COVID-19 Booster Vaccine in Autoimmune Disease Non-Responders: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for COVID-19 Booster Vaccine in Autoimmune Disease Non-Responders (NCT05000216), a randomized phase 2 study. The primary outcome is Percent of Stage 1 Adult Participants Who Have a Protective Antibody Response at Week 4.

2. Clinical Question

3. Trial Design

This Phase 2 trial was randomized, open-label, and parallel-group. The registry describes it as multi-site and adaptive. It lists enrollment of 258. The trial began on 2021-08-13, had a primary completion date of 2023-06-22, and is marked terminated. A reason for termination is not reported in the registry record.

The study addressed people with autoimmune disease who were receiving immunosuppressive medication and had a negative, suboptimal, or low antibody response after previous COVID-19 vaccination. Adult cohorts covered rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, and pemphigus. Pediatric cohorts covered systemic lupus erythematosus, juvenile idiopathic arthritis, pediatric-onset multiple sclerosis, and juvenile dermatomyositis.

Arms differed according to vaccine and medication strategy. Depending on the cohort, participants received an additional dose of Moderna mRNA-1273, BNT162b2, Ad26.COV2.S, an alternative mRNA vaccine, or Monovalent [B.1.351] CoV2 preS dTM-AS03. Strategies included continuing or withholding mycophenolate mofetil or mycophenolic acid, continuing or withholding methotrexate, and continuing B-cell depletion therapy. The registry lists several arms as closed under protocol versions 3.0 or 4.0. It does not describe the adaptive rules, allocation ratio, sequence-generation method, concealment process, or operational details of medication withholding; these are not reported in the registry record.

Randomization supports comparisons between assigned strategies when the planned comparison and analysis are appropriately defined. Open-label conduct means participants and study personnel were not masked to assignment. Because this trial had multiple cohorts and differing treatment options, comparisons need to be interpreted within their specific clinical and design context rather than treated as one universal vaccine or medication comparison.

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: In Stage 2, participants could be newly recruited, consent to rollover from Stage 1 of the trial (43 participants), or could consent to receive a second vaccine (Sanofi-GSK) after receipt of a mRNA vaccine in Stage 2 (19 participants).

Only the first 6 of 22 groups are shown.

Stage 1

Reasons for not completing this period:

Stage 2

Reasons for not completing this period:

Stage 2 Sanofi

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The vaccinated population includes all participants who were randomized or allocated and received study vaccine in the study.

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: Randomized or allocated to study arms for Stage 1, Stage 2 and Stage 2 Sanofi.

Only the first 6 of 23 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percent of Stage 1 Adult Participants Who Have a Protective Antibody Response at Week 4, measured over Week 4 Status Post Receipt of COVID-19 Vaccination.

The primary endpoint was the percentage of Stage 1 adult participants with a protective antibody response at Week 4 after COVID-19 vaccination. The registry defines the primary population as vaccinated participants: those randomized or allocated who received study vaccine. Antibody response was measured using the NIAID-VRC Meso Scale Discovery 3 plex assay, which assessed Wu-1 full-length spike, receptor binding domain, and N proteins.

A percentage is a binary-outcome summary: participants are classified according to whether they meet the endpoint definition, and the proportion meeting it is expressed as a percentage of the relevant analysis population. Such an endpoint can make an immune-response result easier to interpret than a continuous laboratory measurement when a meaningful threshold has been established.

In this trial, however, the registry states that no protective-response threshold was established for the assay. The intent was to use a threshold established in advance, but correlates from previous studies could not be extrapolated to the CoV-2 variants circulating over the course of the trial. Consequently, the registry describes the endpoint but does not supply a usable protective-response cutoff or a primary result. The antibody measurements and endpoint definition should not be read as evidence of clinical protection: the record does not establish that the assay result predicts protection against infection or disease in this trial.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, open-label, parallel-group Phase 2 trial. It does not report the statistical analysis plan or identify the model, test, contrast, or interval method used for the primary endpoint. The explanations below are general interpretations of the planned endpoint and design, not claims about an analysis performed in this trial.

What does a percentage endpoint represent?

Generally, a binary endpoint assigns each participant to one of two categories, such as meeting or not meeting a prespecified response criterion. The percentage is the number meeting the criterion relative to the defined analysis population. For a group comparison, the analysis might estimate a difference or another contrast between groups, but the registry record does not report which contrast was intended for the primary endpoint or how it would be estimated.

The primary population is described as participants who were randomized or allocated and received study vaccine. This definition matters because people who were randomized but did not receive vaccine are not included in the stated vaccinated population. The record does not explain how missing Week 4 measurements, protocol deviations, or participants with incomplete follow-up were to be handled. Nor does it state whether additional analysis populations were planned.

Why does the endpoint threshold matter?

Generally, a binary antibody endpoint requires a rule for deciding which assay values count as a response. That rule should be clear before interpreting a percentage, because different thresholds can classify the same underlying measurements differently. Here, the registry says that an assay threshold for protective response was not established. Although the stated intention was to use a pre-established threshold, prior-study correlates could not be extrapolated to the variants circulating during the trial. The registry therefore does not allow a reader to determine the operational classification rule for the primary endpoint or connect it to clinical protection.

The registry also distinguishes eligibility response categories using the Roche Elecsys Anti-SARS-CoV-2 S result: ≤200 U/mL for a negative or suboptimal response, and >200 U/mL and ≤2500 U/mL for a low response. These eligibility categories should not be confused with a protective threshold for the primary NIAID-VRC MSD assay. They refer to a different assay context and do not supply the missing protective-response cutoff.

What does randomization contribute?

In general, random assignment is intended to make groups comparable at baseline, on average, so that observed differences in outcomes can be interpreted as comparisons of assigned strategies. That interpretation still depends on a clearly defined comparison, adequate follow-up, appropriate analysis, and transparent reporting. This trial had multiple cohorts, medications, vaccine choices, and adult and pediatric arms. A result from one arm or cohort would not automatically answer the question for another. The registry does not report a single pooled primary contrast or detail how the adaptive design affected assignment or analysis.

Open-label means masking was none. This does not necessarily affect a laboratory measurement in the same way that it may affect a participant-reported outcome, but knowledge of assignment can influence treatment behavior, follow-up, or other processes. The record does not describe safeguards or procedures addressing such possibilities.

How should uncertainty be assessed?

Generally, a confidence interval expresses the range of effect estimates compatible with the observed data under the analysis assumptions. Its width reflects statistical precision; a broad interval indicates less precision than a narrow one. A p-value, when reported, describes the compatibility of the data with a specified null hypothesis under a statistical model. Neither quantity is listed for the primary endpoint in the registry record. Without an estimate and its uncertainty, the size and precision of any primary effect cannot be assessed.

For a binary outcome, precision depends in part on the number of participants with evaluable outcome data and on how common the event is. Those endpoint-specific denominators and response counts are not reported for the primary outcome. The enrollment figure alone cannot substitute for them, because it does not identify the number vaccinated or measured at Week 4.

What do the planning calculations mean?

Generally, a sample-size calculation asks how many participants would be needed to detect a specified effect under stated assumptions. The planning illustrations associated with this trial use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence of the trial's original design justification. The registry record does not report the protocol's sample-size justification. Planning sample sizes are hypothetical illustrations and must not be interpreted as observed power or as evidence that an effect was detected.

The record does not list primary analyses or numerical results to establish an observed effect for such planning. Therefore, the planning framework cannot fill the gap in the clinical result. The statistical analysis plan, including model choice, covariate adjustment, handling of multiplicity, missing-data methods, and any interim analyses, is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 58 outcome measures, including the primary endpoint and secondary measures of seroconversion, antibody changes and fold increases, and ACE2-binding inhibition against variant antigens. Multiple outcomes and several vaccine and medication strategies create multiple possible comparisons. In general, examining many outcomes or contrasts increases the chance that at least one result will appear noteworthy by chance if no adjustment or prespecified hierarchy is used.

The registry record does not report a multiplicity strategy, such as a hierarchy of endpoints, adjustment across tests, or a distinction between confirmatory and exploratory analyses. It also does not describe an analysis plan identifying which comparisons were primary within each cohort. The record lists no analyses, so it is not possible to determine how multiplicity was handled in practice or to interpret a family of efficacy results.

Missing-data handling is not reported in the registry record. The primary population is defined as participants who were randomized or allocated and received study vaccine, but there is no accompanying description of how missing Week 4 antibody measurements, withdrawals, or other incomplete observations were treated. The record does not state whether the analysis used observed cases, imputation, or another method. It also does not explain whether participants were analyzed according to randomized assignment when treatment received differed from assignment.

The distinction between the vaccinated population and all randomized or allocated participants is important: the listed primary population excludes people who did not receive study vaccine. The enrollment figure does not disclose how many were randomized, vaccinated, measured at the endpoint, or included in an analysis. The protocol's planned analysis populations and the actual primary-analysis denominator are not reported in the registry record. In the absence of those details and posted results, neither the extent nor the potential consequences of missing data can be assessed.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac failure acute (50.0%), acute myocardial infarction (20.0%), urinary tract infection (11.1%), covid-19 (10.0%), herpes zoster (5.0%).

The registry lists group-level adverse-event entries, including participants at risk, participants affected by serious adverse events, participants affected by other adverse events, and deaths. The counts differ across arms. For example, the Cohort C Moderna arm continuing B-cell depletion therapy lists 40 at risk for serious adverse events and 5 affected; the corresponding Pfizer-BioNTech arm lists 45 at risk and 4 affected. These are arm-specific entries, not a basis for combining groups or estimating a comparative effect.

The listed groups each report 0 deaths. The record also lists serious adverse-event terms with percentages: Cardiac failure acute, 50.0%; Acute myocardial infarction, 20.0%; Urinary tract infection, 11.1%; COVID-19, 10.0%; Herpes zoster, 5.0%; and Cardiomyopathy alcoholic, 2.5%. The denominator and calculation basis for these term percentages are not reported in the registry record. They should not be interpreted as risks for all trial participants or as comparisons between treatment arms.

These descriptive entries do not establish that an intervention caused an event. The record does not provide a comparative safety analysis, uncertainty intervals, or an explanation of event attribution. Differences in the number of participants at risk across arms also limit simple visual comparisons.

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

The trial's central statistical question was whether additional COVID-19 vaccination strategies, used with different immunosuppressive-medication approaches, were associated with antibody outcomes in people with autoimmune disease who had limited responses to prior vaccination. The design was randomized and parallel-group, but the record describes many cohorts and treatment combinations rather than one uniform comparison.

The registry does not report a primary-outcome analysis. Thus it gives no primary estimate of the percentage of Stage 1 adults with a protective antibody response at Week 4, and no interval or test result with which to assess precision or evidence against a null hypothesis. The absence of a posted analysis is not evidence that the strategies were equivalent, nor does it establish benefit or lack of benefit.

The primary endpoint has a further interpretive limitation: the registry says that a protective antibody threshold was not established for the assay. Although antibody response was measured with the NIAID-VRC MSD 3 plex assay, a measured laboratory response cannot be equated with clinical protection based on this record. The registry explains that correlates from previous studies could not be extrapolated to the variants circulating during the trial.

The enrollment figure of 258 describes the trial record but does not establish the endpoint denominator or completeness of follow-up. The record does not report how many participants were vaccinated, had Week 4 measurements, or entered an analysis. It also does not describe how missing measurements or multiple comparisons were handled. Those omissions make it impossible to judge the precision, robustness, or scope of any primary treatment comparison.

The adverse-event entries are descriptive and arm-specific. They should not be treated as causal comparisons or as proof that a particular vaccine or medication strategy is safer. Overall, the record supports understanding what the investigators set out to compare and how the antibody endpoint was framed; it does not provide the primary outcome evidence needed to draw a treatment-effect conclusion.

13. Why This Trial Matters Statistically

This trial raises a recurring problem in clinical immunology: a laboratory measurement may be available while a clinically interpretable threshold is not. A percentage endpoint can be straightforward to summarize once participants can be classified consistently as responders or nonresponders. Here, the registry states that a protective-response threshold for the NIAID-VRC MSD assay was not established. That makes the endpoint's interpretation uncertain before statistical precision is even considered.

The design also illustrates why a randomized trial with several cohorts cannot be reduced to a single broad comparison without careful specification. Vaccine choice, prior vaccine, age group, and immunosuppressive treatment varied across arms. Each comparison answers a narrower question, and a result in one cohort would not automatically generalize to another. The registry does not identify a single pooled primary contrast.

For biostatistical interpretation, the distinction between a planned endpoint and a reported analysis is essential. The record gives an endpoint definition and lists many outcomes, but no primary analysis is listed. Without outcome counts, an effect estimate, and its uncertainty, readers cannot assess magnitude or precision. Enrollment alone does not resolve this: the relevant denominator is the number in the endpoint analysis population with usable measurements.

The record also underscores the need to document multiplicity and missing-data procedures when many outcomes and comparisons are possible. Those methods are not reported in the registry record. Finally, the termination status is a relevant context, but it does not explain whether or how trial completion affected analyses. The reason is not reported. These issues make transparent endpoint definitions, analysis populations, and reporting of estimates with uncertainty central to understanding this study.

14. Limitations

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

The main limitation for interpreting the primary endpoint is that the registry says no protective-response threshold was established for the NIAID-VRC MSD assay. It describes an intention to use a pre-established threshold but says correlates from prior studies could not be extrapolated to the variants circulating over the trial period. The endpoint therefore lacks a reported operational definition of protection.

No primary analysis is listed, and primary outcome results are not reported in the registry record. There are no posted response percentages, group contrasts, confidence intervals, or tests to assess. The record's enrollment figure does not reveal the number of participants randomized, vaccinated, measured at Week 4, or included in an analysis.

The design spans adult and pediatric populations and several disease and medication cohorts, with multiple vaccine options and some arms closed under later protocol versions. That breadth makes the exact target comparison important. The adaptive-design rules, allocation details, protocol's sample-size justification, and reason for termination are not reported in the registry record. Neither are the statistical analysis plan, multiplicity procedures, interim analyses, or missing-data methods.

The stated primary population includes participants randomized or allocated and receiving study vaccine; the record does not explain how other analysis populations or deviations from assignment were addressed. Safety entries are descriptive, and their term-percentage denominators are not reported. These limitations prevent assessment of the strength, precision, and generalizability of treatment comparisons from the registry information alone.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: COVID-19 Booster Vaccine in Autoimmune Disease Non-Responders — NCT05000216.
• Registry record last updated 2026-06-10; status last verified 2026-05.
• Results first posted 2025-08-22.
• 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

NCT05000216, titled COVID-19 Booster Vaccine in Autoimmune Disease Non-Responders, is a Phase 2 randomized, open-label, parallel-group trial sponsored by the National Institute of Allergy and Infectious Diseases. The registry describes it as multi-site and adaptive, lists enrollment of 258, and marks the study terminated. The listed start date is 2021-08-13 and primary completion date is 2023-06-22.

The trial studied additional COVID-19 vaccine doses and immunosuppressive-medication strategies in adults and pediatric participants with autoimmune disease and a limited antibody response to previous vaccination. The primary endpoint was the percentage of Stage 1 adults with a protective antibody response at Week 4. The record states that no protective-response threshold was established for the assay. It lists 58 outcome measures but no analyses. Primary outcome results and the reason for termination are not reported in the registry record.