A Study to Evaluate the Safety, Tolerability and Immunogenicity of V114 in Healthy Adults and Infants (V114-005): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety, Tolerability and Immunogenicity of V114 in Healthy Adults and Infants (V114-005) (NCT02531373), a randomized phase 1, phase 2 study. The primary outcome is Adults: Percentage of Participants With an Adverse Event.

2. Clinical Question

3. Trial Design

The registry describes a Phase I-II, randomized, double-blind study with a parallel-group design and triple masking. Its stated purpose was to evaluate the safety, tolerability, and immunogenicity of different V114 formulations in healthy adults and infants. Enrollment was 338, and the record marks the study completed. The study start was 2015-09-15 and primary completion was 2017-04-14.

The adult groups received one of four V114 formulations: medium dose, high dose, medium dose with an alternative carrier protein, or high dose with an alternative carrier protein. Each adult formulation was administered as a single 0.5 mL intramuscular injection on Day 1. The posted primary safety endpoint includes 20 adults in each of these groups.

Infants were assigned to medium-dose V114, high-dose V114, either dose with an alternative carrier protein, or Prevnar 13™. Infant injections were scheduled at 2, 4, 6, and 12 to 15 months of age. Those infant groups contribute to the broader study but are not the population for the posted primary adult endpoint.

The primary endpoint was the percentage of adult participants with an adverse event up to 6 weeks after vaccination. The registry also lists adult antibody concentration and fold-rise outcomes, along with infant antibody concentration and threshold outcomes. The record lists 13 outcome measures and 46 analyses. The detailed original protocol, including the trial’s original sample-size justification and any planned interim analyses, is 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.

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 analysis population included all randomized adult participants who received study vaccination.

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: All participants who received at least one study vaccination

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Adults: Percentage of Participants With an Adverse Event, measured over Up to 6 weeks after vaccination.

The primary endpoint is the percentage of vaccinated adult participants who experienced an adverse event up to 6 weeks after vaccination. The registry defines an adverse event broadly: an unfavourable or unintended sign, symptom, or disease that occurs in temporal association with a medicinal product or protocol-specified procedure. A worsening of a preexisting condition may also qualify. The event does not need to have a causal relationship with the product.

This type of endpoint is used to describe the frequency of reported medical occurrences during a specified observation window. It can support a descriptive comparison of the recorded event proportions across randomized groups. The percentage alone does not establish that vaccination caused an event, and it does not convey the event’s severity, duration, or clinical importance.

The endpoint is reported separately for each adult formulation group, with a 95% confidence interval for each percentage. Those intervals communicate uncertainty around the group-level estimates. The registry’s analysis population includes randomized adult participants who received study vaccination. The reported endpoint therefore concerns that defined population, rather than every person enrolled in the overall adult-and-infant study.

7. Results Posted in the Registry

• Adults: V114 High Dose: 95.0% (19/20) versus 90.0% (18/20) on control; risk difference 5.0 percentage points (95% CI -11.3 to 21.3), risk ratio 1.06 (0.88–1.26); unadjusted two-proportion z-test p = 0.548.
• Adults: V114 Medium Dose + ACP: 95.0% (19/20) versus 90.0% (18/20) on control; risk difference 5.0 percentage points (95% CI -11.3 to 21.3), risk ratio 1.06 (0.88–1.26); unadjusted two-proportion z-test p = 0.548.
• Adults: V114 High Dose + ACP: 95.0% (19/20) versus 90.0% (18/20) on control; risk difference 5.0 percentage points (95% CI -11.3 to 21.3), risk ratio 1.06 (0.88–1.26); unadjusted two-proportion z-test p = 0.548.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage with an adverse event represent?

The primary measure is a binary outcome at the participant level: each participant either had at least one qualifying adverse event during the stated observation window or did not. The displayed percentage describes the proportion of participants with that outcome in a group. It is not a count of every event, because a participant with more than one event still contributes to the percentage as a participant with an event.

The adverse-event definition is intentionally broad. It includes occurrences temporally associated with a product or procedure even when a causal relationship has not been established. This supports systematic safety monitoring, but it also means that the endpoint should not be interpreted as the percentage of participants whose events were caused by vaccination. Attribution and the endpoint’s definition are different questions.

How should the group comparison be read?

The posted comparisons describe risk differences between each alternative adult formulation and the medium-dose V114 reference group. A risk difference is the difference between two group proportions, expressed on the proportion scale. A value of zero corresponds to equal observed proportions. The posted estimate for each comparison is 0.05, with an interval that crosses zero. That interval includes both a possible increase and a possible decrease relative to the reference; it does not identify one direction with precision.

The registry also gives an unadjusted p-value of 0.548 for each comparison. A p-value evaluates how compatible the observed data are with a specified null model, under the assumptions of that test. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference. A value that does not indicate a clear departure from the null is not a demonstration of equivalence or noninferiority. No equivalence or noninferiority margin is reported in the registry record.

What does a confidence interval add?

A confidence interval describes the range of values reasonably compatible with the data and the statistical procedure used, under its assumptions. In general, wider intervals indicate less precision. The adult group percentages have 95% confidence intervals from 68.3% to 98.8% for medium-dose V114 and from 75.1% to 99.9% for each other formulation. The intervals are wide, reflecting the limited information in each small adult group. Confidence intervals do not account for every source of uncertainty, such as limitations in outcome collection or analysis choices that are not reported.

The registry gives the confidence interval method for the primary group percentages as a 95% confidence interval. The detailed method used to calculate the comparison intervals, and any adjustment to the reported p-values or intervals, is not reported in the registry record. The displayed comparison p-values are explicitly unadjusted.

How do immunogenicity measures differ?

The other listed outcomes include geometric mean concentrations of pneumococcal serotype IgG antibodies, geometric mean fold rise from baseline, and infant percentages meeting a concentration threshold at specified times. A geometric mean summarizes positive measurements on a multiplicative scale and is commonly used when laboratory measurements are skewed. A geometric mean fold rise describes change relative to baseline on that scale. These are immunogenicity measures, not the primary adult adverse-event endpoint. Detailed posted results for those outcomes are not included in the registry record described in this analysis.

In general, antibody measurements can help characterize an immune response, but a laboratory response is not itself a clinical outcome such as prevention of infection. The registry’s stated study purpose includes immunogenicity, while the primary result under discussion is a safety percentage.

What does randomization contribute?

In general, random allocation can reduce systematic differences between groups at the outset, making group comparisons more interpretable. It does not guarantee that groups are identical, especially when groups are small. The record describes the study as randomized, double-blind, parallel, and triple-masked, but the precise masking roles and implementation details are not reported in the registry record. The adult results are comparisons among formulation groups; they should not be treated as a general comparison with an unvaccinated group, which is not listed.

The primary analysis population is specified as randomized adult participants who received study vaccination. The registry record does not report the analysis handling for participants with missing endpoint data, deviations from the assigned formulation, or other exclusions. Those details can affect which observations contribute to estimates and how well the analysis preserves the benefits of randomization.

10. Confidence Intervals and Precision

Precision is limited for the adult primary endpoint because each formulation group has 20 participants in the posted analysis. The 95% confidence interval for the medium-dose group’s 90.0% estimate extends from 68.3% to 98.8%. For each of the other three groups, the 95% confidence interval around the 95.0% estimate extends from 75.1% to 99.9%. These ranges are broad relative to the point estimates, so the observed percentages should not be treated as exact estimates of the event frequencies that would occur in a larger population.

The comparison intervals likewise span zero on the risk-difference scale. That means the data do not precisely distinguish a difference in either direction from no difference. The matching point estimates and p-values across the three posted comparisons reflect the reported summaries; they do not establish that the formulations have identical safety profiles. The uncertainty is especially important because the endpoint is common in these adult groups, leaving few participants without a recorded adverse event and limiting the range of possible information about between-group differences.

Confidence intervals quantify sampling uncertainty under the statistical method used. They do not resolve questions about event attribution, completeness of adverse-event ascertainment, missing data, or the generalizability of the study population. Details on missing-data handling are not reported in the registry record. The interval estimates should therefore be read as a measure of statistical precision, not as a complete account of uncertainty.

11. 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 sample-size figures are planning illustrations based on the observed adult comparison between high-dose V114 and medium-dose V114. They report participants per arm, not a total across arms or the total number of events. The illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect equal to the stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

For planning at 100% of the observed effect, the illustration gives 435 participants per arm for 80% power and 582 participants per arm for 90% power. At 75% of the observed effect, it gives 833 participants per arm for 80% power and 1,114 participants per arm for 90% power. At 50% of the observed effect, it gives 2,005 participants per arm for 80% power and 2,683 participants per arm for 90% power.

In plain terms, the 80% power column describes the planned group size that would give an assumed comparison an 80% chance of meeting the stated statistical criterion if the assumed effect and planning assumptions held. The 90% column represents a higher target chance under those same assumptions. Smaller effects require more participants to detect, which is why the illustrated group sizes increase as the assumed fraction of the observed effect decreases. These are planning scenarios, not observed power; they do not describe the probability that this completed study’s result is true or reliable.

The registry record does not report the original study’s design assumptions, so these illustrations should not be mistaken for the trial’s enrollment rationale. Their assumptions are stated for interpretation, but actual study conduct and analysis may differ from a planning scenario.

12. 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 = 0.900; treatment proportion p₁ = 0.950; average p̄ = 0.925.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3725 = 0.7301.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3708 = 0.3121.
4. n = (0.7301 + 0.3121)² / (0.0500)² = 434.4, rounded up to 435 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 <- 0.9                          # control proportion
p1 <- 0.95                          # 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(2531373)
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 = 435 (80% power), 582 (90% power)
 75% of observed effect: n per arm = 833 (80% power), 1,114 (90% power)
 50% of observed effect: n per arm = 2,005 (80% power), 2,683 (90% power)
power.prop.test: 434.4 
Simulated power at n = 435 per arm: 0.812 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 46 analyses, including multiple safety and immunogenicity outcomes. The three posted adult comparisons share the same medium-dose V114 reference group, and each has an unadjusted p-value of 0.548. The registry record does not report whether a multiplicity strategy was prespecified or used for the family of comparisons and outcomes.

Multiplicity matters because, when many statistical tests are considered, the chance of at least one apparently notable result can increase. In general, adjustment procedures can address this issue, but they may change the interpretation of individual p-values and intervals. No adjustment method, testing hierarchy, or confirmatory status for the comparisons is reported in the registry record. The posted p-values should therefore be understood as unadjusted, rather than as a familywise conclusion across all analyses.

The primary analysis population is described as randomized adult participants who received study vaccination. The registry record does not report how missing adverse-event information was handled, whether any participants were excluded after vaccination, or whether sensitivity analyses assessed alternate assumptions about missing observations. It also does not report a complete statistical analysis plan, the exact analysis method for the comparisons, or whether interim analyses were conducted.

These omissions limit evaluation of the full analysis process. They do not change the observed percentages, but they leave uncertainty about how participant flow, missingness, multiple comparisons, and analysis choices were addressed. The record identifies the population and endpoint, yet a fuller assessment of protocol adherence and inferential safeguards is not possible from the reported details.

14. 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: bronchiolitis (3.8%), cellulitis (2.0%), respiratory syncytial virus bronchiolitis (2.0%), respiratory syncytial virus infection (2.0%), viral infection (2.0%).

The serious-adverse-event figures are counts of participants with a reported serious event in each listed group; they are separate from the primary endpoint, which includes adverse events broadly. No serious adverse events were reported in any adult group. In the infant groups, the reported serious-event counts were 5 for medium-dose V114, 4 for high-dose V114, 1 for medium-dose V114 with an alternative carrier protein, 3 for high-dose V114 with an alternative carrier protein, and 4 for Prevnar 13™.

These counts are descriptive and should be read alongside the number at risk listed for each group, without treating them as a randomized comparison or as proof of causation. The record lists serious-event terms including bronchiolitis at 3.8%, and cellulitis, respiratory syncytial virus bronchiolitis, respiratory syncytial virus infection, viral infection, and third-degree burns at 2.0% each. The record does not establish from these terms alone whether an event was caused by a study product. The adult and infant counts also concern different populations and should not be combined.

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

The posted adult results show that adverse events were recorded in 90.0% of the medium-dose V114 group and 95.0% of each of the other three formulation groups during the endpoint window of up to 6 weeks after vaccination. The corresponding confidence intervals are broad, and the comparison intervals span zero. These data describe the observed study groups, while leaving substantial uncertainty about the underlying event frequencies and the size or direction of differences between formulations.

The results do not demonstrate that the formulations are equivalent, nor do they establish that one has a safer profile. The unadjusted p-values do not resolve those questions. The endpoint includes events that need not be causally related to the product, so a recorded adverse event is not proof of a vaccine-caused event. Conversely, the absence of a reported serious adverse event in an adult group does not establish that serious events cannot occur.

The primary endpoint is a safety measure, not a test of protection against pneumococcal infection. Although antibody outcomes are listed as secondary outcomes, the result does not establish clinical efficacy or the meaning of any antibody response. The registry record describes a study of healthy adults and infants and reports a defined adult analysis population; applicability to other populations is not established by these figures.

The most defensible interpretation is therefore descriptive: the posted adult percentages are high and similar as point estimates, but precision is limited by the small group sizes. Broader conclusions about comparative safety, causation, immune response, or clinical benefit require information beyond this endpoint and its reported comparisons.

16. Why This Trial Matters Statistically

This study illustrates a common challenge in early-stage clinical research: several formulation choices are evaluated while safety and immunogenicity are characterized in more than one age group. The adult primary endpoint is a participant-level safety percentage, while the listed antibody outcomes address a different scientific question. Keeping those endpoints distinct prevents a safety comparison from being mistaken for evidence about immune response or clinical protection.

The posted adult proportions are close, but their confidence intervals are broad. This is a useful reminder that similar point estimates in small groups do not establish equivalence. A non-significant comparison is not a positive equivalence finding, and the record does not report an equivalence margin or noninferiority framework. Precision and study purpose matter as much as the direction of the point estimate.

The record also makes visible the distinction between observed trial results and planning illustrations. The sample-size scenarios use stated assumptions and scaled effects; they are not the original trial’s rationale and do not measure observed power. Readers can use them to understand how smaller target effects demand larger planned groups, while keeping the completed study’s actual group sizes and uncertainty in view.

Finally, the wider outcome set raises questions about multiplicity, missing data, and the analysis population. The registry gives some relevant information, including the adult population definition and unadjusted p-values, but does not report a full statistical analysis plan or missing-data procedures. Recognizing those limits is central to a careful statistical reading rather than an attempt to draw more from the record than it supports.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The adult safety endpoint covers events up to 6 weeks after vaccination, so it does not by itself describe longer-term safety. The endpoint is broad and includes events without a required causal relationship to vaccination. The posted summaries do not provide detail on event severity, duration, relatedness assessments, or the number of separate events per participant for this primary endpoint.

Each adult group has 20 participants in the endpoint results, and the confidence intervals are wide. The comparisons therefore have limited precision. The registry record does not report an equivalence or noninferiority design, a clinically meaningful difference threshold, detailed allocation procedures, the roles covered by triple masking, missing-data handling, or a full statistical analysis plan. It also does not report whether multiplicity adjustment was used.

The primary analysis population includes randomized adults who received study vaccination, rather than an explicitly described intention-to-treat analysis of all randomized participants. Participant flow and reasons for any post-randomization exclusions are not reported in the registry record. The posted primary endpoint is adult-only; infant safety counts and the infant comparator do not substitute for an adult active-comparator result.

These limitations constrain claims about causality, rare events, longer-term outcomes, and comparative safety. The registry results are best treated as a limited descriptive record of the specified endpoint and groups, not as a complete characterization of all safety or immunogenicity evidence.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety, Tolerability and Immunogenicity of V114 in Healthy Adults and Infants (V114-005) — NCT02531373.
• Registry record last updated 2019-04-02; status last verified 2019-03.
• Results first posted 2018-04-17.
• 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.

21. Record Summary

The registry describes a completed, randomized, double-blind, parallel Phase I-II study of V114 formulations in healthy adults and infants. The primary endpoint was the percentage of vaccinated adults with an adverse event up to 6 weeks after vaccination. The posted group estimates were 90.0% for medium-dose V114 and 95.0% for each of the other three adult formulations, with broad 95% confidence intervals.

Each posted comparison with the medium-dose group had a risk-difference estimate of 0.05 and an unadjusted p-value of 0.548. The record also lists infant safety groups and multiple immunogenicity outcomes. Details needed to assess multiplicity, missing-data handling, and the original sample-size rationale are not reported in the registry record.