Alternative Schedule Study For VLA15, a Vaccine Candidate Against Lyme Borreliosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Alternative Schedule Study For VLA15, a Vaccine Candidate Against Lyme Borreliosis (NCT03970733), a randomized phase 2 study. The primary outcome is GMTs for IgG Against Each OspA Serotype.

2. Clinical Question

3. Trial Design

This was a randomized, controlled, observer-blind Phase 2 study with a parallel-group model. The registry record identifies quadruple masking. The Main Study Phase randomized 246 participants in a 2:2:1 allocation among VLA15 with Alum at the lower dose, VLA15 with Alum at the higher dose, and placebo. Vaccinations were intramuscular injections given on Day 1, Day 57 and Day 180.

The record describes a subsequent Booster Phase for participants in the higher-dose group who completed the primary immunization schedule according to protocol. Those participants were randomized 2:1 to an additional higher-dose VLA15 vaccination or placebo at Month 18. The lower-dose and main-study placebo arms did not continue into that phase. The booster comparison therefore concerns a selected group of participants from the higher-dose arm, not the original randomized groups as a whole.

The registry lists the condition as Lyme Borreliosis and the study population as healthy adults aged 18 to 65 years. It describes the Main Study Phase duration per participant as a maximum of 20 months and estimates the overall study duration as 22 months. The Booster Phase duration per participant is described as a maximum of approximately 13 months; the combined Main Study and Booster Phase duration per participant is estimated as a maximum of approximately 33 months. Overall study duration from first participant in to last participant out is estimated as approximately 37 months.

The record gives the study start as 2019-07-01, primary completion as 2020-04-07, and status as completed. It does not report a sample-size justification or explain how the group allocation ratios were selected. Those design rationales 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.

Main Study Phase (18 Months)

Reasons for not completing this period:

Booster Phase (Approx. 12 Months)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per-protocol population, excluded those participants with at least one relevant protocol deviation (i.e., a protocol deviation with possible impact on immunogenicity). Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

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 participants who entered into the study and received at least 1 dose of vaccination.

6. Primary Endpoint

The registry lists the primary outcome as GMTs for IgG Against Each OspA Serotype, measured over Day 208 (Month 7).

The primary endpoint is the geometric mean titer (GMT) of immunoglobulin G (IgG) against each OspA serotype, measured by enzyme-linked immunosorbent assay (ELISA) at Day 208 (Month 7). The six serotypes are identified as ST1 to ST6, and the measurement unit is Units per milliliter (U/mL). The endpoint is defined for the per-protocol population, excluding participants with at least one relevant protocol deviation that could affect immunogenicity.

General statistical context: antibody titers are commonly summarized with a geometric mean because titers are often unevenly distributed, with some values substantially higher than others. A geometric mean is based on the logarithms of the measurements and then expressed on the original scale. It can describe the central level of a set of positive measurements without allowing unusually large values to dominate in the same way they might affect an arithmetic mean.

The registry specifies a 95% confidence interval as the dispersion measure. General statistical context: a confidence interval conveys uncertainty around an estimated value; it is not a range containing a fixed proportion of individual participants’ measurements. The six serotype-specific GMTs describe antibody measurements, not clinical cases of Lyme borreliosis. Numerical GMT estimates and their confidence intervals are not reported in the registry record, so the magnitude and precision of the antibody responses cannot be assessed from these registry entries.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods can be understood by separating the design, the measurement, and the analysis population. The study was randomized, controlled, parallel-group and observer-blind, with quadruple masking recorded. General statistical context: random allocation is used to reduce systematic differences between groups at the start of a trial, while masking can reduce the influence of expectations on trial conduct or assessment. These design features support interpretation of a comparison, but do not guarantee that all sources of bias are absent.

What does randomization contribute?

The Main Study Phase used a 2:2:1 allocation among lower-dose VLA15 with Alum, higher-dose VLA15 with Alum, and placebo. The Booster Phase used a 2:1 allocation between an additional higher-dose VLA15 vaccination and placebo among eligible participants from the higher-dose group. These are allocation ratios, not results. The registry record does not explain the rationale for either ratio or report whether the actual assignment process had any departures from the planned approach.

General statistical context: randomized allocation aims to make groups comparable, on average, with respect to factors that could affect outcomes. It does not ensure exact balance in every measured or unmeasured characteristic. A parallel-group design assigns participants to a group for the relevant comparison rather than having each participant receive every study intervention. The Booster Phase population is selected by completion of the primary schedule according to protocol, so its comparison has a different participant basis from the Main Study Phase allocation.

What does a geometric mean summarize?

The primary outcome uses GMTs for IgG against each OspA serotype. General statistical context: a geometric mean is calculated by transforming positive measurements to a logarithmic scale, averaging there, and transforming back. This summary is useful when measurements are right-skewed or vary multiplicatively. It describes a central level on the original measurement scale, but it does not show the spread of individual values by itself. The registry specifies a 95% confidence interval as the measure of uncertainty around each GMT.

ELISA is the stated assay for measuring IgG against the OspA serotypes. The record gives the outcome unit as U/mL and the assessment time as Day 208 (Month 7). The GMTs are serotype-specific; the registry does not report a combined overall titer. The number of serotypes and the assay definition describe the outcome structure, not the observed results.

How should the analysis population be read?

The primary outcome is defined for the per-protocol population. The registry explains that participants with at least one relevant protocol deviation were excluded, where relevant means a deviation with possible impact on immunogenicity. General statistical context: a per-protocol analysis focuses on participants who meet specified protocol conditions, but excluding participants after randomization can affect how well the original randomized comparison is preserved. The registry entries do not describe the specific deviations, how they were assessed, or how many participants were excluded or analyzed for each endpoint.

The registry’s stated meaning of “Overall Number of Participants Analyzed” is participants evaluable for that outcome measure. This is an endpoint-specific concept: the number analyzed for an outcome need not be the same across all outcomes. The actual counts analyzed for the primary endpoint are not reported in the registry record. Missing-data methods and the handling of unevaluable assay measurements are also not reported in the registry record.

What do confidence intervals and multiplicity mean?

General statistical context: a confidence interval communicates the uncertainty associated with an estimate under the assumptions of the analysis. A wider interval indicates less precision than a narrower interval, but interpretation depends on the scale and the question being asked. The record specifies 95% confidence intervals for the GMTs, but their limits are not reported as numerical details.

The primary outcome includes measurements for ST1 to ST6, and the secondary outcomes include multiple response summaries and age-stratified analyses. General statistical context: when many outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. A prespecified multiplicity strategy can control or otherwise address that issue. Whether this study used such a strategy, and what it was, is not reported in the registry record. No inferential analysis details or adjustment methods are given.

What can planning calculations tell a reader?

General statistical context: sample-size planning calculations estimate the size of a future study needed to detect a specified effect under stated assumptions. They are planning illustrations, not observed power and not evidence that an effect was present. The registry record does not report the trial’s sample-size justification. Any planning illustrations based on observed effects should be interpreted separately from the trial’s prespecified design rationale and should not be mistaken for outcomes from the trial. The registry entries do not provide numerical planning results to interpret.

Overall, the registry describes the endpoint, design, and analysis population but does not provide the numerical estimates needed to evaluate the observed immunogenicity results. The details of the statistical model, treatment of missing data, hypothesis tests, and any adjusted comparisons are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome covers GMTs for each of six OspA serotypes. The secondary outcomes include seroresponse rates, geometric mean fold rises, and analyses stratified by age group. This creates a set of related but distinct outcomes. The registry record does not report a multiplicity strategy, such as a method for adjusting inference across serotypes, outcomes, or subgroups. It is therefore not possible to determine from the record whether reported inferences, if any, were adjusted for multiple testing.

The registry lists 35 outcome measures and 0 analyses. Numerical results for the primary and secondary immunogenicity outcomes are not reported in the registry record. This means the record does not support reconstruction of the outcome estimates, confidence intervals, or statistical comparisons. A list of planned or registered outcome measures is not a substitute for analysis results.

The primary endpoint uses a per-protocol population that excludes participants with at least one relevant protocol deviation affecting immunogenicity. The record does not report the number excluded, the number analyzed for each serotype, or the reasons for exclusion. Missing-data handling, including how absent or unevaluable assay results were treated, is not reported in the registry record. Nor does the record describe an intention-to-treat analysis for the primary endpoint.

These omissions matter because analysis populations and missing-data procedures can affect the interpretation of estimates, particularly when the analyzed participants differ from those randomized. Without the numerical outcome data and analysis details, the precision and robustness of any group comparison cannot be assessed.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: osteoarthritis (2.6%), spondylolisthesis (2.6%), small intestinal obstruction (2.6%), endometrial cancer (2.0%), prostate cancer metastatic (2.0%).

The registry lists serious adverse event counts separately for the Main Study Phase groups and the Booster Phase groups. In the Main Study Phase, serious adverse events affected 4 of 97 participants in the lower-dose VLA15 with Alum group, 4 of 98 in the higher-dose VLA15 with Alum group, and 2 of 51 in the placebo group. In the Booster Phase, they affected 3 of 39 participants assigned to higher-dose VLA15 and 0 of 19 assigned to placebo. The record reports 0 deaths in each listed group.

These are group-specific counts and denominators. They should not be combined across phases: the Booster Phase involved a selected group from the higher-dose arm, and its comparison is separate from the original Main Study Phase allocation. The figures describe participants with serious adverse events, not the total number of serious events, and the registry record does not provide enough detail to infer event timing, causality, or whether participants experienced more than one event.

The record also lists serious-event terms with percentages: osteoarthritis, 2.6%; spondylolisthesis, 2.6%; small intestinal obstruction, 2.6%; endometrial cancer, 2.0%; prostate cancer metastatic, 2.0%; and invasive ductal breast carcinoma, 1.0%. These terms and percentages do not by themselves establish a relationship to study intervention. Serious adverse event counts are descriptive safety information and do not answer the primary immunogenicity question.

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

The registry record establishes what this study set out to measure: IgG GMTs against six OspA serotypes at Day 208 (Month 7), with ELISA and a per-protocol analysis population. It also describes randomized comparisons of two VLA15 doses with placebo in the Main Study Phase and a later booster comparison within the higher-dose group. These design and outcome details help define the question, but the numerical primary-outcome results are not reported in the registry record.

Consequently, the registry entries do not show the observed GMT for any serotype, the precision of those estimates, or the size and direction of a difference between groups. They do not establish whether antibody responses were higher, lower, or similar across study groups. They also do not show whether any response threshold was met. Secondary outcome names indicate additional immunogenicity measures that were specified, but without their numerical results they cannot support conclusions about seroresponse rates, fold rises, or age subgroups.

The posted safety counts describe serious adverse events by study group and phase. They should be interpreted as descriptive counts, not as proof that an event was caused by an intervention or that a group’s overall safety profile was better or worse. The record does not provide a causal assessment in the registry record, and the booster groups are not interchangeable with the original Main Study Phase groups.

General statistical context: a randomized design can strengthen a comparison when results are reported and the analysis preserves the relevant assignment structure. It cannot compensate for missing outcome estimates. Likewise, a confidence interval would help convey precision, but the numerical interval limits are not reported in the registry record. The completed status is a study-status fact, not a substitute for the results.

The findings therefore cannot be summarized as evidence for or against a clinical effect on Lyme borreliosis from these registry entries. The primary endpoint measures antibody titers, not Lyme borreliosis incidence or clinical disease outcomes. Conclusions about clinical outcomes, long-term protection, or the meaning of antibody levels are not reported in the registry record and should not be inferred from the endpoint definition alone.

13. Why This Trial Matters Statistically

This trial is statistically notable for its outcome structure. The primary endpoint is not a single summary across participants: it includes a GMT for each of six OspA serotypes. The registry also identifies several secondary response measures and age-stratified outcomes. This structure makes it important to distinguish each serotype-specific estimate from an overall treatment comparison and to know how multiplicity was handled. That strategy is not reported in the registry record.

The study also has two related but distinct randomized comparisons. The Main Study Phase allocated participants among lower-dose VLA15 with Alum, higher-dose VLA15 with Alum, and placebo. The Booster Phase then randomized eligible participants from the higher-dose group to an additional VLA15 vaccination or placebo. Because the Booster Phase applies to participants who completed the primary schedule according to protocol, its results would need to be interpreted for that selected population rather than treated as a continuation of the full original comparison.

The per-protocol definition is another important statistical feature. Excluding participants with relevant deviations may focus the analysis on participants evaluable under the protocol, but it also makes the reported analysis population different from everyone randomized. Knowing the exclusions, endpoint-specific analysis counts, and missing-data approach would help readers understand how that choice affected the estimates. Those details are not reported in the registry record.

Finally, the record illustrates the difference between a detailed outcome definition and a report of results. It identifies the assay, time point, units, confidence-interval type, and analysis population, yet provides no numerical primary outcome estimates in the registry record. Without those estimates, neither effect magnitude nor precision can be judged. The trial design can be described, but the immunogenicity findings cannot be quantitatively interpreted from the registry record.

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 main limitation for interpretation is that numerical results for the primary endpoint are not reported in the registry record. The record defines serotype-specific GMTs, the assay, time point, unit, and confidence-interval type, but does not give the estimates, confidence interval limits, or endpoint-specific participant counts. A treatment contrast, p-value, or adjusted analysis is also not reported.

The primary endpoint uses a per-protocol population, excluding participants with relevant deviations that could affect immunogenicity. The record does not state how many participants were excluded, how deviations were judged relevant, or how the number analyzed varied by outcome. Missing-data handling and the treatment of unevaluable assay results are not reported in the registry record.

The primary endpoint involves multiple serotypes, and the secondary outcomes add response summaries and age strata. The multiplicity approach is not reported, so it is not possible to tell whether statistical inference accounted for the number of outcomes or comparisons. The registry also does not report a sample-size justification, detailed statistical model, or interim-analysis plan.

The Booster Phase is limited to participants from the higher-dose group who completed the primary schedule according to protocol, and it has a separate randomization. Any booster comparison would therefore apply to that eligible group rather than all participants in the Main Study Phase. Numerical booster outcome results are not reported in the registry record.

Finally, the stated primary outcome is an antibody measure, not a clinical Lyme borreliosis outcome. The registry entries do not provide clinical disease results or establish how antibody measurements relate to clinical outcomes. These limitations prevent quantitative conclusions about immunogenicity differences or clinical effects.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Alternative Schedule Study For VLA15, a Vaccine Candidate Against Lyme Borreliosis — NCT03970733.
• Registry record last updated 2023-04-21; status last verified 2023-03.
• Results first posted 2021-07-08.
• 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.

18. Record Summary

The registry describes a completed randomized, controlled, observer-blind Phase 2 parallel-group study of VLA15 with Alum in healthy adults aged 18 to 65 years. The Main Study Phase enrolled 246 participants and compared lower-dose VLA15, higher-dose VLA15, and placebo, with vaccinations on Day 1, Day 57 and Day 180. The Booster Phase randomized eligible participants from the higher-dose group to an additional VLA15 vaccination or placebo at Month 18.

The primary endpoint was GMT of IgG against each OspA serotype ST1 to ST6, measured by ELISA at Day 208 (Month 7), with a 95% confidence interval in a per-protocol population. Numerical primary outcome results, analysis counts, and multiplicity procedures are not reported in the registry record. The registry also lists secondary immunogenicity outcomes and group-specific serious adverse event counts. The record gives the study start as 2019-07-01, primary completion as 2020-04-07, and status as completed.