RECOVAC - Long Term Efficacy and Safety of COVID-19 (SARS-CoV-2) Vaccination in Kidney Disease Patients

The RECOVAC LESS CoV-2 Study - Long Term Efficacy and Safety of SARS-CoV-2 Vaccination in Patients in Patients With Chronic Kidney Disease Stage G4-G5, on Dialysis or After Kidney Transplantation

Rationale: COVID-19 is associated with severely increased morbidity and mortality in patients with chronic kidney disease stage G4-G5 and patients on dialysis or after kidney transplantation. Therefore, effective SARS-CoV-2 vaccination would be of great clinical importance in these patients. However, SARS-CoV-2 vaccination studies have excluded these patients so-far. Literature data indicate that vaccination may be less effective in these patient groups.

Objective: To assess the efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease stage G4-G5, patients on dialysis or after kidney transplantation during two years follow-up after vaccination.

Study design: prospective single center observational cohort study.

Study population:

• all Dutch patients on dialysis with data registered in the Dutch Dialysis registry (RENINE)
• all Dutch patients after kidney transplantation with data registered in the Dutch national kidney transplant registry (NOTR).
• All Dutch patients with chronic kidney disease stage G4-G5 registered in the Santeon hospitals.

Intervention: After SARS-CoV-2 vaccination according to standard of care, blood will be drawn for antibody response measurements at day 28 and month 6 after 2nd vaccination at by mailer-based finger-prick in 3400 hemodialysis patients, 600 peritoneal dialysis patients, 4000 patients after kidney transplantation and 4000 patients with chronic kidney disease stage G4-G5. Patients who will undergo a 3rd SARS-CoV-2 vaccination via the national vaccination program for immunocompromised patients will be asked to carry out the mailer-based finger-prick 28 days after the 3rd SARS-CoV-2 vaccination, instead of the antibody measurement 6 months after the 2nd SARS-CoV-2 vaccination.

Main study parameters/endpoints:

The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as:

- the incidence of COVID-19 after vaccination.

Secondary endpoints are

• mortality
• adverse events of specific interest according to (inter)national authorities in collaboration with LAREB
• presence of HLA-antibodies in dialysis patients on the waiting list for a first kidney transplantation
• acute rejection and graft failure in patients after kidney transplantation In a subset of patients additional secondary endpoints will be assessed
• the antibody based immune response at 28 days after completion of SARS-CoV-2 vaccination.
• the durability of antibody based immune response at 6 months compared to at 28 days after having received two subsequent SARS-CoV-2 vaccinations, in patients that have not received a 3rd SARS-CoV-2 vaccine.
• the antibody based immune response at 28 days after having received the 3rd SARS-CoV-2 vaccination.

The incidence of these endpoints will be compared, if applicable, to those:

• in the general population who are vaccinated
• in patients on dialysis or after kidney transplant who are not vaccinated Within these patient groups endpoints will be compared between recipients of different vaccines.

1. OBJECTIVES

   Primary objective:

   To assess the efficacy of SARS-CoV-2 vaccination by the incidence of COVID-19 in patients with chronic kidney disease stage G4-G5, on dialysis and patients after kidney transplantation who received SARS-CoV-2 vaccination

   Secondary Objectives:

   - To assess the safety of vaccination

   In a subgroup of participants:

   • To assess the level of antibody response at 28 days and 6 months after SARS-CoV-2 vaccination
   • To assess durability of the antibody response at 6 months after having received two subsequent SARS-CoV-2 vaccinations, in a subset of patients that have not received a 3rd SARS-CoV-2 vaccine
   • the antibody based immune response at 28 days after having received the 3rd SARS-CoV-2 vaccination.

   Exploratory Objectives:

   • The vaccination coverage rate
   • The severity of COVID-19 in case of infection
   • The influence of vaccination on health-related quality of life by patient reported outcome measures (PROMs) in patients on dialysis.
   • The SARS-CoV-2 genotype in patients with COVID-19

   In a subgroup of participants:

   • To assess the level of antibody response after vaccination between patients with COVID-19 and without COVID-19 at:

     • 28 days after the 2nd SARS-CoV-2 vaccination
     • 28 days after the 3rd SARS-CoV-2 vaccination
     • 6 months after the 2nd SARS-CoV-2 vaccination in patients who have not received a 3rd vaccine.

   • To assess change in behaviour towards measures against COVID-19 before and after vaccination

   If data are available and applicable, outcomes in vaccinated patients on dialysis or after kidney transplantation will be compared:

   • with outcomes in the general population
   • with outcomes in patients with severely impaired kidney function (CKD stages G4/5), on dialysis or with a kidney transplant who are not vaccinated.
   • according to the type of vaccination they received

2. STUDY DESIGN

   This is a prospective observational registry-based cohort study to evaluate the long-term efficacy and safety after SARS-CoV-2 vaccination on clinically important outcomes in patients with chronic kidney disease stage G4-G5, on dialysis or after kidney transplantation.

   All participants will receive vaccination against COVID-19 via the national vaccination program and according to the manufacturer's instructions. To assess the immune response after vaccination, blood samples will be collected at 28 days after the 2nd SARS-CoV-2 vaccination, 28 days after the 3rd SARS-CoV-2 vaccination, and 6 months after the 2nd SARS-CoV-2 vaccination in patients who have not received a 3rd vaccination. In total a maximum of 1 ml blood will be drawn.

   Data of the following cohorts will be analyzed in this study.

   • Patiens with chronic kidney disease stage G4-G5, data to be derived from the Santeon hospitals.
   • Patients on hemodialysis and peritoneal dialysis, data to be derived from the existing national registry RENINE
   • Kidney transplant recipients, data to be derived from the existing national registry NOTR
   • Patients on dialysis or after kidney transplantation with COVID-19 disease, data to be derived from the ERACODA database.

3. METHODS

Main study parameter/endpoint:

The primary endpoints is the incidence of COVID-19 in a two years period after SARS-CoV-2 vaccination in patients with chronic kidney disease stage G4-G5, on dialysis or after kidney transplantation.

Secondary study parameters/endpoints:

Safety in all patients:

• Incidence of mortality
• Incidence of adverse events of specific interest as defined by (inter)national authorities in collaboration with LAREB
• Incidence of a combined endpoint of acute rejection or graft failure in patients after kidney transplantation
• Incidence of HLA antibodies defined as calculated Panel Reactivity Antibodies (cPRA) > 5% in patients on the waiting list for their first kidney transplantation

Efficacy in a subgroup of patients:

• The antibody response against the SARS-CoV-2 Receptor Binding Domain at 28 days after the final SARS-CoV-2 vaccination.
• The antibody response against the SARS-CoV-2 Receptor Binding Domain at 28 days after the 3rd SARS-CoV-2 vaccination.
• The durability of antibody based immune response against SARS-CoV-2 Receptor Binding Domain at 6 months compared to 28 days after completion of SARS-CoV-2 vaccination in patients who did not receive a 3rd SARS-CoV-2 vaccination.

Exploratory study parameters:

• Vaccination coverage rates
• Disease severity in patients who develop COVID-19, assessed as
• Hospitalization
• ICU admission
• Mechanical ventilation
• Mortality
• The influence of vaccination on health-related quality of life by patient reported outcome measures (PROMs) in dialysis patients
• SARS-CoV-2 genotype in patients with COVID-19

In a subgroup of participants:

• To assess the level of SARS-CoV-2 Receptor Binding Domain antibody response after vaccination between patients with COVID-19 and without COVID-19 at:

  • 28 days after the 2nd SARS-CoV-2 vaccination
  • 28 days after the 3rd SARS-CoV-2 vaccination
  • 6 months after the 2nd SARS-CoV-2 vaccination in patients who have not received a 3rd vaccine.

• To assess change in behaviour towards measures against COVID-19 before and after vaccination

These data collected after SARS-CoV-2 vaccination in patients with chronic kidney disease stage G4-G5, on dialysis and after a kidney transplantation will (if applicable data are available) be compared:

• to those obtained in the general population
• to those obtained in patients with chronic kidney disease stage G4-G5, on dialysis or with a kidney transplant who are not vaccinated
• according to the type of vaccination received These comparisons will allow us to analyze whether SARS-CoV-2 vaccination offers efficacy to prevent COVID-19 and sufficient safety in patients with chronic kidney disease stage G4-G5, dialysis and kidney transplant patients when compared to non-vaccinated patients with chronic kidney disease stage G4-G5, dialysis and kidney transplant patients, whether the efficacy is similar as in the general population, and whether there are differences in the risk-benefit ratio between the various vaccines.

Inclusion Criteria:

1. 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 (signed informed consent form has been obtained)

4. Either

   • eGFR < 30 ml/min/1.73m2 but not on dialysis or with a kidney transplant
   • Hemodialysis, or peritoneal dialysis
   • Kidney Transplant recipient at least 6 weeks after transplantation

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).
• Patients who opted out for research in the Santeon, RENINE and NOTR registries.
• Patients who participate in the RECOVAC-IR study.
• Of note, patients will be eligible whether or not they have a history of COVID-19. Analyses will be performed in the overall population, but also shown separately for those without and with a history of COVID-19.