Optimal Booster Strategy for SARS-CoV-2 Vaccination in Kidney Transplant patients

INTERVENTION: Trade Name: Spikevax Pharmaceutical Form: Solution for injection INN or Proposed INN: INN‐COVID‐19 mRNA Vaccine Other descriptive name: COVID‐19 mRNA vaccine Moderna (CX‐024414) Concentration unit: mg/g milligram(s)/gram Concentration type: equal Concentration number: 0.10‐ Trade Name: Spikevax Pharmaceutical Form: Solution for injection INN or Proposed INN: INN‐COVID‐19 mRNA Vaccine Other descriptive name: COVID‐19 mRNA vaccine Moderna (CX‐024414) Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 0.10‐ Trade Name: COVID‐19 Vaccine Janssen Pharmaceutical Form: Solution for injection INN or Proposed INN: Ad26.COV2‐S recombinant Other descriptive name: COVID‐19 Vaccine Janssen (Ad26.COV2.S) Concentration unit: Infectious unit Concentration type: equal Concentration number: 831763771‐ CONDITION: COVID‐19 is associated with severely increased morbidity and mortality in kidney transplant patients. Available data show that the immune response after a standard regimen of two mRNA vaccinations is severely attenuated in kidney transplant patients compared to controls, especially when their immunosuppressive regimen contains mycophenolate mofetil (MMF) / mycophenolic acid (MPA). ; MedDRA version: 23.1 Level: LLT Classification code 10084401 Term: COVID‐19 respiratory infection System Organ Class: 100000004862 ; MedDRA version: 23.1 Level: LLT Classification code 10084464 Term: COVID‐19 immunization System Organ Class: 100000004865 ; MedDRA version: 23.1 Level: LLT Classification code 10084465 Term: COVID‐19 vaccination System Organ Class: 100000004865 ; MedDRA version: 23.1 Level: LLT Classification code 10084508 Term: COVID‐19 antibody test System Organ Class: 10022891 ‐ Investigations ; MedDRA version: 20.0 Level: PT Classification code 10023439 Term: Kidney transplant rejection System Organ Class: 10021428 ‐ Immune system disorders ; MedDRA version: 20.0 Level: LLT Classification code 10023438 Term: Kidney transplant System Organ Class: 100000004865 ; MedDRA version: 23.0 Level: LLT Classification code 10084270 Term: SARS‐CoV‐2 acute respiratory disease System Organ Class: 100000004862 ; MedDRA version: 23.0 Level: LLT Classification code 10084272 Term: SARS‐CoV‐2 infection System Organ Class: 100000004862 ; MedDRA version: 23.0 Level: LLT Classification code 10084462 Term: SARS‐CoV‐2 vaccination System Organ Class: 100000004865 ; MedDRA version: 23.0 Level: LLT Classification code 10084463 Term: SARS‐CoV‐2 immunisation System Organ Class: 100000004865 ; MedDRA version: 23.0 Level: LLT Classification code 10084466 Term: SARS‐CoV‐2 immunization System Organ Class: 100000004865 ; MedDRA version: 23.1 Level: PT Classification code 10084501 Term: SARS‐CoV‐2 antibody test System Organ Class: 10022891 ‐ Investigations Therapeutic area: Diseases [C] ‐ Respiratory Tract Diseases [C08] PRIMARY OUTCOME: Main Objective: To assess the immunogenicity (expressed as percentage of responders) of various COVID‐19 booster vaccination strategies in kidney transplant patients that failed to mount a sufficient antibody response after two primary doses of the mRNA‐1273 vaccine. Primary end point(s): The primary endpoint is the percentage of subjects with a serum anti‐S1 IgG concentration =10 BAU/mL at 28 days after the third vaccine administration. Secondary Objective: ‐ To measure the concentration of SARS‐CoV‐2 spike S1‐specific IgG antibodies in serum at 28 days after the 3rd vaccine administration; ‐ To assess the durability of the SARS‐CoV‐2 spike S1‐specific IgG antibody response at 6 and 12 months after the 3rd vaccine administration; ‐ To measure the presence and titer of neutralizing anti‐SARS‐CoV‐2 antibodies after booster vaccination; ‐ To evaluate SARS‐CoV‐2 specific T cell responses; ‐ To measure anti‐S1 antibody (IgG and IgA) responses and neutralizing capacity of these antibodies in nasal mucosal fluid; ‐ To evaluate vaccine safety in terms of incidence of solicited local and systemic adverse events (AEs) graded according to severity, including the incidence of acute rejections within 6 months after the third vaccination . Timepoint(s) of evaluation of this end point: 28 days after the third (and possibly a fourth) vaccination SECONDARY OUTCOME: Secondary end point(s): o SARS‐CoV‐2 specific antibody concentrations in serum at 28 days after the 3rd vaccine administration; o SARS‐CoV‐2 specific antibody concentrations in serum at 6 and 12 months after the 3rd vaccine administration; o The titer of neutralizing anti‐SARS‐CoV‐2 antibodies at 28 days after the 3rd vaccine administration; o SARS‐CoV‐2 specific antibody concentrations in nasal mucosal fluid at 28 days and 6 months after the 3rd vaccine administration; o SARS‐CoV‐2 specific T cell responses at 28 days after the third vaccine administration by:; ? Measuring interferon‐gamma concentration in whole blood after ex vivo stimulation with SARS‐CoV‐2 specific peptides; ? Measuring ex vivo production of T cell related cytokines by peripheral blood mononuclear cells (PBMC) in ELISpot assays; o Incidence of acute rejection within 6 months after the third vaccine administration; o Safety in terms of incidence of solicited local and systemic adverse events (AEs) within one week after vaccine administration graded according to severity. The following items will be specifically addressed:; ? Percentage of participants reporting local reactions (pain at the injection site, redness and swelling) within 7 days after vaccine administration; ? Percentage of participants reporting systemic events (fever, fatigue, headache, chills, vomiting, diarrhea, new of worsened muscle pain, and new or worsened joint pain) within 7 days after vaccine administration; ? Percentage of participants with serious adverse events within 6 months after the third vaccine administration Timepoint(s) of evaluation of this end point: 6 and 12 months after the third vaccination INCLUSION CRITERIA: 1. Age 18 years or older 2. Received 2 doses of mRNA‐1273 according to the recommended vaccination schedule, with the last administration within the last nine months 3. Insufficient response to vaccination, defined as anti‐spike IgG in serum < 10 BAU/mL measured between 25 and 56 days after the second dose of the mRNA‐1273 vaccine with a validated test 4. Eligible for COVID‐19 vaccination as described by the instructions of the manufacturers of the vaccine (Moderna and Janssen) 5. Capable of understanding the purpose and risks of the study, fully informed and given written informed consent (signed informed consent form has been obtained) 6. Willing to adhere to the protocol and be available during the study period Additional inclusion criteria to be eligible for stratum A: 7. Maintenance immunosuppressive therapy consisting of a calcineurin inhibitor (tacrolimus or cyclosporine), MMF/MPA, and prednisone 8. In case of tacrolimus treatm