A new SOC vaccination strategy was implemented for patients who are immunocompromised at 3 university hospitals in Germany, the University Hospital of Aachen, Cologne, and Essen. This approach targets a vaccination strategy that is guided by individual immune responses to COVID-19 vaccines [20] (Multimedia Appendix 1).

This is a multicenter, prospective, noninterventional study conducted at university hospitals in Germany that have implemented the SOC COVID-19 vaccination for patients who are immunocompromised [20]. This study aims to analyze the humoral and cellular immune response data generated within the procedures of the SOC COVID-19 vaccination [20]. Patients who are immunocompromised and will be vaccinated according to the vaccination standard [20] are eligible for study inclusion. To define immunocompromised, the classification “Stages of Immunosuppression” [21] was considered (Multimedia Appendix 2). Patients in stage 3 (eg, patients with a hemato-oncological underlying disease or patients receiving biologicals) are eligible for study inclusion. At each vaccination visit and follow-up visit, both defined in the vaccination standard, enrolled patients will undergo study-related assessment in addition to routinely performed assessments and interventions within their standard care. At the first visit, a SARS-CoV-2 antigen test will be performed. In case of a positive test result, the patient will be excluded from study enrollment. According to the vaccination standard [20], blood draws will be performed at each visit. For study purposes, additional blood samples will be drawn by using the same vein puncture at these visits (see visits and study-related assessments). These samples will be used for additional analysis of the immune response. The samples will be collected and stored until the analysis, which will be performed after the recruitment period. This guarantees that results obtained from study-related immune response assessments do not affect the standard vaccination strategy. Patients will also receive a patient diary before the first vaccination to document adverse drug reactions (ADRs) to the COVID-19 vaccine.

Peripheral blood mononuclear cells will be isolated from whole blood ethylenediaminetetraacetic acid–containing tubes using density-based separation with Ficoll. Cells will be cryopreserved for immune phenotyping by flow cytometry at the end of the study. Immune phenotyping of lymphocytes allows specific analyses of lymphocytic subsets, which are defined by a higher number and composition of surface antigens. Using a customized panel of antibodies, we will be able to detect the major subsets of B- and T-cell lymphocyte lineages. All study-related immune response measurements will be performed in batches from stored samples after last-patient-last-visit at the University Hospital of Cologne. Sample remains are disposed of after study completion.

Data for primary and secondary objectives are generated within the routine procedures of SOC COVID-19 vaccination [20]. Data for exploratory objectives will be generated from study-related assessments based on study-related blood sampling. Study-related blood sampling will be performed at the same timepoints and from the same vein puncture as for routine standard procedures (Textbox 1).

The end points are listed in Textbox 2.

Eligibility criteria and other details have been listed in Textbox 3.

Visit details are listed in Textbox 4 and Table 1. The visit schedule is displayed in Table 1.

The study sites will be monitored to ensure the quality of the data collected. The objectives of the monitoring procedures are to ensure that the subject’s safety and rights as a study participant are respected; that accurate, valid, and complete data are collected; and that the study is conducted in accordance with the study protocol, the principles of Good Clinical Practice (GCP), and local legislation. The exact extent of the monitoring procedures is described in a separate monitoring plan. Monitoring will follow a risk-adapted on-site monitoring strategy. All principal investigators (PIs) agree that the monitor regularly visits the study site and assures that the monitor will receive appropriate support in their activities at the study site, as agreed in separate contracts with each study site. The declaration of informed consent includes a statement allowing the monitor to compare the CRFs with the study subject’s medical records (doctor’s notes, laboratory printouts, etc). The PI will secure access for the monitor to all necessary documentation for study-related monitoring. A monitoring visit report is prepared for each visit describing the progress of the study and any challenges. The PI will reasonably consider the corrective and preventive measures suggested by the monitor. All participant data relating to the study will be recorded on eCRFs. The investigator is responsible for verifying that data entries are accurate and correct by electronically signing the CRF. The investigator must permit study-related monitoring, audits, Research Ethics Committee or National Competent Authority review, and regulatory agency inspections, and provide direct access to source data documents.

PIs will oversee and coordinate data collection, entry, and protection. Study-specific data will be collected by the study staff using designated source documents. Standard GCPs will be followed to ensure accurate, reliable, and consistent data collection. All study data must be verifiable to the source documentation. All source documents will be kept in a locked facility at the study site.

Data management activities will be conducted by the Clinical Trials Centre Cologne (CTCC). The IT infrastructure and data management staff will be provided by the CTCC. The study database will be developed and validated before data entry based on standard operating procedures at the CTCC. The data management system is based on commercial trial software and stores the data in a database. All changes made to the data are documented in an audit trail. The trial software has a user and role concept that can be adjusted on a trial-specific basis. The database is integrated into a general IT infrastructure and safety concept with a firewall and backup system. The data are backed up daily. After completion and cleaning of data, the database is locked and the data are exported for statistical analysis. The data will be entered online at the study sites via the internet. Plausibility checks are run during data entry, thereby detecting many discrepancies immediately. The CTCC data management will conduct further checks for completeness and plausibility and will clarify any questions with the study sites electronically via the trial software. These electronic queries have to be answered by the study site without unreasonable delay. Further details will be specified in the data management manual. A guidance document for data entry in the eCRF will be provided. All participant data relating to the study will be recorded on eCRFs unless transmitted to the sponsor or designee electronically (eg, laboratory data) via secure platform transfer or encrypted email. The investigator is responsible for verifying that data entries are accurate and correct by electronically signing the CRF.

All essential documents according to GCP of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH-GCP) chapter 8 will be archived for at least 10 years unless longer times are foreseen by local regulatory requirements. No records may be destroyed during the retention period without the written approval of the lead PI of the investigator-initiated trial. No records may be transferred to another location or party without written notification to the lead PI of the investigator-initiated trial. Digitization of paper-based documentation must meet regulatory requirements, especially concerning quality assurance, completeness, and correctness. Paper-based documentation must not be destroyed after digitization and must be archived according to applicable regulations.

Within a SOC vaccination [20], every patient will receive a varying number of COVID-19 vaccinations. Accordingly, patients will be documented within this study for varying durations depending on the number of vaccine doses needed according to the recent version of the COVID-19 vaccination standard [20] (Table 2).

The primary analysis set comprises all enrolled patients who received at least one vaccination within the COVID-19 vaccination standard [20]. The statistical analysis is essentially descriptive and focuses on estimation of the time to event, that is, primary and secondary end points. The event-time distributions are described by the Kaplan-Meier method [24] with pointwise 95% confidence bounds [25] (18, “log-log”). Relevant percentiles (eg, quartiles) with 95% CIs are derived. Generally, quantitative variables are summarized by mean, SD, and percentiles (0, 25, 50, 75, 100), and qualitative variables by absolute (ie, count) and relative (ie, percentage) frequencies. Extreme values (“outliers”) are flagged and listed.

The target sample size of 100 is sufficient to estimate event-free probabilities around the median “survival” with acceptable precision (half-width of a 95% CI) of about 10% for censoring rates less than 20% (Table 3).

The COVID-19 vaccination standard, implemented at the University Hospital of Aachen, Cologne, and Essen, poses an individual vaccination approach for each patient depending on their individual immune response. The evaluation of the data on humoral and cellular immune responses generated within this COVID-19 vaccination standard will be used to optimize vaccination schedules for patients who are immunocompromised. Results may further help to identify the optimal timing of booster vaccinations within this patient population and their subsets and will lead to increased rates of protection against severe SARS-CoV-2 infections. As the patients included in this study have varying underlying diseases (eg, multiple myeloma, Hodgkin lymphoma) and follow different treatment concepts (eg, chemotherapy, immunotherapy, hematopoietic stem cell transplantation), study results may identify risk and treatment factors on the humoral and cellular immune response in patients receiving COVID-19 vaccination.

This study design has several a priori limitations. The study focuses on COVID-19 vaccination only. Patients with SARS-CoV-2 infection are excluded when tested positive; however, studies have shown that SARS-CoV-2 infections also induce immune responses and therefore increase protection [26]. Future study results have to be interpreted cautiously due to the potential risk of bias as data are collected as part of an observational study and in the frame of a SOC COVID-19 vaccination schedule. Patients therefore are not randomized. Further, potential confounders are not included in the statistical analysis.

Patients who are immunocompromised are at high risk for severe SARS-CoV-2 infections. Data on the efficacy of COVID-19 vaccination in this group are still lacking. The study aims to determine the immunogenicity and reactogenicity of the COVID-19 vaccination standard in patients who are immunocompromised by evaluating the available data on humoral and cellular immune responses.