Study of Recombinant Protein Vaccines With Adjuvant as a Primary Series and as a Booster Dose Against COVID-19 in Adults 18 Years of Age and Older: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Recombinant Protein Vaccines With Adjuvant as a Primary Series and as a Booster Dose Against COVID-19 in Adults 18 Years of Age and Older (NCT04762680), a randomized phase 2, phase 3 study. The primary outcome is Phase 2 and Phase 3 (Cohorts 1, 2 and Comparator): Number of Participants With Immediate Unsolicited Adverse Events (AEs).

2. Clinical Question

The primary endpoint addresses a narrow, short observation window after vaccination. It counts participants with an event; it does not capture all possible adverse events or establish whether an event was caused by vaccination. An adverse event was defined as an untoward medical occurrence temporally associated with study intervention, regardless of whether it was considered related.

The registry describes the study as randomized, quadruple-masked, and parallel, with Phase 2 and Phase 3 components. The listed primary comparisons include different formulations and cohorts, but the comparison populations differ in vaccination history and treatment context. Thus the clinical question is not simply whether one vaccine is better than another across a single common population. For the primary endpoint, the posted counts describe immediate events in the named groups, while the unadjusted comparisons quantify observed contrasts against the specified comparator.

3. Trial Design

The study was a randomized, quadruple-masked, parallel trial listed as Phase 2 and Phase 3. It enrolled 3159 adults and is marked completed in the registry record. Its stated start date was 2021-02-24, and its primary completion date was 2023-06-29. COVID-19 was the listed condition.

The Phase 2 primary-series arms received two injections of one of three formulations on Day 1 and Day 22. In Phase 3, previously vaccinated participants in booster cohorts received a single injection, with arms differing by vaccine formulation and prior vaccination history. The registry describes booster participants as having received an authorized mRNA or adenovirus-vector vaccine, or a SARS-CoV-2 vaccine, 4 to < 10 months earlier, depending on the cohort. A separate comparator group of previously unvaccinated, naïve participants received two injections of monovalent D614-AS03 vaccine.

The design therefore includes more than one clinical setting: primary-series vaccination in naïve participants, boosters after prior vaccination, and exploratory booster arms. The primary endpoint reports events by arm rather than pooling these settings. This preserves distinctions in the posted data, but it also means that differences between arms should be read in light of their cohort definitions and vaccination histories. The registry record does not report the original sample-size justification or the full statistical analysis plan.

The listed enrollment is 3159; the endpoint-specific denominators vary by arm. For the primary safety outcome, the registry says the safety analysis set included randomized participants who had received at least one dose. It also notes that 1 participant assigned to Phase 2 Formulation 3 received Formulation 2. The further handling of that participant in all 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.

Before assignment: 722 participants were enrolled in Phase 2 and 2647 participants (supplemental Phase 3=2617 and exploratory Phase 3=30) were enrolled in Phase 3 of the study. A total of 3159 unique participants were enrolled in the study. Participants from the Original Cohort were included in the Booster Cohorts because these assessed separate objectives. To be eligible, participants in the Booster Cohorts were required to have received a primary series, as administered in the Original Cohort.

Only the first 6 of 22 groups are shown.

Phase 2

Reasons for not completing this period:

Phase 3

Reasons for not completing this period:

Phase 3 - Exploratory

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety analysis set included participants randomized and who had received at least 1 dose of study vaccines. 1 participant from "Phase 2:CoV2 preS dTM-AS03(D614) Formulation 3" received vaccine formulation of "Phase 2:CoV2 preS dTM-AS03(D614) Formulation 2". So, number analyzed was 240(N) for "Phase 2:CoV2 preS dTM-AS03(D614) Formulation 2". Results data was not collected for 'Phase 3-Exploratory reporting groups' because study vaccine used in exploratory arms were different from booster cohort.

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 Randomized set included all participants with a randomized group allocated by interactive response technology. Participants from the Original Cohort were included in the Booster Cohorts because these assessed separate objectives. To be eligible, participants in the Booster Cohorts were required to have received a primary series, as administered in the Original Cohort.

Only the first 6 of 23 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase 2 and Phase 3 (Cohorts 1, 2 and Comparator): Number of Participants With Immediate Unsolicited Adverse Events (AEs), measured over Up to 30 minutes after each vaccination (Phase 2: Postdose on Days 1 and 22; Phase 3: Between 4 to 10 months after priming vaccine).

The primary endpoint is the number of participants with immediate unsolicited adverse events after vaccination. The observation window was up to 30 minutes after each vaccination: postdose on Days 1 and 22 in Phase 2, and between 4 to 10 months after the priming vaccine in Phase 3. The registry defines an adverse event as any untoward medical occurrence temporally associated with study intervention, whether or not it was considered related. An immediate event was recorded to capture medically relevant unsolicited systemic events in the first 30 minutes. Unsolicited events were those not listed as solicited reactions in the case report form by diagnosis and post-vaccination onset window.

This endpoint is used to describe acute events in a prespecified, brief observation period. Counting participants with an event makes the result interpretable as a frequency of affected participants in each arm. It does not measure severity, duration, or causal attribution, and it cannot describe events that occur outside the observation window. The posted primary counts are therefore a limited safety summary, not a complete account of safety over the study follow-up. Other adverse-event information is reported separately in the registry record.

7. Results Posted in the Registry

• Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 1: 0.8% (2/240) versus 1.9% (9/473) on control; risk difference -1.1 percentage points (95% CI -2.8 to 0.6), risk ratio 0.44 (0.10–2.01); unadjusted two-proportion z-test p = 0.274.
• Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 2: 0.4% (1/240) versus 1.9% (9/473) on control; risk difference -1.5 percentage points (95% CI -3.0 to -0.0), risk ratio 0.22 (0.03–1.72); unadjusted two-proportion z-test p = 0.111.
• Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 3: 0.4% (1/241) versus 1.9% (9/473) on control; risk difference -1.5 percentage points (95% CI -3.0 to -0.0), risk ratio 0.22 (0.03–1.71); unadjusted two-proportion z-test p = 0.110.
• Phase 3: Cohort 1: PBP - CoV2 preS dTM-AS03 (D614): 0.0% (0/328) versus 1.9% (9/473) on control; risk difference -1.9 percentage points (95% CI -3.1 to -0.7); unadjusted two-proportion z-test p = 0.012.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Phase 2: Percentage of Participants With Serologically-Confirmed SARS-CoV-2 Infection

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 2: 10.8% (26/240) versus 12.1% (29/240) on control; risk difference -1.2 percentage points (95% CI -6.9 to 4.4), risk ratio 0.90 (0.54–1.48); unadjusted two-proportion z-test p = 0.667.
  • Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 3: 14.1% (34/241) versus 12.1% (29/240) on control; risk difference 2.0 percentage points (95% CI -4.0 to 8.1), risk ratio 1.17 (0.74–1.85); unadjusted two-proportion z-test p = 0.511.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 2 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 3 and the control. The interval gives the range of effects that remain compatible with the data.

Phase 2 and Phase 3 (Cohorts 1, 2 and Comparator): Percentage of Participants With Laboratory-Confirmed Symptomatic COVID-19

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 1: 3.3% (8/240) versus 8.2% (39/473) on control; risk difference -4.9 percentage points (95% CI -8.3 to -1.6), risk ratio 0.40 (0.19–0.85); unadjusted two-proportion z-test p = 0.012.
  • Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 2: 1.7% (4/240) versus 8.2% (39/473) on control; risk difference -6.6 percentage points (95% CI -9.5 to -3.6), risk ratio 0.20 (0.07–0.56); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 1 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Phase 2: CoV2 preS dTM-AS03 (D614) Formulation 2 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry’s secondary outcomes broaden the study beyond immediate safety events. They include neutralizing and binding antibody measures at scheduled time points, rises in antibody levels, responder definitions, serologically confirmed infection, and laboratory-confirmed symptomatic COVID-19. The antibody outcomes address immune response, while infection outcomes describe events during follow-up. These answer different questions from the primary endpoint, which concerns unsolicited events in the first 30 minutes after vaccination.

Across the posted infection outcomes, observed percentages vary among groups and their confidence intervals differ in width. The groups also differ by phase, cohort, prior vaccination history, and follow-up duration. The Phase 2 infection outcome is followed from first dose through 387 days, while the Phase 3 Cohorts 1 and 2 symptomatic COVID-19 outcome runs through 366 days; the comparator and Phase 2 groups have a different stated timeframe for symptomatic disease. These variations limit simple comparisons across every arm.

The antibody objectives are central to the study’s stated aims, including assessment of primary-series responses and booster responses. However, antibody measurements are not interchangeable with clinical outcomes. A difference in antibody response does not by itself establish a difference in symptomatic disease, and infection percentages do not measure the immediate safety endpoint.

Unadjusted secondary comparisons carry less weight because the registry lists many outcomes, arms, time points, and response definitions. Repeated testing can produce apparently notable findings by chance, particularly when no multiplicity adjustment or analysis hierarchy is reported. The registry record does not report inferential analyses for the listed secondary comparisons. Their posted summaries are informative descriptions of observed outcomes, but they should not be treated as a single confirmatory test of efficacy or safety.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Phase 2: Geometric Mean Titers of Neutralizing Antibodies Against SARS-CoV-2 D614G Strain at Days 22, 78, 134, 202, 292, and 387
• Phase 2: Number of Participants With >=2-Fold and >=4-Fold Rise in Serum Neutralization Antibody Titers Against SARS-CoV-2 D614G Strain at Days 22, 78, 134, 202, 292, and 387
• Phase 2: Number of Responders as Determined by Neutralizing Antibody Titers Against SARS-CoV-2 D614G Strain at Days 22, 78, 134, 202, 292, and 387
• Phase 2: Geometric Mean Concentration (GMC) of Binding Antibodies Against SARS-CoV-2 D614G Strain at Days 1, 22, 36, 78, 134, 202, 292, and 387
• Phase 2: Number of Participants With >=2-Fold and >=4-Fold Rise in Binding Antibody Concentration Against SARS-CoV-2 D614G Strain at Days 22, 36, 78, 134, 202, 292, and 387
• Phase 2: Number of Responders as Determined by Binding Antibody Concentration Against SARS-CoV-2 D614G Strain at Days 22, 36, 78, 134, 202, 292, and 387
• Phase 3: Cohort 1: Geometric Mean Titers of Neutralizing Antibodies Against SARS-CoV-2 D614G Strain and B.1.351 Variant at Days 29, 91, 181, and 366
• Phase 3: Cohort 1: Number of Participants With >=2-Fold and >=4-Fold Rise in Serum Neutralization Antibody Titers Against SARS-CoV-2 D614G Strain and B.1.351 Variant at Days 15, 29, 91, 181, and 366

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is a binary event measure at the participant level: each person either had at least one immediate unsolicited adverse event in the defined window or did not. The arm counts and denominators describe how frequently that outcome was recorded. Because the primary endpoint counts participants rather than total event episodes, repeated events in one participant are not represented as multiple affected participants in this endpoint.

What does a risk difference express?

A risk difference subtracts the comparator event proportion from the event proportion in the named arm. A negative estimate means the observed proportion was lower in the named arm; a positive estimate would mean it was higher. The comparison estimates are reported as proportions, while the arm counts give the underlying observed event counts. For example, the posted Phase 2 Formulation 1 risk difference is -0.011, with a confidence interval from -0.028 to 0.006. The interval includes zero, which is the value corresponding to no difference under this scale.

This is a simple, unadjusted comparison. It does not account for possible differences in participant characteristics or other factors, and the registry record does not report an adjusted model for this endpoint. Unadjusted comparisons are useful for describing the observed data but do not necessarily isolate a causal treatment effect. This qualification is especially relevant when the groups belong to different cohorts or have different prior vaccination histories.

How should a confidence interval be read?

In general, a confidence interval describes a range of estimates compatible with the observed data under the assumptions of the method. A wider interval indicates less precision; a narrower interval indicates greater precision. If an interval for a risk difference includes zero, the data are compatible with no difference as well as with differences in either direction within the interval. If it does not include zero, that indicates a contrast inconsistent with zero under the interval method, but it does not establish clinical importance or eliminate bias, confounding, or multiplicity concerns.

For the Phase 3 comparisons, the reported estimate is -0.019 and the interval is -0.031 to -0.007. This is the same reported estimate and interval across the listed comparisons, although the unadjusted p-values differ. Such summaries should be interpreted with care, especially when event counts are zero in the named arms and the groups have different denominators. The registry does not report a detailed method for these comparisons, so the method used to obtain every interval and p-value is not reported in the registry record.

What does a p-value contribute?

In general, a p-value describes how unusual the observed data, or more extreme data, would be under a specified null model. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The listed p-values are unadjusted. That matters because many comparisons are reported: repeated testing increases the chance that some results appear statistically notable by chance. The registry record does not report a correction for multiple comparisons or a prespecified hierarchy that would indicate which comparisons should carry priority.

The comparisons for the primary outcome are not the same as a complete model of safety over time. They concern participants with immediate events in a short observation window, and the registry’s primary description specifies the safety analysis set as randomized participants who received at least one dose. The record also notes a participant who received a different Phase 2 formulation from the one assigned. The full analysis handling of this case and any missing-data procedures are not reported in the registry record.

The study also reports percentages for secondary binary outcomes and geometric summaries for antibody outcomes. For binary outcomes, proportions and confidence intervals describe event occurrence in an arm. For antibody outcomes, geometric mean titers and geometric mean concentrations summarize measurements on a scale where values may be multiplicative; a geometric mean is not the same as an arithmetic average. In general, the geometric scale can be useful for antibody measurements that vary over a wide range. The registry lists several antibody time points and response thresholds, but a full account of the statistical models and adjustments for those outcomes is not reported in the registry record.

General statistical context is important: sparse binary outcomes can produce unstable estimates because a small number of participants may account for much of the observed contrast. Zero events in an arm do not prove that the underlying event risk is zero. Conversely, a difference in observed counts does not alone establish a real difference in the population. The estimates, confidence intervals, cohort definitions, outcome window, and unadjusted nature of the comparisons should be considered together.

11. Confidence Intervals and Precision

The primary endpoint has sparse counts in several arms. The Phase 2 arms reported 2, 1, and 1 participants with an immediate unsolicited event, while the listed Phase 3 booster arms reported zero. The comparator reported 9 participants with an event. With uncommon outcomes, a small change in the number of observed events can materially change the estimated contrast. Zero observed events should not be read as proof that no event could occur in the underlying population.

The risk-difference intervals communicate uncertainty in the size and direction of the contrast. For Formulation 1, the interval is -0.028 to 0.006, crossing zero. For Formulations 2 and 3, the reported interval is -0.030 to -< 0.001, with its upper end close to zero. The Phase 3 interval is -0.031 to -0.007. These intervals describe statistical precision for the reported comparisons; they do not address whether the groups are fully comparable or whether the endpoint captures later adverse events.

Precision also differs across arms because their denominators vary. Some booster arms have smaller denominators than the comparator, and their event counts are zero. The registry does not report a separate analysis of precision by cohort or a method for borrowing information across groups. The posted estimates should therefore be read as arm-specific summaries, not as evidence that all formulations share one common event rate.

More generally, confidence intervals are not guarantees that the true value lies within the displayed range. They are calculated under statistical assumptions, and the exact method used for every comparison is not reported in the registry record. Cohort differences, outcome classification, and multiple unadjusted comparisons are additional sources of uncertainty beyond the width of an interval.

12. 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 illustrations use participants per arm for binary outcomes such as the primary endpoint. They are planning illustrations based on the observed effect, not the trial’s own design calculations. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The original trial’s sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the number of participants per arm that the illustration estimates would be needed to have an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding number for a 90% chance. These are prospective planning quantities, not observed power and not descriptions of what the completed study achieved.

Rows for smaller fractions of the observed effect require more participants per arm. This is expected in general: a smaller difference is harder to distinguish from random variation, so a larger study is needed to detect it at the same significance level and power. The illustrations also depend on the observed effect used as their starting point. When an observed effect is based on sparse event counts, it may be an uncertain basis for planning future work.

These figures should not be interpreted as evidence that a future study would necessarily obtain the displayed power or reproduce the observed effect. They are conditional calculations under the stated assumptions. The record does not report the original design rationale, any planned interim monitoring, or other protocol assumptions, so those cannot be inferred from the illustrations.

13. 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 = 0.019; treatment proportion p₁ = 0.008; average p̄ = 0.014.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.1643 = 0.3220.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.1641 = 0.1381.
4. n = (0.3220 + 0.1381)² / (-0.0107)² = 1,850.9, rounded up to 1,851 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 <- 0.0190274841437632                          # control proportion
p1 <- 0.00833333333333333                          # 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(4762680)
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 = 1,851 (80% power), 2,478 (90% power)
 75% of observed effect: n per arm = 3,609 (80% power), 4,830 (90% power)
 50% of observed effect: n per arm = 8,831 (80% power), 11,822 (90% power)
power.prop.test: 1850.9 
Simulated power at n = 1,851 per arm: 0.804 (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.

14. Multiplicity, Missing Data and Analysis Populations

The record lists a broad collection of outcomes across Phase 2 and Phase 3, several vaccine formulations, multiple cohorts, and repeated follow-up time points. The primary endpoint comparisons also include numerous contrasts with the comparator. When many hypotheses are tested, the chance of seeing at least one small p-value by chance increases. This is the general reason statistical analyses often prespecify a hierarchy of outcomes or adjust for multiple comparisons.

The p-values listed for the primary endpoint are unadjusted. A multiplicity adjustment, gatekeeping strategy, or prespecified priority among comparisons is not reported in the registry record. The secondary outcome summaries also cover multiple antibody measures and time points, but reported inferential analyses for those secondary comparisons are not listed. Consequently, individual p-values should be treated as exploratory evidence rather than as a family-wise confirmatory conclusion.

The registry identifies a safety analysis set consisting of randomized participants who received at least one dose. The primary endpoint description notes that one participant assigned to the Phase 2 Formulation 3 group received Formulation 2; the record does not fully describe how this was handled in the analysis. The exact missing-data rules, handling of participants without endpoint assessments, and definitions of any additional analysis populations are not reported in the registry record.

The record also does not report the original statistical analysis plan, model specifications for all outcomes, interim analyses, or the trial’s original sample-size rationale. These absences limit assessment of whether the posted comparisons follow prespecified procedures and whether any data-dependent decisions were made. They do not imply that such procedures were or were not used; they mean that the details are not reported in the registry record.

For these reasons, interpretation should distinguish what is directly posted—the arm counts, percentages, confidence intervals, and unadjusted comparisons—from what would require additional documentation. A registered outcome and a numerical contrast do not by themselves show that the analysis was prespecified, adjusted for multiplicity, or robust to missing data.

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: anal abscess (25.0%), cholecystitis (25.0%), motor neurone disease (11.1%), abscess (11.1%), periumbilical abscess (11.1%).

The registry also reports serious adverse event counts by group. These are distinct from the primary endpoint: the primary endpoint captures immediate unsolicited events within 30 minutes, whereas the serious adverse event summary is a separate safety report. The listed serious adverse event counts vary across groups; for example, the Phase 3 D614 primary-series group reports 8 among 328, and the comparator reports 14 among 473. The record lists 1 death in the comparator group and zero deaths in the other groups shown.

These counts should be read with their group denominators and without assuming that events were caused by the study vaccine. The registry’s definition of an adverse event allows events temporally associated with intervention whether or not they are considered related; the serious event summary does not, in the registry record reported, provide a causal assessment for each event. The number of participants with events is also not a complete account of event timing, severity, duration, or recurrence.

The record lists serious-event terms with percentages, including Anal Abscess and Cholecystitis at 25.0%, and Motor Neurone Disease, Abscess, and Periumbilical Abscess at 11.1%. The denominator for these term percentages is not reported in the registry record, so they cannot be interpreted as percentages of all trial participants. Small or varying group sizes and the descriptive nature of the reporting also argue against ranking formulations by these counts alone.

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

The primary result describes how many participants in each posted group had an immediate unsolicited adverse event during the short observation period. The observed counts were low in the Phase 2 formulation groups, zero in the listed Phase 3 booster arms, and 9 in the comparator. The unadjusted contrasts were generally in the direction of fewer recorded immediate events in the named arms than in the comparator, but a contrast in event counts is not proof of a causal safety difference.

That distinction matters because the comparator group and the booster groups came from different vaccination contexts. The comparator received a two-dose primary series as previously unvaccinated, naïve participants; booster arms had previously vaccinated participants. Differences between these groups could reflect cohort context as well as intervention. In addition, the endpoint does not cover events occurring after the first 30 minutes, and it does not include all adverse-event categories.

The confidence intervals show uncertainty around the estimated risk differences. Some intervals include zero, while the posted Phase 3 interval does not. This statistical pattern is not a complete basis for judging clinical importance, and the p-values are unadjusted among multiple comparisons. The record does not report an analysis plan or multiplicity strategy that would support treating each comparison as a definitive test.

The trial also includes antibody and infection outcomes, but those outcomes have different meanings and follow-up windows. Antibody responses describe immunogenicity; infection outcomes describe observed infections; neither changes the scope of the immediate safety endpoint. The registry summaries do not establish that any formulation prevents infection, prevents symptomatic disease, or causes or prevents adverse events.

In practical statistical terms, the posted data support descriptive statements about the recorded events and estimates. They do not support broad conclusions about all safety outcomes, rare events, long-term risk, or comparative clinical benefit. Those questions require outcomes, analyses, and context beyond the primary endpoint counts.

17. Why This Trial Matters Statistically

This trial illustrates why endpoint definition and study population matter in clinical interpretation. “Immediate unsolicited adverse events” is a specifically bounded outcome: it counts participants with medically relevant events not on the solicited-reaction list during the first 30 minutes after vaccination. It is not a general measure of all safety concerns. The distinction helps prevent a narrow short-window endpoint from being mistaken for an overall safety assessment.

The study also demonstrates the challenge of interpreting comparisons when trial arms represent different clinical contexts. Primary-series vaccination in naïve adults and booster vaccination after prior vaccination are not identical settings. Even in a randomized study, comparisons should be interpreted according to the groups actually compared and their cohort definitions. Randomization does not make different cohort histories interchangeable when the registry reports contrasts across those contexts.

Statistically, sparse event counts highlight the importance of uncertainty. A zero observed count is a sample result, not proof that the underlying risk is zero. Confidence intervals and denominators help convey how much information the event counts provide. Multiple unadjusted comparisons add another layer: a low p-value can arise in a broad set of tests even when no single comparison was designated as the main confirmatory contrast.

The trial’s outcomes also span immunogenicity, infection, and safety. Keeping these concepts separate is essential. Antibody measures can characterize immune response, while clinical infection outcomes describe disease events; immediate safety counts address a different question. A statistically careful reading avoids treating one type of evidence as a substitute for another.

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.

The primary endpoint is limited to a 30-minute post-vaccination window, so it does not capture later events. It also concerns unsolicited events rather than all solicited reactions or all safety outcomes. The registry’s event definition does not require that an event be considered related to intervention, so event counts alone do not establish causation.

Groups differ in their vaccination histories and treatment context. The primary-series comparator consists of previously unvaccinated, naïve participants, while several Phase 3 groups received a booster after prior vaccination. This makes direct interpretation of contrasts across those groups difficult. The registry also includes exploratory arms with small denominators, but the primary comparisons do not list all exploratory groups.

Several primary endpoint arms have zero or very few events. Sparse data limit precision and make comparisons sensitive to small changes in counts. Many arms and outcomes are reported, while a multiplicity adjustment and analysis hierarchy are not reported in the registry record. The posted p-values are unadjusted.

The record does not report the full statistical analysis plan, missing-data methods, original sample-size rationale, or detailed methods for each comparison. It notes one Phase 2 participant received a different formulation from the assigned formulation, but the handling of this case beyond the stated note is not reported in the registry record. The secondary outcome summaries also span different follow-up windows and populations, limiting broad cross-arm comparisons.

Finally, registry summaries do not provide all the context needed to interpret serious adverse event terms, including the denominator for the listed term percentages. These limitations call for restrained interpretation of descriptive counts and unadjusted contrasts rather than conclusions about overall safety or comparative clinical benefit.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Study of Recombinant Protein Vaccines With Adjuvant as a Primary Series and as a Booster Dose Against COVID-19 in Adults 18 Years of Age and Older — NCT04762680.
• Registry record last updated 2025-09-18; status last verified 2025-09.
• Results first posted 2025-09-18.
• 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

NCT04762680 is a completed randomized, quadruple-masked, parallel Phase 2 and Phase 3 study of recombinant protein SARS-CoV-2 vaccines with AS03 adjuvant in adults 18 years of age and older. The registry lists enrollment of 3159 and a primary completion date of 2023-06-29.

The primary outcome counts participants with immediate unsolicited adverse events after vaccination. Counts were low in the Phase 2 formulations, zero in the listed Phase 3 booster arms, and 9 in the primary-series comparator. Reported contrasts are unadjusted, and the cohorts differ in prior vaccination history.

Secondary outcomes include antibody measurements and infection endpoints. Their summaries address different questions and should not be conflated with the short-window primary safety measure. The registry record does not report the full analysis plan, multiplicity handling, or original sample-size justification.