Study of an Live-Attenuated Respiratory Syncytial Virus Vaccine in Infants and Toddlers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of an Live-Attenuated Respiratory Syncytial Virus Vaccine in Infants and Toddlers (NCT04491877), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Immediate Unsolicited Systemic Adverse Events (AEs).

2. Clinical Question

The study also had objectives relating to safety after each and any administration, RSV A neutralizing antibody responses, vaccine-virus shedding and infection, and antibody responses after the RSV surveillance season. Those objectives provide broader context, but the primary result is the count of participants with immediate unsolicited systemic adverse events. Results for this endpoint should therefore be interpreted as a narrowly timed safety measure. They do not, by themselves, characterize events outside the immediate observation window or answer the study's immunogenicity and infectivity questions.

3. Trial Design

This was a randomized, quadruple-masked, sequential Phase 1 and Phase 2 study of an investigational live-attenuated RSV vaccine in infants and toddlers. The registry record lists an enrollment of 259 and a completed status. The recorded study start was 2020-09-17, and primary completion was 2023-04-13. The sponsor was Sanofi Pasteur, a Sanofi Company.

The trial included four cohorts and three intervention types: RSV vaccine formulation 1, RSV vaccine formulation 2, and placebo. Cohort 1 compared one administration of formulation 1 with one placebo administration on Day 0. Cohort 2 compared two administrations of formulation 1 with two placebo administrations, on Day 0 and Day 56. Cohort 3 compared one administration of formulation 2 with one placebo administration on Day 0. Cohort 4 included two administrations on Day 0 and Day 56 of formulation 1, formulation 2, or placebo.

The reported outcome groups are not of equal size. For example, the Cohort 1 groups included 17 participants in the RSV low-dose group and 18 in the placebo group; Cohort 4 included 61 in the RSV low-dose group, 57 in the RSV high-dose group, and 61 in the placebo group. These figures are group-specific endpoint denominators, not a basis for combining cohorts. The sequence and rationale for moving through cohorts, allocation procedures, and the roles covered by quadruple masking are not reported in the registry record.

The study's stated objectives included safety across administrations and baseline serostatus, as well as immune-response and vaccine-virus measures. The registry record lists 13 outcome measures and six posted secondary outcomes. The present primary endpoint concerns immediate unsolicited systemic adverse events, rather than the secondary measures of shedding, infection, or antibody titers.

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 259 participants were enrolled and randomized in the study.

Only the first 6 of 9 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety analysis set (SafAS) included participants who received at least 1 administration of the study vaccine.

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: Randomized participants included all participants allocated to a vaccine group.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Immediate Unsolicited Systemic Adverse Events (AEs), measured over Cohorts 1 and 3: Within 30 minutes after vaccination on Day 0; Cohorts 2 and 4: Within 30 minutes after vaccination on Days 0 and 56.

The primary endpoint is the number of participants with immediate unsolicited systemic adverse events after vaccination. An adverse event is an untoward medical occurrence and does not necessarily have a causal relationship with the administered product. An unsolicited event is one that does not meet the conditions pre-listed in the case report book for diagnosis or onset window. Systemic events are events other than injection or administration site reactions.

The endpoint's immediate window was the first 30 minutes after vaccination. Cohorts 1 and 3 were assessed after vaccination on Day 0; Cohorts 2 and 4 were assessed after vaccination on Days 0 and 56. The purpose of this measure is to capture medically relevant unsolicited systemic events occurring shortly after administration, including events that may be considered related to the product. The endpoint is a count of participants with an event, not a count of all event episodes or a measure of severity.

As a general statistical point, a short-window safety endpoint can make an observation period explicit and comparable with the planned schedule. It also necessarily addresses only events within that window. It cannot summarize later events or establish whether an event was caused by vaccination. In this trial, the endpoint is distinct from the broader safety objectives and from the secondary outcomes on vaccine-virus shedding, infection, and antibody responses.

The safety analysis set included participants who received at least one administration of study vaccine. The posted counts show no immediate events in most groups and one participant with an event in the Cohort 4 placebo group. Because the outcome is uncommon in these data, counts and their uncertainty are more informative than interpreting an absence of recorded events as proof that risk is absent.

7. Results Posted in the Registry

• Cohort 1: RSV Low Dose: 0.0% (0/17) versus 0.0% (0/18) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Cohort 2: RSV Low Dose: 0.0% (0/10) versus 0.0% (0/18) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Cohort 2: Placebo: 0.0% (0/10) versus 0.0% (0/18) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Cohort 3: RSV High Dose: 0.0% (0/10) versus 0.0% (0/18) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either had at least one qualifying immediate unsolicited systemic adverse event in the specified observation window or did not. The posted arm values are counts of participants with an event. This is different from counting repeated event episodes. When event counts are reported in this form, the first interpretive step is to look at the number of affected participants alongside the number assessed in each group.

For a binary outcome, a risk is the proportion of participants with the event in a group. A risk difference compares two such risks by subtracting one from the other. A positive risk difference means the event risk is higher in the group placed first in the contrast; a negative value means it is lower. A value of 0.0 indicates no observed difference in the recorded proportions. General statistical explanation: a risk difference is usually easiest to interpret when the groups being compared are the randomized groups for the same cohort and schedule. Differences between cohorts can reflect cohort composition or timing as well as treatment assignment.

The registry's comparisons use Cohort 1 placebo as the reference group. This matters because the displayed comparison for Cohort 4 placebo is a contrast with Cohort 1 placebo, not with a placebo group from the same cohort. Cohort 1 placebo received one administration on Day 0; Cohort 4 placebo received administrations on Day 0 and Day 56. The vaccine arms in Cohorts 2 and 4 also had two-administration schedules. Comparisons across these groups do not have the same direct interpretation as a randomized vaccine-versus-placebo contrast within one cohort.

What does a confidence interval describe?

General statistical explanation: a confidence interval represents uncertainty in an estimated quantity under the assumptions of the method used to calculate it. For a risk difference, an interval spanning zero is compatible with no observed difference and with differences in either direction within the interval's limits. It does not give the probability that the true effect lies inside the particular interval. Interpretation also depends on whether the calculation method behaves appropriately for the data.

The posted interval for the Cohort 4 placebo contrast is -0.015 to 0.048. It includes zero and extends in both directions. The unadjusted p-value is 0.585. The interval and p-value describe this posted contrast; neither resolves the fact that the two placebo groups come from different cohorts and schedules. For all-zero comparisons, the posted estimate and limits are 0.0, but all-zero observations do not eliminate sampling uncertainty. A method that returns a zero-width interval in this situation is not a useful representation of the uncertainty in the underlying risk.

How should sparse counts be handled?

General statistical explanation: when events are rare, conventional approximations designed for data with more events may perform poorly. A zero count is especially challenging because an estimated risk of zero can be mistaken for certainty. Methods designed for sparse binary outcomes can give more realistic uncertainty, but the registry record does not identify the method used for every displayed estimate or report an alternative sparse-data analysis. No recalculated estimate should replace a sponsor analysis if the two differ; the registry record does not report a discrepancy for these results.

The study is randomized and quadruple masked, but those design features alone do not specify the analysis. The analysis population is described as participants who received at least one administration of study vaccine. The registry record does not report whether the primary endpoint was analyzed by assigned group, how participants with missing immediate observations were handled, or whether any adjustment or stratification was used. The listed comparisons and estimates should therefore be treated as descriptive registry results, with their design and analysis context kept in view.

The outcome is not a time-to-event measure, and no event-time model is reported. It is also not an antibody titer or geometric mean outcome. Concepts such as over-dispersion that arise with some count models are not the main issue for this participant-level binary endpoint; the more immediate concern is the rarity of observed events and the limitations of uncertainty estimates with zero counts.

10. Confidence Intervals and Precision

The observed counts are sparse: all displayed groups have zero participants with the primary event except Cohort 4 placebo, which has one. Sparse data limit precision because there are few observed events to distinguish among plausible underlying event risks. A zero count should not be interpreted as proof that the risk is zero, particularly when the group is modest in size and the observation window is short.

The posted Cohort 4 placebo comparison has a risk difference of 0.016 and a confidence interval from -0.015 to 0.048. The interval includes zero and extends to values on either side of it. This indicates that the posted estimate does not tightly distinguish between a modest difference favoring either group. The unadjusted p-value of 0.585 likewise does not provide evidence of a clear difference under the test used, but it is not evidence that the risks are identical.

The other comparisons have point estimates and confidence limits of 0.0. These limits should not be taken literally as showing perfect precision. With no events observed in either group, the observed risk difference is zero, but the data do not make the underlying risks known with certainty. The registry record does not report enough methodological detail to assess the interval procedure for these sparse comparisons.

General statistical explanation: precision depends on both the number of observations and the amount of event information in them. For uncommon outcomes, even a group with many participants may contain little information if almost no events occur. A confidence interval communicates uncertainty more completely than a point estimate alone, provided the interval method is suitable for the data. In this case, the event scarcity and the use of a cross-cohort placebo contrast limit what can be inferred about differences in risk.

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 13 outcome measures and six posted secondary outcomes. The primary endpoint is one part of a broader set of safety, infectivity, shedding, and immunogenicity objectives. When many outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. General statistical explanation: multiplicity procedures can control that risk, but whether and how they are used depends on the prespecified analysis plan.

Multiplicity handling, a hierarchy of outcomes, and a prespecified comparison strategy are not reported in the registry record. The comparisons include several cohort groups against Cohort 1 placebo, and the record does not explain the rationale for that reference structure or identify which contrasts were primary for inference. The unadjusted p-value of 0.585 is therefore described as posted and unadjusted, not as a multiplicity-controlled result.

Missing-data procedures are not reported in the registry record. The Safety analysis set is defined as participants who received at least one administration of study vaccine, but that definition alone does not explain how missing event observations, withdrawal, or incomplete follow-up were handled. The registry record also does not state whether all participants in the listed groups had complete observation during the immediate post-vaccination windows.

The analysis population's relationship to randomized assignment is not described in detail, and the record does not report an intention-to-treat analysis or a per-protocol analysis for this endpoint. It also does not report interim analyses or a statistical analysis plan. These omissions limit assessment of whether the displayed estimates and comparisons correspond to the planned primary analysis. As a general matter, interpretation of randomized trial results depends on clear reporting of the analysis population, missing-data handling, and multiplicity approach, especially when several cohorts and outcomes are involved.

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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cellulite (10.0%), respiratory syncytial virus infection (8.3%), atypical pneumonia (1.8%), diarrhoea (1.6%), intussusception (1.6%).

The serious adverse event summary is separate from the primary endpoint of immediate unsolicited systemic adverse events. Across the listed safety groups, the serious-event counts are 0 for Cohort 1 RSV low dose, 0 for Cohort 1 placebo, 1 for Cohort 2 RSV low dose, 0 for Cohort 2 placebo, 0 for Cohort 3 RSV high dose, 1 for Cohort 3 placebo, 2 for Cohort 4 RSV low dose, 1 for Cohort 4 RSV high dose, and 2 for Cohort 4 placebo. The death count is 0 in every listed group.

These are observed counts, not estimates of comparative risk. The registry record does not report a formal analysis of serious adverse events or the method used to assess differences between groups. Nor does it establish that events were caused by study product. The serious adverse event terms listed most often include Cellulite at 10.0%, Respiratory Syncytial Virus Infection at 8.3%, Atypical Pneumonia at 1.8%, Diarrhoea at 1.6%, Intussusception at 1.6%, and Bronchiolitis at 1.6%. The registry record does not provide the denominators and calculation context for those term percentages in the posted summary, so they should not be treated as directly comparable group risks.

General statistical explanation: serious-event counts need context on exposure, follow-up, event definitions, and attribution. Small counts can vary substantially by chance, and a count alone cannot establish a treatment effect. The displayed data describe reported events in the safety groups; they do not support causal conclusions.

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

The primary results show that no immediate unsolicited systemic adverse events were recorded in most listed groups during the specified post-vaccination windows. One such event was recorded in Cohort 4 placebo. The counts offer a description of short-term observations in the safety analysis set, not a complete account of safety across the study or beyond those immediate windows.

The posted risk difference for Cohort 4 placebo compared with Cohort 1 placebo is 0.016, with a confidence interval from -0.015 to 0.048 and an unadjusted p-value of 0.585. Because these are placebo groups from different cohorts and schedules, this contrast does not estimate the randomized effect of vaccine versus placebo within Cohort 4. Other contrasts with zero observed events have zero point estimates, but do not establish that the underlying risks are exactly zero.

These data do not show whether the vaccine generated RSV A neutralizing antibodies or anti-F IgG responses, how much vaccine virus was shed, or what proportion of participants were infected with vaccine virus. Those topics were included among the study objectives and secondary outcomes, but the primary endpoint counts do not answer them. The registry record lists six posted secondary outcomes, but the results for those outcomes are not included in the registry record for this interpretation.

The results also do not establish that vaccination caused an adverse event, prevented an adverse event, or changed the risk of RSV disease. Absence of a recorded immediate event is not proof of no risk, and a small count in one group is not evidence of a causal difference. General statistical explanation: randomized comparisons can support causal inference when the relevant groups, outcome, analysis, and assumptions are appropriately specified. Here, sparse outcomes and cross-cohort contrasts constrain that interpretation.

The most defensible reading is narrow: the registry reports very few immediate unsolicited systemic adverse events, and the available contrasts are imprecise or not directly matched by cohort and schedule. Broader safety and immunogenicity conclusions require their respective outcome results and analysis details.

14. Why This Trial Matters Statistically

This trial illustrates a recurring challenge in early clinical research: a carefully defined safety outcome may be clinically relevant while remaining statistically difficult to compare when events are rare. The endpoint captures a specific period immediately after vaccination, and the posted counts are easy to understand. However, the scarcity of events means the estimates cannot sharply characterize underlying risks.

The study also uses multiple cohorts and schedules. Cohort 1 and Cohort 3 received one administration, while Cohorts 2 and 4 received two. Formulations also differ by cohort. Those design features make it important to keep each comparison tied to the appropriate randomized groups and schedule. A contrast against Cohort 1 placebo is not automatically equivalent to a comparison against placebo within another cohort.

There is a useful statistical distinction between an observed zero and a true zero risk. In the displayed results, most groups had no recorded primary events. That is informative about what was observed in the specified window, but it does not mean the event is impossible or that the confidence interval should have no width. This distinction matters in safety reporting, where readers may otherwise interpret zero counts too strongly.

The record also highlights how trial design labels do not substitute for reporting analytic details. Randomization and quadruple masking are important design characteristics, yet multiplicity handling, missing-data methods, comparison strategy, and interval methods are not reported. Those details help readers judge whether estimates reflect the planned analysis and how uncertainty should be interpreted.

Statistically, the study is best read as an early, cohort-based assessment with sparse immediate safety outcomes, rather than as a definitive comparison of event risks. Its broader objectives span safety, infectivity, and immune response, but each requires its own outcome-specific evidence.

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.

Several limitations are specific to interpreting this endpoint. First, the primary event is uncommon in the posted results, with zero recorded events in most groups and one in Cohort 4 placebo. Such sparse counts provide limited information about the underlying risk. The zero-width confidence intervals reported for all-zero comparisons do not adequately express that general uncertainty.

Second, the posted comparisons use Cohort 1 placebo as the reference for multiple groups. A contrast between placebo groups in different cohorts, such as Cohort 4 placebo and Cohort 1 placebo, crosses schedules: the former received two administrations and the latter received one. The resulting estimate is not a direct randomized treatment comparison within the same cohort.

Third, the endpoint has a narrow observation window: within 30 minutes after vaccination. It does not cover events occurring later, and it is not a summary of all safety outcomes. The registry record does not report the completeness of immediate observation or how missing endpoint data were handled.

Fourth, the registry record does not report the analysis plan, the methods used to calculate all confidence intervals, a multiplicity strategy, or adjusted comparisons. It also does not report a detailed explanation of the comparison structure. These gaps limit assessment of whether the displayed estimates align with prespecified analyses.

Finally, the results are counts of participants with events and do not establish causality. The serious adverse event summary is a separate safety measure and cannot be substituted for the primary immediate-event endpoint. The registry record does not report results for the secondary antibody, shedding, and vaccine-virus infection outcomes in the registry record for this interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of an Live-Attenuated Respiratory Syncytial Virus Vaccine in Infants and Toddlers — NCT04491877.
• Registry record last updated 2025-09-09; status last verified 2025-09.
• Results first posted 2024-06-13.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes a completed, randomized, quadruple-masked, sequential Phase 1 and Phase 2 study of an investigational live-attenuated RSV vaccine in infants and toddlers. It lists an enrollment of 259 and four cohorts testing formulation 1, formulation 2, and placebo, with one- or two-administration schedules.

The primary outcome was the number of participants with immediate unsolicited systemic adverse events within 30 minutes after vaccination. The posted counts are zero in most groups and one in Cohort 4 placebo. The Cohort 4 placebo contrast against Cohort 1 placebo has a risk difference of 0.016, a confidence interval from -0.015 to 0.048, and an unadjusted p-value of 0.585.

Rare events, zero-count interval estimates, and comparisons across cohorts and schedules constrain interpretation. Analysis-plan details, missing-data methods, and multiplicity handling are not reported in the registry record.