The REnal Patients COVID-19 VACcination Immune Response (RECOVAC IR) Study

Rationale: COVID-19 is associated with severely increased morbidity and mortality in patients with severely impaired kidney function, on dialysis or alive with a kidney transplant. Therefore, effective SARS-CoV-2 vaccination would be of great clinical importance in these patients. However, SARS-CoV-2 vaccination studies have excluded patients with chronic kidney disease (CKD) so-far.

Objective: To assess the efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages 4/5, on dialysis or alive with a kidney transplant as compared to controls.

Study design: prospective, controlled multicenter study Study population: 175 patients with CKD stages 4/5 (eGFR \< 30 ml/min/1.73m2), 175 on dialysis , 300 alive with a kidney transplant and 200 controls (partners or sibblings of patients) Intervention: SARS-CoV-2 vaccination according to standard of care. Blood will be drawn at 4 different time points (baseline and at day 28, month 6 and in a subset 28 days after a third vaccination).

Main study parameters/endpoints: The primary endpoint is the antibody based immune response on day 28 after the second vaccination. Participants will be classified as responders or non-responders based on a spike (S)1 specific antibody levels of \>=10 or \<10 BAU/mL. The percentage of responders of each patient cohort will be compared with the percentage responders in the control group. Safety is a secondary endpoint which will be reported in terms of percentage of solicited local and systemic adverse events (AEs)graded according to severity. Other secondary endpoints include longevity of the immune response at 6 months, antibody respons 28 days after a third vaccination and levels of SARS-CoV-2 specific T and B cell responses.

OBJECTIVES

Primary objective:

To assess the antibody response after SARS-CoV-2 vaccination in patients with CKD stages 4/5, on dialysis or alive with a kidney transplant as compared to controls.

Secondary Objectives:

To assess in these groups of subjects after SARS-CoV 2 vaccination:

* durability of the antibody response
* the SARS-CoV-2-specific T and B cell response
* adverse events
* antibody response after third vaccination in patients on dialysis and kidney transplant recipients

Exploratory Objectives:

To assess in these groups of subjects after SARS-CoV 2 vaccination:

* the association between baseline (immune) parameters and the immune response to SARS-CoV-2 vaccination
* the neutralizing capacity of anti-COVID-19 antibodies
* the incidence of SARS-CoV-2 infection and outcome of COVID-19 disease during 6 months after SARS-CoV-2 vaccination and in a subset 28 days after third vaccination

STUDY DESIGN

This is a prospective, controlled multicenter cohort study to evaluate the efficacy and safety after SARS-CoV-2 vaccination in patients with CKD4/5, dialysis patients and kidney transplant recipients as compared to controls. Therefore, 4 cohorts will be included in this study.

* Cohort A: Patients with CKD stages 4 and 5 (eGFR \<30 ml/min\*1.73m2) (n = 175)
* Cohort B: Patients on hemodialysis and peritoneal dialysis (n = 175)
* Cohort C: Kidney Transplant Recipients (n= 300)
* Cohort D: Controls (n = 200)

Assessment of immune response:

Blood samples will be collected at baseline (i.e. prior to first vaccination) and 28 days, and 6 months after the second vaccination and in a subset 28 days after the third vaccination.

Evaluation other parameters:

To evaluate hematology parameters, liver and kidney function, additional blood samples will be collected at baseline, and 28 days and 6 months after the second vaccination.

Information on clinical course, incidence of SARS-CoV-2 infection, outcome of COVID-19 will be collected up to 6 months after second and in a subset 28 days after third vaccination for descriptive purposes.

METHODS

Main study parameter/endpoint:

The primary endpoint is the antibody based immune response to vaccination against COVID-19 on day 28 after the second vaccination as compared to controls.

Secondary study parameters/endpoints:

1. Duration and in-depth assessment of immune response through:

   * Measurement of SARS-CoV2 specific antibodies at 6 months after vaccination to test the durability of response
   * Assessment of SARS-CoV2 specific T and B cell response, 28 days, and 6 months after the second vaccination using a high throughput Interferon ɣ, IL-21 SARSCoV-2 specific T cell ELISPOT and SARS-CoV2 specific B cell memory ELISPOT.
2. Safety assessment through:

   - Incidence and severity of solicited AEs during 7 days after each vaccination
3. Antibody based immune response after third vaccination:

   * Measurement of SARS-CoV-2 specific antibodies at 28 days after third vaccination in patients on dialysis and kidney transplantation recipients.

Exploratory study parameters:

* Baseline (immune) parameters associated with vaccination response
* Neutralizing capacity of antibodies to test functionality
* In-depth flow-cytometric analyses for functional and phenotypical characterization of SARS-CoV-2 specific T cell responses will be performed followed by assessment of proliferative capacity, cytokine production and phenotypical markers in a subset of patients.
* Information on incidence of SARS-CoV-2 infection and outcome of COVID-19 disease during 6 months after second vaccination and in a subset 28 days after third vaccination will be collected.
* In a substudy in Radboudumc nasal strips will be collected and mucosal antibody response to COVID-19 analysed

Eligibility Criteria:
Inclusion Criteria:

1. All patients should be eligible for COVID-19 vaccination as described by the instructions of the manufacturer.
2. Age of 18 years or older
3. Capable of understanding the purpose and risks of the study, fully informed and given written informed consent
4. Either

   * CKD4/5, with an eGFR \<30 ml/min\*1.73m2 by CKD-EPI
   * Hemodialysis, or peritoneal dialysis
   * KT recipient at least 6 weeks after transplantation
   * Partner, sibling or family member of participating patient

Exclusion Criteria:

* History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g. anaphylaxis) to any component of the study intervention(s)
* Multi-organ transplant recipients
* Previous or active COVID-19 disease
* Pregnancy or breastfeeding
* Active (haematological) malignancy
* Inherited immune deficiency
* Infection with Human Immunodeficiency Virus (HIV)
* Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.

Additional exclusion criterion for patients with CKD stages 4/5, on dialysis and controls:

- Individuals who receive maintenance treatment with immunosuppressive therapy in the 6 months before inclusion, including cytotoxic agents or systemic corticosteroids.

Additional exclusion criterion for controls:

- severely impaired kidney function, with an eGFR \< 45 ml/min\*1.73m2 by CKD-EPI