives each participant a defined event status for the stated period, rather than counting repeated episodes as separate primary events. This is useful for comparing the proportion of participants who experienced the specified outcome during follow-up. General statistical point: a clear clinical and laboratory definition helps make outcome classification more consistent, but the result remains specific to the definition, population, and follow-up period used in the trial.

7. Results Posted in the Registry

• Group 1: Ad26.RSV.preF and RSV preF Protein: 0.3% (44/16263) versus 0.8% (63/8152) on control; risk difference -0.5 percentage points (95% CI -0.7 to -0.3), risk ratio 0.35 (0.24–0.51); unadjusted two-proportion z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Participants With First Occurrence of Any RT-PCR-Confirmed RSV-mediated Acute Respiratory Infection (ARI)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Group 1: Ad26.RSV.preF and RSV preF Protein: 0.5% (77/16263) versus 1.2% (101/8152) on control; risk difference -0.8 percentage points (95% CI -1.0 to -0.5), risk ratio 0.38 (0.28–0.51); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Group 1: Ad26.RSV.preF and RSV preF Protein than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Number of Participants With First Occurrence of RT-PCR-Confirmed RSV Mediated LRTD During the Second Year

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Group 1: Ad26.RSV.preF and RSV preF Protein: 0.2% (16/10031) versus 0.6% (29/5011) on control; risk difference -0.4 percentage points (95% CI -0.6 to -0.2), risk ratio 0.28 (0.15–0.51); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Group 1: Ad26.RSV.preF and RSV preF Protein than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Number of Participants With First Occurrence of Any RT-PCR-Confirmed RSV Mediated ARI During the Second Year

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Group 1: Ad26.RSV.preF and RSV preF Protein: 0.4% (39/10031) versus 0.9% (44/5011) on control; risk difference -0.5 percentage points (95% CI -0.8 to -0.2), risk ratio 0.44 (0.29–0.68); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Group 1: Ad26.RSV.preF and RSV preF Protein than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry posts secondary outcomes covering acute respiratory infection, events during the second year, predefined clinically relevant disease, and safety outcomes. The available secondary comparisons with event counts show estimates in the same general direction as the primary comparison: the vaccine-group event risks are lower than the placebo-group risks for the posted respiratory outcomes. This provides context that the primary finding is not isolated to one outcome definition, although different endpoints capture different clinical events and periods.

Secondary endpoints are related to the primary result but are not interchangeable with it. Acute respiratory infection is broader than lower respiratory tract disease, and outcomes measured during the second year address a different follow-up period from the primary endpoint's first 12 months. A result for one endpoint does not automatically establish the same effect for another, nor can the secondary outcomes replace the prespecified primary question.

The registry reports 13 secondary outcomes, but does not report analysis details for them in its reported-analyses field. The posted secondary comparisons include unadjusted p-values. When many outcomes are examined, the chance of seeing at least one apparently strong result by chance can increase. General statistical explanation: multiplicity procedures can control that risk, but the registry record does not report whether any adjustment or hierarchy was planned or used. Accordingly, unadjusted secondary results carry less weight than a primary result specified as the main efficacy question.

These secondary findings should be treated as supportive context rather than independent confirmation. The registry record does not provide enough detail to establish which secondary analyses were prespecified, how missing data were handled, or how the set of outcomes was considered collectively. The overall pattern is informative, but each endpoint remains subject to its own definition, analysis population, and uncertainty.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of Participants With First Occurrence of Any RT-PCR-Confirmed RSV-mediated Acute Respiratory Infection (ARI)
• Number of Participants With First Occurrence of RT-PCR-Confirmed RSV Mediated LRTD During the Second Year
• Number of Participants With First Occurrence of Any RT-PCR-Confirmed RSV Mediated ARI During the Second Year
• Number of Participants With First Occurrence of Predefined Clinically Relevant Disease Associated With RT-PCR-Confirmed RSV-Mediated ARI Over the Whole Study
• Number of Participants With Serious Adverse Events (SAEs)
• Number of Participants With Potential Adverse Events of Special Interest (AESIs)
• Number of Participants With Solicited Local Adverse Events (AEs) up to 7 Days After Vaccination
• Number of Participants With Solicited Systemic AEs up to 7 Days After Vaccination

9. Statistical Interpretation

10. Statistical Methods Explained

What is being compared? The primary outcome is binary at the participant level: each participant either met the first-occurrence case definition during the stated follow-up period or did not. The posted comparison gives group-specific risks and a risk difference. The risk difference is the vaccine-group risk minus the placebo-group risk according to the comparison order in the record. A value below zero therefore indicates a lower observed risk in the vaccine group. General statistical explanation: unlike a relative measure, a risk difference uses the same absolute probability scale as the risks themselves.

What does the relative risk describe? The relative risk compares the event risk in one group with the risk in the other. A value below 1 indicates a lower observed risk in the first group relative to the comparator; a value of 1 would represent equal risks. The posted relative risk is 0.350, with an interval from 0.238 to 0.514. The odds ratio is another relative measure, based on odds rather than risks. When outcomes are uncommon, odds and risks can be numerically similar, but they are not the same quantity. The posted odds ratio is 0.348, with an interval from 0.237 to 0.512.

How should the confidence interval be read? A confidence interval gives a range of effect estimates compatible with the observed data under the statistical method and assumptions used. In repeated use of the same method under those assumptions, intervals constructed this way would cover the true value at the stated confidence level at the stated long-run frequency. It is not a probability statement that the particular true value lies within this particular interval. For the primary risk difference, the interval is -0.007 to -0.003. Its position below zero is consistent with the direction of the point estimate. General statistical explanation: interval width reflects precision; narrower intervals indicate less statistical uncertainty on the scale being measured.

What does the p-value add? The posted p-value is unadjusted and reported as <0.001. It evaluates the observed data against a null model of no group difference, under the assumptions associated with that analysis. It is not a measure of how likely the result is to be due to chance in a general sense, nor does it quantify the size of an effect. A small p-value does not remove concerns about bias, incomplete follow-up, endpoint definition, or multiple comparisons. The registry record does not report the full model specification, test procedure, or whether any prespecified adjustment was intended.

What is the role of randomization and masking? Random allocation is a design method intended to balance measured and unmeasured baseline factors between groups on average. Double masking is intended to limit differences in behavior, reporting, and assessment that could arise if treatment assignment were known. These are general design principles, not a description of the trial's exact implementation. The registry identifies the study as randomized and double-blind but does not provide additional operational details in the record summarized for this analysis.

Why distinguish the analysis population? The primary endpoint is described for the per-protocol efficacy population, not simply everyone enrolled. It includes randomized and vaccinated participants and excludes participants with major protocol deviations expected to affect efficacy outcomes; the description also refers to timing-related exclusions. A per-protocol analysis can focus on participants meeting specified study requirements, but exclusions after randomization can affect comparability if they differ between groups or relate to outcomes. General statistical explanation: an intention-to-treat analysis, by contrast, generally retains participants in their randomized groups, but the registry record does not establish that such an analysis was reported for this result.

What cannot be inferred from the record? The registry lists no reported analyses in its analysis field, and the detailed analysis plan is not reported in the registry record. The displayed comparison should therefore not be mistaken for a complete account of the sponsor's prespecified statistical procedures. The record does not state how missing endpoint assessments were handled, whether covariates were included, whether confidence intervals were adjusted for multiple testing, or whether interim analyses occurred. Those details should not be inferred from the reported point estimate, interval, or p-value.

General statistical point: treatment comparisons are strongest when interpreted together with the design, endpoint definition, analysis population, uncertainty interval, and completeness of follow-up. No single statistic can substitute for those elements. Here, the posted count-based outcome and risk comparison offer a direct description of the primary result, while the absence of fuller analysis details limits assessment of every assumption underlying inference.

11. Confidence Intervals and Precision

The primary risk difference is -0.005, with a 95% confidence interval from -0.007 to -0.003. The interval does not cross zero, so values within the reported range all represent a lower risk in the vaccine group under the comparison's subtraction order. This supports the direction of the observed difference, but it does not mean the exact effect is known. The interval allows for a range of possible absolute differences, and estimates nearer either endpoint remain compatible with the data under the method used.

The relative measures give a complementary view. The relative risk is 0.350, with an interval from 0.238 to 0.514, while the odds ratio is 0.348, with an interval from 0.237 to 0.512. Both intervals lie below 1, the value corresponding to no relative difference. They indicate that the estimated relative effect is below 1 across the reported interval, while still showing uncertainty about its exact magnitude.

Confidence intervals are affected by the amount of information in the data and by the analysis method. General statistical explanation: fewer observed events often mean less precision for event-risk comparisons, even when group denominators are substantial. The primary endpoint has 44 and 63 reported events, so reading the interval alongside the point estimate is important. The point estimate alone gives a sharper-sounding answer than the data warrant.

The interval describes statistical uncertainty under the analysis assumptions; it does not include every source of uncertainty. It cannot account for unreported missing-data procedures, possible outcome misclassification, departures from protocol, or questions about generalizability. The registry record does not report enough detail to assess those issues fully. Statistical precision should therefore be distinguished from certainty about broader interpretation.

12. 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 for 80% power and participants per arm for 90% power. They are calculated under a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect used for each illustration is the stated fraction of the observed effect. These are planning assumptions for an illustration, not reported assumptions from the trial's original design; the original design assumptions are not reported in the registry record.

In plain terms, the 80% power column gives the number of participants per arm that the planning calculation estimates would be needed to have an 80% chance of detecting the selected effect under those assumptions. The 90% power column uses a higher target chance of detection and consequently requires more participants per arm for the same selected effect. The entries are not totals across both groups.

The effect scenarios are labeled as 100%, 75%, and 50% of the observed effect. Planning for 75% of the observed effect requires 6,427 participants per arm for 80% power and 8,604 participants per arm for 90% power. Planning for 50% of the observed effect requires 16,005 participants per arm for 80% power and 21,426 participants per arm for 90% power. The entries for 100% of the observed effect are 3,229 participants per arm for 80% power and 4,322 participants per arm for 90% power. Smaller effects need more participants to distinguish them from random variation under the same assumptions.

These figures are planning illustrations based on the observed effect, not observed power. They do not show the probability that the trial's result is true or the chance that the trial succeeded after its results were known. The relationship across scenarios is the key reading: a more demanding power target or a smaller effect calls for a larger planned sample under the stated assumptions.

13. 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 = 0.008; treatment proportion p₁ = 0.003; average p̄ = 0.005.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.1019 = 0.1997.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.1018 = 0.0857.
4. n = (0.1997 + 0.0857)² / (-0.0050)² = 3,228.1, rounded up to 3,229 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 <- 0.00772816486751717                          # control proportion
p1 <- 0.002705527885384                          # 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(4908683)
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 = 3,229 (80% power), 4,322 (90% power)
 75% of observed effect: n per arm = 6,427 (80% power), 8,604 (90% power)
 50% of observed effect: n per arm = 16,005 (80% power), 21,426 (90% power)
power.prop.test: 3228.1 
Simulated power at n = 3,229 per arm: 0.815 (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.

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes or makes several statistical comparisons. Even if each comparison uses the same nominal threshold, a larger collection of tests raises the chance that one or more will appear statistically notable by chance alone. The registry lists 13 secondary outcomes in addition to the primary endpoint. The posted secondary comparisons report unadjusted p-values. The registry record does not report whether multiplicity was addressed through a formal adjustment, a prespecified testing sequence, or another strategy.

The primary outcome should therefore be distinguished from secondary findings. It addresses the principal efficacy question described in the registry, while secondary outcomes span different respiratory events, time periods, and safety measures. A small unadjusted p-value for a secondary outcome should not be interpreted as if it had the same evidential role as a result from a prespecified primary analysis with a documented multiplicity plan. The plan and implementation are not reported in the registry record.

Missing data can also influence a comparison if participants do not complete follow-up or do not have outcome assessments. The record gives analysis denominators for the primary endpoint but does not explain how those denominators arose from enrollment, how missing endpoint status was handled, or whether any imputation or sensitivity analyses were performed. It does not report a complete participant flow for this result. These omissions limit assessment of whether missingness could have affected the group comparison.

The primary analysis population is described as per-protocol efficacy. It includes randomized and vaccinated participants and excludes major protocol deviations expected to affect efficacy outcomes, with further timing-related exclusions mentioned in the description. The full operational definition and the numbers excluded for each reason are not reported in the registry record. General statistical explanation: exclusions after randomization can change the balance created by randomization, especially if exclusion is related to treatment assignment or outcome risk. This does not establish that bias occurred in this trial; it identifies a question that requires fuller reporting.

The registry does not report the full statistical analysis plan, interim analyses, missing-data methods, or details of any adjusted analyses. These unknowns should not be filled in by assumption. The posted estimates remain interpretable as reported comparisons, but a complete assessment of multiplicity and analysis-population sensitivity requires information that is not reported in the registry record.

15. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (0.3%), death (0.2%), chronic obstructive pulmonary disease (0.2%), covid-19 (0.2%), pulmonary embolism (0.2%).

The registry reports serious adverse events among participants at risk in each group: 842 among 16709 in the vaccine group and 457 among 8367 in the placebo group. These figures describe counts and denominators recorded for the serious adverse event outcome. They are not, by themselves, a causal comparison or an adjusted estimate of treatment-related harm. The record also lists deaths as 105 in the vaccine group and 61 in the placebo group, without an inferential comparison in the information.

The most frequently listed serious adverse event terms include Pneumonia at 0.3%, Death at 0.2%, Chronic Obstructive Pulmonary Disease at 0.2%, Covid-19 at 0.2%, Pulmonary Embolism at 0.2%, and Atrial Fibrillation at 0.2%. The registry record does not establish that these events were caused by vaccination. Nor does it provide, in the material reported for these figures, a detailed breakdown of timing, severity beyond the serious-event classification, or an adjusted between-group analysis.

Adverse event counts need context, including the number at risk, follow-up duration, event definitions, and whether events are considered related to study intervention. The record reports other adverse-event counts as well, but the serious-event figures alone cannot determine comparative safety. These observations describe events recorded during the study, not a recommendation about treatment.

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

The primary comparison shows fewer participants meeting the stated RT-PCR-confirmed LRTD definition in the vaccine group than in the placebo group during the primary follow-up period. The risk difference is -0.005, and its 95% confidence interval ranges from -0.007 to -0.003. The relative risk and odds ratio are also below 1, with reported confidence intervals below 1. Taken together, the posted estimates describe a lower observed occurrence of the protocol-defined endpoint in the vaccine group in this trial.

This is not a statement that every participant's outcome would differ, nor does it predict an individual's experience. Group-level risk estimates summarize what was observed across participants under the study conditions. The result does not mean that no cases occurred in the vaccine group; 44 participants in that group met the primary endpoint, compared with 63 in the placebo group. It also does not say that every respiratory illness was prevented, because the primary endpoint required a particular combination of symptoms and laboratory confirmation.

The finding is limited to the adult population described by the trial, its per-protocol efficacy population, its endpoint definition, and the period from Baseline (Day 1) up to 12 months. The endpoint depends on both symptom criteria and RT-PCR confirmation. It does not measure all RSV infections, all respiratory disease, or outcomes beyond the specified period. Secondary outcomes address other events and periods, but they do not change the scope of the primary endpoint.

The registry record does not report the full statistical analysis plan, handling of missing primary outcomes, or details of multiplicity control. It also does not provide the original sample-size justification. These gaps do not erase the posted comparison, but they limit how fully its assumptions and robustness can be evaluated. The unadjusted p-value is evidence against a no-difference model under its analysis assumptions; it is not proof of a causal explanation or a measure of clinical importance.

Safety counts should be interpreted separately from the efficacy result. Serious adverse events were recorded in both groups, and the listed terms do not by themselves establish causation or a comparative risk. The trial results describe benefits and harms observed in a particular study context; no individual treatment decision follows from these statistics alone.

17. Why This Trial Matters Statistically

This trial illustrates how a large randomized study can evaluate a relatively uncommon, carefully defined clinical endpoint. The primary comparison is expressed in absolute and relative terms, and those measures emphasize different aspects of the same data. The risk difference conveys the absolute scale of the observed group contrast, while the relative risk and odds ratio express the contrast proportionally. Considering them together helps avoid relying on a single summary.

The endpoint definition is also central to statistical interpretation. Participants had to satisfy symptom criteria and have RSV confirmed by RT-PCR. That combination makes clear which events count for the primary analysis, but it also means the result pertains to this operational definition rather than every possible RSV-related event. The follow-up period and analysis population further define what the estimate represents.

The confidence interval is an important complement to the point estimate and unadjusted p-value. It shows a range of absolute differences compatible with the data under the analysis assumptions, rather than making the point estimate appear exact. The posted relative-effect intervals provide another view of uncertainty. This is particularly relevant when the observed event counts are modest compared with the group denominators.

The record also demonstrates why registered outcomes and analysis reporting need to be read together. Multiple secondary outcomes are listed, but adjustment for multiplicity and detailed analysis procedures are not reported. The primary finding can be described from the posted comparison, while the secondary results require more caution because their prespecification and collective interpretation are unclear. Transparent reporting of populations, missing outcomes, and analysis plans would help readers judge the robustness of the findings.

Finally, planning calculations based on an observed effect can illustrate how sample-size requirements change when a target effect is smaller or a power target is higher. Such illustrations are not evidence about the trial's achieved power and do not replace its original design justification. Together, these statistical features show why effect size, precision, design, outcome definition, and reporting completeness all matter when reading an efficacy result.

18. 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 a full statistical analysis plan, including the analysis model, test procedure, or any prespecified covariate adjustment. It does not state whether interim analyses occurred. These details are relevant to understanding the inferential procedures behind the posted comparison and cannot be inferred from its p-value or confidence interval.

The primary outcome is presented for a per-protocol efficacy population. Although the record describes the broad eligibility of this population and names certain exclusions, the full implementation and participant flow are not reported. The record does not explain how missing endpoint assessments were treated or provide sensitivity analyses for missing data. This limits assessment of how dependent the result may be on population selection or incomplete follow-up.

The primary endpoint requires both a symptom threshold and RT-PCR confirmation. This is a clearly described outcome definition, but the registry record does not report additional information about adjudication procedures, completeness of specimen collection, or endpoint assessment across groups. The result should therefore be read as specific to the recorded definition and available analysis population.

Thirteen secondary outcomes are listed, while multiplicity handling and a hierarchy for interpreting them are not reported. Unadjusted secondary comparisons are consequently less conclusive than a fully documented primary analysis. The safety figures are counts and selected serious-event terms; the record does not give a causal assessment or detailed adjusted comparison for those events.

The study enrolled 25236 participants, while the brief summary describes an aim of enrolling up to 27,200. The record does not explain this difference. The original sample-size justification is also not reported, so the planning illustrations based on the observed effect should not be taken as a record of the trial's original design. These reporting limits do not determine the direction of the primary result, but they constrain a complete evaluation of its robustness and generalizability.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study of an Adenovirus Serotype 26 Pre-fusion Conformation-stabilized F Protein (Ad26. RSV. preF) Based Respiratory Syncytial Virus (RSV) Vaccine in the Prevention of Lower Respiratory Tract Disease in Adults Aged 60 Years and Older — NCT04908683.
• Registry record last updated 2025-11-13; status last verified 2025-11.
• Results first posted 2024-02-08.
• 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.

22. Record Summary

NCT04908683 is a completed, randomized, double-blind, placebo-controlled Phase 3 study of an Ad26.RSV.preF-based vaccine in adults aged 60 years and older. The primary endpoint was the first occurrence of RT-PCR-confirmed RSV-mediated LRTD from Baseline (Day 1) up to 12 months in the per-protocol efficacy population.

The posted counts were 44 among 16260 participants in the vaccine group and 63 among 8152 in the placebo group. The risk difference was -0.005, with a 95% confidence interval from -0.007 to -0.003 and an unadjusted p-value of <0.001. The registry also reports relative risk and odds ratio estimates below 1, with confidence intervals below 1.

Interpretation is bounded by the endpoint definition and analysis population. The registry record does not report the full analysis plan, multiplicity approach, or missing-data methods. Serious adverse event counts are reported for both groups, but those counts alone do not establish causation or provide a complete comparative safety assessment.