Replacing Mycophenolate Mofetil by Everolimus in Kidney Transplant Recipients to Increase Vaccine Immunogenicity: The PREPARE-iVAC Trial

Background: Vaccine immunogenicity is diminished in kidney transplant recipients (KTR) due to the use of immunosuppressive agents. Patients on long-term everolimus (EVR) elicit a higher immune response after vaccination compared to patients on mycophenolate mofetil (MMF). Whether short-term replacement of MMF by EVR improves vaccine immunogenicity needs yet to be established. Methods: In this multicenter, open-label randomized controlled trial, KTR were randomized 1:1 to continue MMF or replace MMF by EVR (ClinicalTrials.gov:NCT05924685). After randomization, patients received a COVID-19 vaccination (mRNA Omicron XBB.1.5) at 6 weeks and two herpes zoster (HZ) vaccinations (Recombinant Zoster Vaccine) at 10 and 14 weeks. Primary objective was to investigate whether vaccine immunogenicity was superior in the EVR group by comparing neutralizing antibody titers 28 days after COVID-19 vaccination, for which a minimum sample size of 88 patients was calculated. Secondary objectives were to evaluate antibody responses 28 days after COVID-19 and HZ vaccination and safety of replacing MMF by EVR. Results: A total of 110 KTR from 7 UMCs across the Netherlands were randomized, 55 to MMF and 55 to EVR. Neutralizing Omicron XBB.1.5 titers (PRNT50) after COVID-19 vaccination were comparable between the MMF and EVR group (log10 difference -0.07 [-0.37-0.22], p=0.62). Results were supported by SARS-CoV-2 S1-specific IgG levels (4280 (1425-14250) vs. 3870 (1018-9535) BAU/mL, p=0.38). After second HZ vaccination however, the VZV gE-specific IgG titer was higher in the EVR group (1101 (440-2078) vs. 2192 (888-4523) 50% endpoint titer, p=0.004). Next to usual side effects of EVR (edema, oral ulcers, thrombocytopenia), more bacterial infections were observed with EVR (11.1 vs. 27.3%, p=0.03), which were in general easily manageable. There were no cases of acute rejection. Conclusion: Short-term replacement of MMF by EVR does not improve COVID-19 vaccine immunogenicity but may enhance HZ vaccine immunogenicity in KTR. This discrepancy may be explained as patient have received multiple prior COVID-19 vaccinations, whereas this was a primary HZ vaccination. These data indicate that replacing MMF by EVR may be a valuable strategy to improve vaccine immunogenicity in case of novel viral threats and contribute to pandemic preparedness. Funding: Private Foundation Support, Government Support - Non-U.S.