Safety, Tolerability, and Immunogenicity of V114 Compared to Prevnar 13™ in PPSV23-vaccinated Healthy Adults ≥65 Years of Age (V114-007): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, and Immunogenicity of V114 Compared to Prevnar 13™ in PPSV23-vaccinated Healthy Adults ≥65 Years of Age (V114-007) (NCT02573181), a randomized phase 2 study. The primary outcome is Percentage of Participants With an Adverse Event (AE).

2. Clinical Question

The trial also set out to assess tolerability and immunogenicity. The registry lists secondary outcomes based on serotype-specific opsonophagocytic killing activity: geometric mean titers, geometric mean fold rise from baseline, and the percentage of participants with a fourfold or greater rise from baseline. Those outcomes address antibody activity and changes from baseline, rather than the primary safety question.

The primary outcome is a broad measure of adverse events, defined in the registry as any untoward medical occurrence in a participant given a pharmaceutical product, whether or not it has a causal relationship with the treatment. The comparison therefore concerns the frequency of recorded events during the stated follow-up period; it does not, by itself, establish whether an event was caused by vaccination.

3. Trial Design

This was a randomized, double-blind, parallel-group Phase 2 study. The registry records an enrollment of 253 and a completed status. The study began on 2015-10-30, and primary completion was recorded as 2016-01-28. The registry names Merck Sharp & Dohme LLC as sponsor.

Participants were healthy adults aged 65 years or older who had previously received 23-valent pneumococcal polysaccharide vaccine at least 1 year before study vaccination. One group received a single 0.5 mL intramuscular injection of V114 on Day 1; the other received a single 0.5 mL intramuscular injection of Prevnar 13™ on Day 1. The posted primary outcome population includes all participants who received study vaccination. The outcome timeframe is up to Day 44 after vaccination.

Randomization indicates that assignment to the two groups was by chance, while double masking means the registry describes the study as blinded at two levels. The identities of the people or roles masked, the method used to generate and conceal the allocation sequence, and procedures for maintaining masking are not reported in the registry record. The parallel design means participants were assigned to one of the two vaccine groups rather than receiving both in sequence.

The study description identifies safety, tolerability, and immunogenicity as the aims. The registry lists nine outcome measures and five analyses. The registry record does not report the original sample-size justification, the planned statistical analysis method for the primary endpoint, or whether interim analyses were planned. The listed enrollment and completed status describe the study record, but do not establish the rationale for its planned size.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: All participants who received study vaccination are included.

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.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With an Adverse Event (AE), measured over Up to Day 44 after vaccination.

The primary endpoint is the percentage of vaccinated participants with an adverse event up to Day 44 after vaccination. The registry defines an adverse event as any untoward medical occurrence in a participant administered a pharmaceutical product; a causal relationship to treatment is not required. It is therefore an all-event safety measure, not a measure limited to events judged to be caused by vaccination.

For a binary endpoint such as whether a participant had at least one event, the percentage gives the proportion of the study group with the outcome. This makes the two randomized groups comparable on a common scale and is straightforward to interpret as an observed frequency during the specified period. The primary outcome population is all participants who received study vaccination.

The reported percentages are 68.5% for V114 and 64.3% for Prevnar 13™. These figures describe the posted primary outcome. They do not alone explain event severity, event counts per participant, or whether individual events were considered vaccine-related. The registry's broader safety listings include serious and other adverse events, but those categories should not be treated as interchangeable with the primary endpoint without additional definitions. The primary endpoint also does not measure protection against pneumococcal infection or long-term outcomes.

7. Results Posted in the Registry

• Prevnar 13™: 64.3% (81/126) versus 68.5% (87/127) on control; risk difference -4.2 percentage points (95% CI -15.8 to 7.4), risk ratio 0.94 (0.79–1.12); unadjusted two-proportion z-test p = 0.478.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary at the participant level: a participant either had an adverse event during the specified period or did not. For each group, the registry reports the percentage with an event. A percentage is a proportion expressed on a scale that is easy to interpret as the share of participants experiencing the outcome. The endpoint definition is broad and includes medical occurrences whether or not they are judged related to vaccination.

What does a risk difference describe?

A risk difference subtracts one group's event proportion from the other's. The recalculation uses Prevnar 13™ minus V114, giving -0.042. Its confidence interval runs from -0.159 to 0.074. Negative values in this orientation correspond to a lower observed event proportion in Prevnar 13™ than in V114, while positive values correspond to the reverse. The interval includes zero, the value that represents no difference in proportions. The calculation is unadjusted and is based on the posted summary statistics.

The sponsor's posted analysis reports a difference of 4.2, with a 95% confidence interval from -7.4 to 15.8. This is on a percentage-point scale and uses the opposite contrast orientation from the recalculated risk difference. Reversing the direction of a contrast reverses its sign, so a positive sponsor estimate can correspond to a negative estimate under the other orientation. The two presentations should be read with their stated scale and direction in mind.

How do relative measures differ?

A relative risk compares the event probability in one group with the event probability in the other. The recalculated relative risk is 0.938, with a 95% confidence interval from 0.787 to 1.119. An odds ratio compares the odds of an event rather than the event probabilities themselves; its recalculated value is 0.828, with a 95% confidence interval from 0.491 to 1.395. For these ratio measures, a value of 1 represents no relative difference. Both intervals include 1. The risk difference directly expresses an absolute contrast, while relative measures express a ratio; neither measure is a substitute for understanding the endpoint, population, and timeframe.

General statistical explanation: a confidence interval describes a range of estimates compatible with the observed data under the method's assumptions. It reflects uncertainty in the estimate and is not a range that contains a fixed proportion of individual participants' outcomes. An interval that includes the no-difference value does not prove equivalence. A claim of equivalence or noninferiority would require a prespecified margin and a design and analysis addressing that question; such a margin is not reported in the registry record.

What does the p-value add?

The unadjusted p-value for the recalculated comparison is 0.478. In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the statistical model were correct. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The registry does not report a p-value for the sponsor's analysis.

The recalculated risk difference and relative measures are explicitly unadjusted re-calculations from posted summary statistics. The sponsor's reported analysis remains the sponsor's own result; the record does not identify its method. The analysis method, covariate adjustment, stratification, and handling of any clustering are not reported in the registry record. It would therefore be inappropriate to attribute a particular model or adjustment to the sponsor.

For binary data, the precision of a group comparison depends in part on the number of participants and the frequency of events. General statistical explanation: when outcomes are more variable than a model assumes, standard errors can be underestimated unless the analysis accounts for that extra variability. This is called over-dispersion in settings where it applies. The registry record does not report that over-dispersion was assessed or that a model requiring such an assessment was used in this comparison.

The primary endpoint population is described as all participants who received study vaccination. The record does not state how missing primary endpoint observations were handled, whether every vaccinated participant had complete follow-up, or whether any additional analysis populations were used. Those omissions matter because the denominators and missing-outcome assumptions affect the interpretation of a participant-level percentage. The posted group sizes for the recalculation are 127 and 126, and the recalculation uses the posted event counts of 87 and 81. The separate adverse-event listing reports other counts; their relation to the primary endpoint counts is not explained in the registry record.

The registry lists nine outcome measures, five analyses, and three posted secondary outcome categories. This indicates that the primary endpoint is not the only outcome of interest, but the number of outcomes alone does not reveal which comparisons were confirmatory or how they were prioritized. The multiplicity approach, if any, is not reported in the registry record. General statistical explanation: when many outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase; prespecified testing strategies can address that issue. No such strategy can be inferred from the count of listed outcomes.

10. Confidence Intervals and Precision

The recalculated risk difference is -0.042, with a 95% confidence interval from -0.159 to 0.074. The interval extends across zero, so the data are compatible with a negative difference, no difference, or a positive difference under this unadjusted calculation. It is not sufficiently narrow to identify a single precise value for the underlying contrast.

The recalculated relative risk is 0.938, with a 95% confidence interval from 0.787 to 1.119. The odds ratio is 0.828, with a 95% confidence interval from 0.491 to 1.395. Both intervals include 1, the no-relative-difference value. The odds ratio interval covers a broad range of relative associations, and the point estimate should not be read without its uncertainty interval.

The sponsor's reported difference is 4.2, with a 95% confidence interval from -7.4 to 15.8. That interval includes zero, as does the recalculated risk-difference interval. The sponsor's scale and contrast direction differ from the recalculation, and the registry does not report the sponsor's statistical method. The two results are therefore best read as separate presentations of the comparison rather than as identical quantities.

General statistical explanation: a 95% confidence interval describes the uncertainty of an estimate under its method and assumptions. It does not establish that every value in the interval is equally plausible, nor does it show the probability that a particular treatment effect is true. An interval spanning the null value is not proof that the groups are the same; it means the data do not pin the contrast down to one side of that value at the stated confidence level. The registry does not report a clinical interpretation threshold for the primary endpoint, so the practical importance of values within the interval cannot be determined from the record alone.

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 planning figures are participants per arm for this binary percentage endpoint, not total events. The rows describe planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For the first scenario, the figures are 1,968 participants per arm for 80% power and 2,634 participants per arm for 90% power. For the second, they are 3,471 and 4,646 participants per arm, respectively. For the third, they are 7,747 and 10,370 participants per arm, respectively.

In plain terms, the 80% power column gives the estimated participants per arm needed for an assumed design to have an 80% chance of detecting the stated effect under its planning assumptions. The 90% power column gives the corresponding planning size for a 90% chance. These are conditional planning calculations, not guarantees about the result of a future study. They are not observed power.

The stated calculation assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The trial's own original sample-size assumptions and justification are not reported in the registry record. The planning values are therefore illustrations based on the observed effect, not evidence that the completed trial was designed using those assumptions.

The pattern is important: planning for a smaller fraction of the observed effect requires more participants per arm. A study intended to detect a subtler difference generally needs more information than one intended to detect a larger difference, given the other assumptions held fixed. The sample-size figures should be interpreted as planning scenarios for a future comparison, not as observed participant counts or a retrospective assessment of the trial's power.

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 = 0.685; treatment proportion p₁ = 0.643; average p̄ = 0.664.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6680 = 1.3093.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6673 = 0.5617.
4. n = (1.3093 + 0.5617)² / (-0.0422)² = 1,967.2, rounded up to 1,968 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 <- 0.68503937007874                          # control proportion
p1 <- 0.642857142857143                          # 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(2573181)
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 = 1,968 (80% power), 2,634 (90% power)
 75% of observed effect: n per arm = 3,471 (80% power), 4,646 (90% power)
 50% of observed effect: n per arm = 7,747 (80% power), 10,370 (90% power)
power.prop.test: 1967.2 
Simulated power at n = 1,968 per arm: 0.802 (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. Analyses Reported by the Sponsor

The registry reports the sponsor's analysis as a difference of 4.2, with a 95% confidence interval from -7.4 to 15.8. It does not report a p-value or identify the statistical method for this analysis. The contrast is presented in the opposite direction and on a percentage-point scale relative to the unadjusted recalculated risk difference, which is Prevnar 13™ minus V114 at -0.042, with a 95% confidence interval from -0.159 to 0.074. Signs should therefore not be compared without accounting for the direction and scale.

Both reported confidence intervals include the value representing no difference for their respective scales. The recalculated analysis also reports an unadjusted p-value of 0.478. The registry does not flag a discrepancy between the sponsor analysis and the recalculation. The sponsor's own analysis remains the primary reported analysis; the recalculation is a simple, unadjusted comparison derived from the posted summary statistics and does not reproduce an undocumented model or adjustment.

The record does not explain whether the sponsor used adjustment, stratification, or a particular statistical model. Differences in analytic choices can affect results, so the recalculation should not be presented as a replacement for the sponsor's analysis. The available information supports describing both estimates and their uncertainty, while noting that neither confidence interval isolates a difference on one side of the null value.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures, five analyses, and three posted secondary outcome categories. The secondary categories concern serotype-specific opsonophagocytic killing activity: geometric mean titers, geometric mean fold rise from baseline, and the percentage of participants with a fourfold or greater rise from baseline. Their numerical results are not included in the registry record for this account. The registry record does not report how the primary endpoint was prioritized relative to the other outcomes or whether a hierarchy of hypotheses was specified.

Multiplicity refers to the statistical issue that can arise when many outcomes, time points, or comparisons are tested. General statistical explanation: as the number of tests increases, the chance of at least one result appearing statistically unusual can increase, depending on how the tests relate to one another. Prespecified approaches can control or otherwise address this issue. The multiplicity strategy for this trial is not reported in the registry record, so no adjustment should be assumed and the listed count alone does not show whether one was needed.

The primary endpoint population is stated as all participants who received study vaccination. The registry does not report whether this was the only analysis population, whether immunogenicity analyses used a different population, or how participants with missing measurements were handled. It also does not report the amount or pattern of missing data, if any, or the method used to address it. These details affect the interpretation of percentages and of the secondary outcomes.

Likewise, the record does not report whether outcome assessments were analyzed according to randomized assignment, actual vaccination received, or another population definition beyond the stated vaccinated primary population. The method for handling protocol deviations and any exclusions is not reported. There is no basis in the registry record to infer imputation, complete-case analysis, or another missing-data approach. These absences limit the ability to assess the full analysis plan but do not alter the descriptive percentages that are posted.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute myocardial infarction (0.8%), periprosthetic fracture (0.8%).

The serious adverse event listing reports 0 serious events among 127 participants in the V114 group and 2 among 126 participants in the Prevnar 13™ group. It reports 0 deaths in each group. The registry's serious-event terms include acute myocardial infarction and periprosthetic fracture, each listed at 0.8%. The term listing does not assign each term to a specific group in the information, so an arm-specific attribution should not be inferred.

These serious adverse event figures are distinct from the primary endpoint, which counts participants with any adverse event up to Day 44 and is reported as 68.5% for V114 and 64.3% for Prevnar 13™. The adverse-event listing also reports 86 other adverse events among 127 participants in the V114 group and 74 among 126 in the Prevnar 13™ group. The registry record does not explain how those counts relate to the primary endpoint counts.

Serious-event counts are descriptive and should be read in light of the group sizes and the limited follow-up recorded for the primary endpoint. The registry information does not establish causality for individual events. A zero count in a group is not evidence that an event could never occur, and the listed terms do not by themselves support a causal comparison.

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

The result describes the proportion of vaccinated participants who had a broadly defined adverse event during follow-up up to Day 44: 68.5% in the V114 group and 64.3% in the Prevnar 13™ group. The unadjusted recalculation of the difference has a 95% confidence interval that includes zero, and the recalculated relative risk and odds ratio intervals include 1. This means the posted data leave uncertainty about the direction and size of the difference; they do not establish equality between the groups.

The endpoint includes any untoward medical occurrence and does not require that the event be considered related to vaccination. Consequently, the percentages should not be read as percentages with vaccine-caused effects. They also do not indicate how many events each participant experienced, how severe the non-serious events were, or whether they persisted. The serious adverse event listing is a separate summary and reports 0 and 2 serious events in the respective groups, with 0 deaths in each.

The finding is limited to a specific population: healthy adults aged 65 years or older previously vaccinated with PPSV23 at least 1 year earlier. It concerns two single-dose injections and the stated follow-up. It does not establish comparative safety outside that population or beyond the recorded period. Nor does this primary endpoint answer whether either vaccine prevents pneumococcal infection.

Although immunogenicity was among the study aims, the numerical results for the listed secondary immunogenicity outcomes are not reported in the registry record for this analysis. The primary safety result cannot be used to infer antibody response or clinical protection. Overall, the registry data support a cautious description of observed adverse-event frequencies and the uncertainty of their comparison, rather than a definitive claim that one vaccine is safer, equivalent, or more effective than the other.

17. Why This Trial Matters Statistically

This trial is statistically informative because it makes a direct randomized comparison of a safety endpoint between two vaccine groups in a defined population. Random assignment and double masking are design features intended to support a fair comparison, although the registry does not provide enough detail to assess allocation procedures or how masking was implemented. The parallel design also keeps the comparison between separate groups of vaccinated participants.

The analysis illustrates why an observed difference and its precision must be considered together. The reported event percentages differ, but the recalculated confidence interval spans zero, and the relative-measure intervals span 1. The point estimate alone does not show how much uncertainty surrounds the contrast. The sponsor's own confidence interval also includes no difference, while its contrast direction and scale differ from the recalculation.

The trial also highlights the limits of a broad safety outcome. A participant-level adverse-event percentage captures whether an event was reported, but does not by itself convey event severity, causal attribution, or repeated events. The separate serious-event counts add context, though they remain descriptive and small in number. The primary observation period is limited to up to Day 44.

Finally, the registry record lists immunogenicity outcomes but does not include their numerical results in the registry record for this analysis. Keeping the safety comparison separate from immunogenicity and clinical outcomes avoids drawing conclusions beyond the posted endpoint. The study's sample-size planning illustrations also show how assumptions about the effect targeted and desired power influence required participants per arm, while not revealing the trial's original design rationale.

18. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record does not report the original sample-size justification or design assumptions. The planning illustrations are based on fractions of the observed effect and specified calculation assumptions, and should not be treated as the trial's own prospective design calculation. The analysis method for the sponsor's primary comparison is also not reported, limiting the ability to assess adjustments, model assumptions, or reproducibility.

The primary endpoint covers adverse events up to Day 44 after vaccination. It therefore does not describe longer-term safety. The endpoint definition is broad and does not require causal attribution, so the event percentages cannot be interpreted as the incidence of events caused by vaccination. The record does not provide detailed severity or duration information for the primary outcome.

The reported group percentages and the separate adverse-event listing contain different posted event counts: the primary recalculation uses 87 and 81, while the listing for other adverse events reports 86 and 74. The registry record does not explain the relationship between these counts. This makes it important not to treat those different listings as interchangeable. The serious adverse event terms are presented without arm-specific assignment in the information.

The registry does not report its approach to missing data, whether every vaccinated participant completed the stated follow-up, or whether additional analysis populations were used. The multiplicity strategy across the listed outcomes is not reported. The numerical results for the secondary immunogenicity outcomes are also not included in the registry record for this analysis. These omissions limit evaluation of the full analysis plan and of the study's immunogenicity findings.

Applicability is limited to the population described: healthy adults aged 65 years or older previously vaccinated with PPSV23 at least 1 year earlier. The registry record does not establish how the findings apply to other populations or vaccination histories. The posted primary endpoint does not measure prevention of pneumococcal infection or long-term clinical outcomes.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety, Tolerability, and Immunogenicity of V114 Compared to Prevnar 13™ in PPSV23-vaccinated Healthy Adults ≥65 Years of Age (V114-007) — NCT02573181.
• Registry record last updated 2019-08-14; status last verified 2019-07.
• Results first posted 2019-08-14.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

This completed randomized, double-blind, parallel-group Phase 2 study enrolled 253 healthy adults aged 65 years or older who had previously received PPSV23 at least 1 year before vaccination. Participants received one intramuscular dose of V114 or Prevnar 13™ on Day 1. The primary endpoint was the percentage of vaccinated participants with an adverse event up to Day 44.

The posted percentages were 68.5% for V114 and 64.3% for Prevnar 13™. The unadjusted recalculated comparison has a confidence interval that includes no difference, as does the sponsor's reported interval. The serious adverse event listing reports 0 events in the V114 group and 2 in the Prevnar 13™ group, with 0 deaths in each group.

The registry also lists immunogenicity outcomes, but their numerical results, the sponsor's statistical method, missing-data procedures, multiplicity approach, and original sample-size justification are not reported in the registry record. The findings therefore describe the posted short-term safety data and their uncertainty, not comparative clinical protection or outcomes beyond the recorded follow-up.