Safety, Reactogenicity and Immunogenicity of Adenovirus Serotype 26 (Ad26)- and Modified Vaccinia Ankara (MVA)-Vectored Vaccine Components in Otherwise Healthy Women With HPV16 or HPV18 Infection of the Cervix: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Reactogenicity and Immunogenicity of Adenovirus Serotype 26 (Ad26)- and Modified Vaccinia Ankara (MVA)-Vectored Vaccine Components in Otherwise Healthy Women With HPV16 or HPV18 Infection of the Cervix (NCT03610581), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Solicited Local Adverse Events (AEs).

2. Clinical Question

This study was registered as randomized, triple-masked, sequential, and placebo-controlled. Its official title describes a first-in-human Phase 1/2a evaluation of safety, reactogenicity, and immunogenicity. The primary outcome is a count of participants with specified local events, rather than a measure of vaccine efficacy. The registry also lists HPV-specific CD4+ and CD8+ T-cell response outcomes, including responses involving IFNg+, IL2+, and TNFa+.

The central statistical question is therefore descriptive: what event counts were recorded in the reported groups, and how much can those counts establish about tolerability or immune response? The posted record gives adverse-event figures for Regimen 1 and placebo, but no inferential analysis and no single primary comparison. It does not establish the event pattern for the other vaccine regimens in the same form. The record also does not report an efficacy outcome, so it cannot answer whether the regimens prevent or clear HPV infection.

3. Trial Design

The study is identified as NCT03610581. It was a randomized, triple-masked, placebo-controlled, sequential Phase 1/2a study sponsored by Janssen Vaccines & Prevention B.V. Its stated focus was safety, reactogenicity, and immunogenicity of monovalent HPV16 and HPV18 Ad26-vectored components and an MVA-vectored HPV16/18 component in otherwise healthy women with HPV16 or HPV18 infection of the cervix.

The registry describes three active regimens. Regimen 1 used a single Ad26.HPV16 or Ad26.HPV18 prime followed by an MVA.HPV16/18 boost. Regimen 2 used a double Ad26.HPV16 or Ad26.HPV18 prime followed by the MVA.HPV16/18 boost. Regimen 3 used a mix of Ad26.HPV16 and Ad26.HPV18 as the prime, followed by MVA.HPV16/18. The control group received matched placebo as both prime and boost. The registry does not give further details of sequence timing or the allocation process.

Enrollment was 9. The study started on 2018-09-27, and the primary completion date was 2020-10-15. Its status is terminated. The registry record does not report why the study was terminated, so the status alone does not explain whether recruitment, safety, operational considerations, or another factor led to termination.

The outcome listing includes 10 outcome measures, but the posted analysis count is 0. No analysis results are listed for the immune-response outcomes. The available adverse-event record contains counts for Regimen 1 and placebo; it does not present a complete set of outcome results for all three active regimens. The record does not report the planned allocation proportions or a 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.

Before assignment: Due to premature study termination, participants were only randomized and treated for Regimen 1 and Placebo. Hence, all results are reported below for Regimen 1 and Placebo only and not for Regimen 2 and 3.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) included all participants with at least one vaccination. Here, "n (number analyzed)" is defined as participants analyzed for specified category.

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: Full analysis set (FAS) included all participants with at least one vaccination.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Solicited Local Adverse Events (AEs), measured over Up to 7 days after each vaccination (Up to Day 64).

The primary endpoint is the number of participants with solicited local adverse events. The events specified are pain or tenderness, erythema, and induration or swelling. The assessment window is up to 7 days after each vaccination, through Day 64. The registry defines the primary outcome as a count of participants, and defines the analyzed population as the full analysis set: participants with at least one vaccination. Within the outcome description, the number analyzed is specific to the category being reported.

Counting participants with an event is a direct way to describe how many people experienced a solicited local reaction during the stated observation period. It differs from counting every event occurrence: a participant with more than one event is still represented as a participant with an event in a participant count. The posted outcome does not provide event duration, intensity, recurrence, or a separate count for each local-event type. Those details are not reported in the registry record.

This endpoint is used to characterize reactogenicity and safety, which the registry identifies as the study's main purpose. It does not by itself measure immune response or clinical benefit. The record's primary-outcome entries include several categories or time points and were not reduced to one comparison. Consequently, the available information supports reading the reported counts as descriptive outcome data, not as a complete inferential comparison between treatment groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the study as randomized, triple-masked, placebo-controlled, and sequential. These labels describe aspects of design, but they do not supply the details of the allocation sequence, masking procedures, or how the sequential regimen structure was operationalized. Those details are not reported in the registry record. A design label alone should not be treated as evidence that every potential source of bias was controlled.

What does a participant count describe?

The primary outcome is a count of participants with solicited local adverse events, not a continuous measurement. A participant is counted as having an event if the specified outcome definition is met during the observation period. This kind of count is straightforward to interpret, but it does not show the number of separate episodes, the severity of each event, or how long an event lasted. The registry specifies local symptoms and a time window, but does not report those additional event details.

Counts also need a denominator to convey how many participants were considered at risk or analyzed. The primary endpoint description says the full analysis set includes participants with at least one vaccination, and that the number analyzed is category-specific. The safety figures list at-risk counts alongside affected-participant counts for the groups reported. These denominators are important context, particularly when group counts are small. They should not be generalized to participants or groups not represented in the reported entries.

What would an inferential comparison add?

In general, an inferential comparison can estimate how outcome frequencies differ between groups while representing uncertainty in that estimate. A confidence interval is a range of values compatible with the observed data under the method's assumptions; its width conveys precision. With sparse counts, uncertainty is often substantial, and a zero observed count does not imply zero underlying risk. These are general statistical principles. The registry does not report confidence intervals, hypothesis tests, or a selected primary contrast for the solicited local-event outcome.

The registry reports 0 analyses. It therefore does not provide a sponsor analysis to interpret for the listed outcomes. The primary-outcome record specifically notes that there are several categories or time points and that the outcome was not reduced to one comparison. A reader should not reconstruct an unadjusted contrast and present it as the trial's planned or definitive result: the record does not establish which category, time point, or comparison would represent the primary analysis.

What is the role of the planning assumptions?

The record describes a sample-size planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. For time-to-event settings, the illustration uses a total event count; other settings use participants per arm. These are planning assumptions, not evidence that the trial was designed around them. The record does not report the trial's own sample-size justification, and a planning illustration must not be interpreted as observed power.

In general, power is a design-stage probability of detecting an effect under stated assumptions; it is not a property that can be established after seeing a small set of results by substituting an observed effect. The registry's planning description does not provide a basis for asserting that the study had adequate power for the primary endpoint, for rare safety events, or for immune outcomes. Any numerical planning outputs should be read as illustrations conditional on their assumptions, not as observed findings or a substitute for an analysis plan.

Why can over-dispersion matter?

In general, a simple count model may assume that event variability follows a specified relationship to the mean. Over-dispersion occurs when the observed variability exceeds that assumption and can make standard errors too small if ignored. It is relevant when outcomes are event counts with variation not captured by a basic model. The primary endpoint is a count of participants with an event, rather than a reported rate of repeated events. The registry does not describe an over-dispersion assessment or a count-model analysis, so no such method should be attributed to this study.

The main statistical message is that the registry gives design labels, endpoint definitions, and selected counts, but not a reported inferential analysis. The methods used for missing observations, multiplicity, confidence intervals, or treatment comparisons are not reported in the registry record. General statistical concepts can explain what such methods would address, but they cannot fill in an undocumented analysis plan.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes: the primary local-adverse-event count and secondary HPV-specific CD4+ and CD8+ T-cell response outcomes involving IFNg+, IL2+, and TNFa+. The primary outcome description also refers to several categories or time points, and the record states that it was not reduced to one comparison. When multiple outcomes or contrasts are assessed, multiplicity can increase the chance of at least one apparently unusual result by chance. In general, a prespecified strategy can control or describe that issue. The registry does not report a multiplicity strategy.

The registry lists 10 outcome measures and 0 analyses. It does not report statistical results for the immune-response outcomes or a complete analysis of the primary endpoint. It also does not report an interim-analysis plan, a missing-data method, or how participants with incomplete follow-up were handled. These omissions mean that the record cannot establish whether missing observations were excluded, imputed, or addressed in another way.

The primary outcome defines the full analysis set as all participants with at least one vaccination, with the analyzed number defined for each category. This describes an analysis population, but it does not explain handling of missing endpoint assessments or deviations from the intended regimen. The registry record does not report a separate safety population definition for the posted event counts.

Without a reported analysis plan and completed outcome analyses, interpretation should remain descriptive. Neither the listed outcome count nor the presence of a defined full analysis set supplies the missing multiplicity, missing-data, or modeling details.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry's serious-event entries list 0 affected participants among 5 at risk in Regimen 1, and 0 among 4 at risk in placebo. Deaths are listed as 0 for both groups. The other adverse-event entries are 2 among 5 at risk for Regimen 1 and 1 among 4 at risk for placebo. These figures are counts as recorded in the registry; they are not adjusted comparisons.

The serious-event figures should not be confused with the primary endpoint. The primary endpoint concerns solicited local events—pain or tenderness, erythema, and induration or swelling—during the specified period after vaccination. The registry does not reduce that endpoint to a single comparison. The serious-event entries also do not provide detail about event type, timing, relatedness, or severity beyond the serious-event classification. More specific descriptions are not reported in the registry record.

When counts are this limited, a zero observed count does not establish that an event cannot occur or that the underlying risk is zero. The figures apply only to the groups and participants represented in these entries. They do not provide a complete safety comparison across all three vaccine regimens, and no uncertainty estimates or statistical tests are reported.

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

The posted results establish that the registry contains selected adverse-event counts for Regimen 1 and placebo, along with a zero death count for each. They also establish that the study was terminated, had enrollment of 9, and has no analyses listed. The record defines the primary outcome as participants with specified solicited local events and describes the relevant observation period. These registry entries are useful for understanding what was intended and which data are available.

The results do not establish a comparative estimate for the primary endpoint. The registry explicitly says that the primary outcome has several categories or time points and was not reduced to one comparison. It does not report the outcomes for all active regimens in a complete, comparable form, and it lists no immune-response analyses. The available numbers therefore should not be recast as evidence of a statistically established difference among groups.

The counts also cannot establish that a regimen is safe in a broad population or that rare adverse events are absent. The reported group sizes are limited, and the registry does not provide uncertainty intervals or detailed event descriptions. The record does not report efficacy outcomes, so it cannot establish whether vaccination changes HPV infection or related clinical outcomes.

In general, a small early-phase study can be designed to characterize initial safety and immune response rather than provide definitive comparative evidence. That general context does not confirm the specific rationale or statistical plan for this study, which is not reported in the registry record. The most defensible reading is limited to the trial design and the observed counts actually posted, with substantial uncertainty about outcomes not reported or not analyzed.

13. Why This Trial Matters Statistically

This trial illustrates why design descriptions and outcome definitions must be separated from evidence of a treatment effect. The registry gives a detailed set of vaccine components and regimens, identifies a randomized, triple-masked, placebo-controlled design, and defines a local-reactogenicity outcome. Those elements clarify what was intended to be studied. They do not substitute for complete outcome reporting or a prespecified analysis.

Its primary endpoint is a participant count, which can be intuitively meaningful, but the record does not consolidate the listed categories or time points into a single comparison. The available safety entries are limited to Regimen 1 and placebo, and no analyses are listed. This creates a useful statistical distinction: event counts can be reported descriptively while still being insufficient to support a comparative inference. Counts without uncertainty estimates should not be read as precise estimates of population risk.

The record also highlights the limits of planning illustrations. The sample-size description specifies assumptions for an illustration, but does not report that these assumptions constituted the study's own design justification. Planning calculations based on observed effects cannot repair missing results or establish observed power.

For biostatisticians and clinical researchers, the key lesson is to inspect what the registry actually reports: population definitions, endpoint windows, group-specific denominators, analysis availability, and missing analysis details. Here, these distinctions prevent selected counts from being overstated as a comprehensive safety or immunogenicity result. The record is informative about study intent and the boundaries of the posted evidence, while leaving major questions unresolved.

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 record's most important limitation is the absence of reported analyses. Although it lists 10 outcome measures, the analysis count is 0. The primary endpoint is not reduced to one comparison, and the listed adverse-event data cover Regimen 1 and placebo rather than providing a complete set of results for all active regimens. The secondary cellular immune-response outcomes are listed, but their results are not reported.

Enrollment was 9, and the study is marked terminated. The registry does not report the reason for termination, the intended enrollment, or a sample-size justification. Without these details, the planned scale and rationale for the observed enrollment cannot be evaluated. The record also does not describe the allocation procedure or the operational details of the sequential design.

Safety reporting is limited in detail. The record gives serious and other adverse-event counts and deaths for the groups listed, but does not provide event-level descriptions, timing, relatedness, or severity details beyond the serious classification. It does not report confidence intervals or other uncertainty measures. Missing-data handling and the treatment of incomplete follow-up are not reported.

The primary outcome window is defined, but results are not separated into the endpoint categories or time points needed for a complete interpretation. No efficacy outcome is reported. Consequently, the posted record supports only a narrow descriptive account of selected safety counts and study intent; it cannot support a complete comparative assessment of the vaccine regimens.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety, Reactogenicity and Immunogenicity of Adenovirus Serotype 26 (Ad26)- and Modified Vaccinia Ankara (MVA)-Vectored Vaccine Components in Otherwise Healthy Women With HPV16 or HPV18 Infection of the Cervix — NCT03610581.
• Registry record last updated 2025-02-04; status last verified 2025-01.
• Results first posted 2021-11-09.
• 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

NCT03610581 was a randomized, triple-masked, placebo-controlled, sequential first-in-human Phase 1/2a study of Ad26- and MVA-vectored HPV vaccine components in otherwise healthy women with HPV16 or HPV18 infection of the cervix. It evaluated three vaccine regimens and a matched-placebo control. Enrollment was 9; the study is marked terminated.

The primary endpoint counted participants with solicited local adverse events up to 7 days after each vaccination, through Day 64. The posted safety entries list serious adverse events, other adverse events, and deaths for Regimen 1 and placebo. The primary endpoint was not reduced to one comparison, and the registry lists 0 analyses. Immune-response outcomes are listed without analyses. The record does not report a statistical analysis plan, multiplicity strategy, or missing-data method.