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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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. Safety assessment through: - Incidence and severity of solicited AEs during 7 days after each vaccination 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

Official Title
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The Immune-response and Safety of COVID-19 Vaccination in Patients With Chronic Kidney Disease, on Dialysis, or Living With a Kidney Transplant - A Prospective, Controlled, Multicenter Cohort Study by the RECOVAC Consortium

Conditions
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Covid19, Chronic Kidney Diseases

Intervention / Treatment
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* Biological: SARS-CoV-2 vaccination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients should be eligible for COVID-19 vaccination as described by the instructions of the manufacturer. Age of 18 years or older Capable of understanding the purpose and risks of the study, fully informed and given written informed consent 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort A<br>Patients with CKD stages 4 and 5 | Biological: SARS-CoV-2 vaccination<br>* All participants will receive two vaccinations against COVID-19 according to the manufacturer's instructions.<br>|
| Cohort B<br>Patients on hemodialysis and peritoneal dialysis | Biological: SARS-CoV-2 vaccination<br>* All participants will receive two vaccinations against COVID-19 according to the manufacturer's instructions.<br>|
| Cohort C<br>Kidney Transplant Recipients | Biological: SARS-CoV-2 vaccination<br>* All participants will receive two vaccinations against COVID-19 according to the manufacturer's instructions.<br>|
| Cohort D<br>Controls | Biological: SARS-CoV-2 vaccination<br>* All participants will receive two vaccinations against COVID-19 according to the manufacturer's instructions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The antibody based immune response to vaccination against COVID-19 as compared to controls | Participants will be classified as responders or non-responders based on seroconversion with a threshold for seropositivity based on Receiver Operator Curve (ROC) analysis and set at 10 BAU/mL in individuals without measurable anti-S antibodies at baseline. | 28 days after the second vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Longevity of the antibody based immune response | Decline in antibodies and change in antibody response (defined as an antibody concentration above or below 10 BAU/mL) | 6 months after the second vaccination | 
| SARS-CoV2 specific T and B cell response | using a high throughput Interferon ɣ, IL-21 SARSCoV-2 specific T cell ELISPOT and SARS-CoV2 specific B cell memory ELISPOT | 28 days and 6 months after the second vaccination | 
| Incidence and severity of solicited adverse events | Using questionaires | during 7 days after each vaccination | 
| SARS CoV-2 spike-1 specific IgG antibody response after third COVID-19 vaccination | 5 drops of blood will be drawn by home finger-prick blood test in a subset of patients | 28 days after the third vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2 vaccination, Antibody based immune response, SARS-CoV-2 specific T and B cell response