Replacing Mycophenolate Mofetil by Everolimus in Kidney Transplant Recipients to Increase Vaccine Immunogenicity: Results of a Randomized Controlled Trial

BACKGROUND: Vaccine immunogenicity is reduced in kidney transplant recipients (KTRs), especially in those using mycophenolate mofetil (MMF). Whether replacement of MMF by everolimus improves vaccine immunogenicity is unknown.

METHODS: KTRs were randomized 1:1 to continue MMF or switch to everolimus. Participants received one coronavirus disease 2019 (COVID-19) booster vaccination and two herpes zoster (HZ) vaccinations at 6, 10 and 14 weeks postrandomization. Primary outcome was the neutralizing antibody response 28 days after COVID-19 vaccination. Secondary outcomes included antibody and T-cell responses 28 days after COVID-19 and HZ vaccination, and safety.

RESULTS: In 110 KTRs, COVID-19 vaccination resulted in comparable Omicron XBB.1.5 neutralizing antibody titers in the everolimus versus MMF group (308 [74.4-1314] vs 327 [115-897]; P = .83), whereas severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Spike-specific T-cell responses were slightly lower with everolimus (118 [32.1-243] vs 228 [113-381] spot-forming cells [SFCs]/106 peripheral blood mononuclear cells [PBMCs]; P = .02). HZ vaccination led to higher varicella zoster virus (VZV) glycoprotein E (gE)-specific immunoglobulin G titers with everolimus (2192 [888-4523] vs 1101 [440-2078] 50% endpoint titer; P = .004), while VZV gE-specific T-cell responses were similar (85.0 [27.5-155] vs 115 [50.0-258] SFCs/106 PBMCs; P = .24). Besides known side effects, everolimus led to more bacterial infections (27.3% vs 11.1%; P = .03).

CONCLUSIONS: Six weeks' replacement of MMF by everolimus in KTRs does not improve COVID-19 booster vaccine immunogenicity, whereas 10 weeks' replacement enhances humoral HZ vaccine immunogenicity. While replacing MMF by everolimus may improve vaccine responses, its timing and potential risks require careful consideration.