A Study to Evaluate the Safety, Reactogenicity and Immunogenicity of Vaccine CVnCoV in Healthy Adults for COVID-19: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety, Reactogenicity and Immunogenicity of Vaccine CVnCoV in Healthy Adults for COVID-19 (NCT04449276), a randomized phase 1 study. The primary outcome is Number of Participants With Grade 3 Adverse Reactions or Any Serious Adverse Event (SAE) Considered Related to Trial Vaccine Within at Least 24 Hours After the First Vaccination.

2. Clinical Question

This is a safety and reactogenicity question, not a test of protection against COVID-19. The registry also lists immunogenicity outcomes, including seroconversion and geometric mean antibody titers for SARS-CoV-2 spike protein, receptor-binding domain and neutralizing antibodies. Those are secondary outcomes and address antibody responses rather than the primary safety endpoint.

The study was conducted in healthy adults and used multiple dose levels in a sequential dose-escalation design. In the arm descriptions, safety data were to inform whether enrollment continued at the current dose level or proceeded to dose escalation. That design addresses early evaluation across dose levels; it does not, by itself, establish that all dose groups form a single direct randomized comparison.

The clinical question should therefore be read narrowly: the primary endpoint concerns a defined short-term safety outcome after the first dose, while the registry’s additional outcomes cover other safety and immune-response measures. The record does not report a separate primary-endpoint estimate or an inferential comparison for this question.

3. Trial Design

This was a Phase 1, randomized, single-masked, sequential, partially blind, placebo-controlled, first-in-human clinical trial sponsored by CureVac. Its official title describes evaluation of safety, reactogenicity and immunogenicity after 1 and 2 doses of CVnCoV administered intramuscularly to healthy adults. The registry lists the trial status as completed, an enrollment of 280, a start date of 2020-06-18 and a primary completion date of 2021-12-21.

The active intervention was CVnCoV, with placebo as the comparator. The arm descriptions specify administrations on Day 1 and Day 29. Dose escalation was sequential: the record says safety data would inform whether enrollment continued at a current dose level or moved to a higher one. It names 2, 4 and 8 μg as initial dose levels. The remaining dose-level description is incomplete in the registry record, although the safety summaries list CVnCoV groups labeled 2 µg, 4 µg, 6 µg, 8 µg, 12 µg, 16 µg and 20 µg.

Sequential dose escalation differs from a design in which every dose group is necessarily enrolled at the same time under one fixed allocation scheme. The record establishes randomization but does not report the randomization procedure, allocation ratio, cohort enrollment schedule, or whether randomization operated within each dose cohort. Those details are not reported in the registry record, so the design label alone cannot establish the basis for every comparison between dose groups and placebo.

The primary endpoint is a count of participants with Grade 3 adverse reactions or a related serious adverse event in the short period after the first vaccination. The listed secondary outcomes concern antibody seroconversion and geometric mean titers. Although the registry lists 21 outcome measures, it lists 0 analyses. Thus, the design and intended outcomes are described, but inferential results and detailed analysis methods are not reported in the registry record.

4. Participant Flow and Accounting

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

Before assignment: Of the 408 participants who were screened, 280 participants were enrolled.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Only participants with available data were used for this analysis.

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.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Grade 3 Adverse Reactions or Any Serious Adverse Event (SAE) Considered Related to Trial Vaccine Within at Least 24 Hours After the First Vaccination, measured over Up to 24 hours after vaccination on Day 1.

The primary endpoint counts participants with a Grade 3 adverse reaction or any serious adverse event considered related to trial vaccine. Its title specifies the period as within at least 24 hours after the first vaccination, while the stated timeframe is up to 24 hours after vaccination on Day 1. The registry’s wording is reproduced in substance; it does not give a separate estimate for this composite endpoint in the posted results.

Grade 3 is described as the highest grading on the FDA toxicity scale, with a higher grade indicating a worse outcome. The serious adverse event definition includes an untoward medical occurrence at any dose that resulted in death, was life-threatening, required inpatient hospitalization or prolonged an existing hospitalization, resulted in persistent disability or incapacity, was a congenital anomaly or birth defect in a participant’s offspring, or was an important medical event.

Counting participants is a direct way to summarize how many people meet a safety endpoint, but a count alone does not convey the full clinical course, severity details within the category, or the precision of a comparison. The endpoint also combines Grade 3 reactions with serious adverse events considered related to trial vaccine. Those components are not separately reported as primary-endpoint results, so the composite cannot be reconstructed from the available summary.

As a general statistical point, a short-term safety endpoint can describe events in the period specified, but it cannot stand in for all possible safety outcomes or longer follow-up. The primary endpoint is limited to the stated period after the first vaccination; other safety outcomes and timeframes require their own reported results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a randomized, single-masked, sequential, partially blind, placebo-controlled Phase 1 trial. These labels describe broad design features, but the record does not provide enough detail to reconstruct the allocation process or the statistical analysis plan. The primary outcome is a participant count for a binary event definition: a participant either meets the endpoint definition or does not. The posted safety summaries also display counts and numbers at risk by group.

What does a count of participants describe?

A count is the number of participants recorded as having an outcome. Its interpretation depends on the outcome definition, observation period and analysis population. A count without its denominator cannot indicate how common the outcome was within a group. Here, the serious adverse event summaries include both the number affected and the number at risk, which allows the count to be read in the context of the group represented. The registry states that only participants with available data were used for the primary endpoint analysis, but it does not give the exact analysis population by group.

The primary endpoint is a composite: it counts participants with a Grade 3 adverse reaction or a serious adverse event considered related to trial vaccine. Composite endpoints can bring multiple clinically distinct events together under one outcome definition. That may provide a single summary for a defined safety question, but it can conceal differences between the components. In this record, separate primary-endpoint counts for Grade 3 reactions and related serious events are not reported in the registry record. Nor are the listed serious-event counts identified as the composite result.

Why does the event timeframe matter?

An event count is meaningful only in relation to the period during which outcomes were assessed. The primary endpoint title refers to events within at least 24 hours after the first vaccination, and the timeframe states up to 24 hours after vaccination on Day 1. The primary question is therefore time-bounded. It should not be read as a count of all safety events over the entire trial. The registry record does not provide a separate primary analysis result or further clarification of the difference in wording.

As a general statistical principle, counts collected over different follow-up periods are not directly comparable without accounting for how long participants were observed and how events were defined. A brief observation window can describe events in that window, but does not summarize the whole safety profile. Other adverse-event summaries may have different periods or definitions; those details are not reported in the registry record for the figures.

How should uncertainty be understood?

A point count is an observed summary, not a measure of precision. A confidence interval, when reported, gives a range of values compatible with the data under the method used, and its width communicates uncertainty. The registry does not report confidence intervals or other uncertainty estimates for the primary endpoint or the listed safety counts. General statistical caution is especially relevant for sparse outcomes: when event counts are small, estimates can be imprecise, and a difference in observed counts does not by itself establish a real difference between groups.

The record reports randomized allocation, but also describes sequential dose escalation. Randomization can support comparisons when groups are formed and analyzed according to the randomized design. It does not make every comparison among sequentially enrolled dose cohorts automatically equivalent to a direct randomized contrast. Allocation details, cohort timing, and a prespecified comparison strategy are not reported in the registry record. Therefore, the group summaries are best treated as descriptive unless a supported analysis specifies otherwise.

What can the planning illustrations establish?

Any sample-size illustrations associated with the posted results are planning exercises, not observed power. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect defined as a stated fraction of the observed effect. Such calculations illustrate how a future study’s required sample size could vary with the target effect and design assumptions. They do not show the probability that this completed trial detected an effect, and they do not establish that the original study was designed using those assumptions.

The record does not report a sample-size justification for the trial, the target effect used in the original design, or a power calculation from the sponsor. It also does not report the statistical model or any planned interim analysis. The planning assumptions should therefore be kept distinct from the trial’s own protocol and from the observed safety counts.

How do the other outcomes fit?

The registry lists secondary outcomes for seroconversion and geometric mean titers of spike protein antibodies, receptor-binding domain antibodies and neutralizing antibodies. These outcomes measure antibody responses, not the primary safety composite. The record lists 21 outcome measures and 0 analyses, so the presence of outcome definitions does not imply that results or statistical tests are available. Multiplicity adjustment, missing-data procedures beyond the stated available-data population, and detailed analysis populations are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 21 outcome measures, including the primary safety endpoint and secondary measures of seroconversion and geometric mean antibody titers. It lists 0 analyses. The endpoint list alone does not show which outcomes were analyzed, how many comparisons were planned, or which results were designated as confirmatory. The registry record does not report a multiplicity strategy, such as an adjustment for testing several outcomes or contrasts, and no inferential results are listed from which to assess how multiplicity was handled.

Multiplicity matters because repeated statistical testing can increase the chance of finding an apparently unusual result even when there is no underlying effect. As a general principle, interpretation depends on whether outcomes and comparisons were prespecified and whether the analysis accounted for the number of tests. Those details are not reported in the registry record. Without them, the secondary outcome list should be treated as a record of measured or planned outcomes, not evidence of statistically established differences.

For the primary endpoint, the registry says that only participants with available data were used. It does not specify how many participants had missing endpoint data, why any data were unavailable, how missing observations were handled, or whether the analysis population differed across groups. It also does not report a detailed definition of the analysis population for the secondary outcomes. These omissions limit assessment of possible bias from missing data or differences in who contributed to each analysis.

Randomization and masking are reported design features, but the method of allocation, the extent of masking by group, and procedures for maintaining the analysis population are not described in detail. The record’s sequential dose-escalation design also makes it important to know which comparisons were prespecified and how cohorts were handled statistically; those methods are not reported. No missing-data sensitivity analysis or interim-analysis plan is reported in the registry record.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: peroneal nerve palsy (3.6%), seizure (3.6%), abdominal pain (3.1%), crohn's disease (2.1%), retinal detachment (2.1%).

The serious adverse event summaries list affected participants and participants at risk separately for each group. The reported counts are 2 among 47 at risk for CVnCoV 2 µg; 0 among 48 for 4 µg; 1 among 48 for 6 µg; 1 among 49 for 8 µg; 2 among 28 for 12 µg; 0 among 16 for 16 µg; 0 among 12 for 20 µg; and 1 among 32 for placebo. The record also lists zero deaths in each group.

These are descriptive serious-event summaries, not the primary endpoint result. The primary endpoint combines Grade 3 adverse reactions with serious adverse events considered related to trial vaccine, within the specified period after the first vaccination. The serious-event figures do not identify whether events were considered related, whether they occurred in that period, or whether participants also met the Grade 3 component of the endpoint. The composite count is not reported in the registry record.

A zero count means no event was recorded in the listed group for that summary; it does not establish absence of risk. Conversely, a nonzero count alone does not show causation or a difference between groups. As a general statistical principle, rare events are difficult to compare precisely when groups are small. No confidence intervals or formal comparisons for these safety figures are reported in the registry record.

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

The registry record gives useful context about an early-phase, sequential dose-escalation study: the population was healthy adults, CVnCoV was evaluated at multiple dose levels, placebo was included, and safety data informed decisions about dose escalation. It also specifies a short-term primary safety endpoint and lists serious adverse event counts by group. Those features describe what was studied and the type of safety information recorded.

The record does not report a result for the primary composite endpoint. In particular, it does not give a count of participants with Grade 3 adverse reactions or related serious adverse events within the stated timeframe, nor does it provide a comparative estimate, confidence interval or p-value. The separately listed serious adverse event counts cannot fill that gap because their relationship to the composite definition and its timing is not stated. The record’s available-data note also leaves the size and composition of the endpoint analysis population unclear.

The descriptive safety counts should not be read as proof that one dose is safer or less safe than another, or that CVnCoV differs from placebo. The study used sequential dose escalation, and the registry does not report a statistical comparison strategy for the groups. No formal dose-response analysis is reported. The antibody outcomes listed as secondary endpoints likewise cannot establish an immune response difference in the absence of posted analyses.

As a general statistical point, estimates from early-phase studies can be imprecise, particularly for uncommon safety outcomes. Counts alone do not quantify uncertainty, and the absence of a reported event in a group does not establish that the event is impossible. The conclusions that can be drawn are therefore limited to the registered design, endpoint definitions and descriptive counts. Treatment benefit, prevention of COVID-19, and comparative safety conclusions are not established by the registry information.

13. Why This Trial Matters Statistically

This trial is statistically notable for combining a placebo-controlled structure with sequential dose escalation. The design uses safety information to guide whether enrollment continues at a dose level or moves to escalation. That is a different inferential setting from a fixed, parallel comparison in which all dose groups are necessarily enrolled under the same schedule. The design labels establish that randomization was used, but details needed to interpret particular dose-level contrasts are not reported in the registry record.

The distinction between the primary composite endpoint and the broader safety summaries is important. The primary outcome is defined around Grade 3 adverse reactions or serious adverse events considered related to trial vaccine within a short period after the first vaccination. The safety summaries separately list serious events and other adverse events. Treating those summaries as if they were the primary composite result would conflate different definitions and potentially different timeframes.

The registry also illustrates why outcome registration and analysis reporting are not the same. It lists a primary endpoint and multiple antibody outcomes, but lists 0 analyses. Without estimates, uncertainty intervals, statistical tests, or a reported analysis plan, readers cannot evaluate the precision or inferential strength of the outcomes. The available counts can still be read descriptively, provided their denominators and limitations remain visible.

Finally, the record is a reminder that planning calculations and observed results answer different questions. A sample-size illustration based on specified assumptions is not evidence of the power achieved by the completed trial. Clear separation of design intent, descriptive safety summaries, and prespecified inferential analyses is essential when interpreting early-phase clinical research.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record leaves important details needed for a full statistical appraisal unreported. It does not provide the primary composite endpoint count or an inferential analysis, despite describing the endpoint and stating that only participants with available data were used. It also does not report endpoint-specific denominators by group, missing-data counts, reasons for unavailable data, or sensitivity analyses. The exact analysis population is therefore unclear beyond the available-data statement.

The primary endpoint wording and timeframe are not fully aligned: the title refers to events within at least 24 hours after the first vaccination, while the timeframe says up to 24 hours after vaccination on Day 1. The record does not clarify the wording. The listed serious adverse event summaries do not state whether events were considered related to vaccine or occurred within the primary endpoint period, so they cannot be interpreted as the composite result.

The trial is described as randomized, single-masked, partially blind and sequential, but the randomization method, allocation ratio, masking procedures and cohort schedule are not reported in detail. The arm description’s dose-level text is incomplete. The registry lists multiple dose groups, but it does not report which between-group comparisons were prespecified or how sequential enrollment was addressed in analysis.

There are no reported confidence intervals, p-values, statistical models, multiplicity procedures or detailed analysis populations. The record lists 21 outcome measures but 0 analyses. Consequently, it is not possible to assess statistical precision, adjustment for multiple comparisons, or whether the analyses followed a prespecified plan. These limitations concern what can be concluded from the registry record and do not establish that such details were absent from other study documentation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety, Reactogenicity and Immunogenicity of Vaccine CVnCoV in Healthy Adults for COVID-19 — NCT04449276.
• Registry record last updated 2023-01-30; status last verified 2022-04.
• Results first posted 2023-01-30.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry describes NCT04449276, a completed, randomized, single-masked, partially blind, sequential, placebo-controlled Phase 1 trial sponsored by CureVac. It evaluated CVnCoV in healthy adults using a dose-escalation design. The registry lists an enrollment of 280, a start date of 2020-06-18 and a primary completion date of 2021-12-21.

The primary endpoint counts participants with Grade 3 adverse reactions or related serious adverse events in the stated short-term period after the first vaccination. Serious adverse event counts and numbers at risk are listed by dose group and for placebo, but the primary composite result and inferential comparisons are not reported. Secondary outcomes include antibody seroconversion and geometric mean titers. The record lists 21 outcome measures and 0 analyses, and does not report detailed missing-data, multiplicity or statistical-model methods.