412.5: Outcomes of the RIVASTIM: Rapamycin randomized controlled trial of immunosuppression modification to improve vaccine responses in kidney transplant recipients.

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Introduction: Kidney transplant recipients (KTRs) have impaired immune responses to vaccination due to chronic immunosuppression, and are vulnerable to vaccine-preventable infections. Previously we found that mechanistic-target-of-rapamycin inhibitors (mToRIs) are associated with improved formation of functional T cell memory to COVID-19 vaccination in KTRs and mice. Virus-specific memory T cells can provide protection against disease in the absence of an effective antibody response, and immunosuppression modification with an mToRI is a potential strategy to improve vaccine-induced immunity in KTRs. Method: A multicenter, randomized, controlled trial (ACTRN12621001412820) was conducted between November 2021 – April 2022. KTRs receiving triple therapy with tacrolimus, mycophenolate mofetil (MMF) and prednisolone, who exhibited a sub-optimal response (anti-receptor-binding-domain IgG < 100 U/mL) following two COVID mRNA vaccine doses, were randomised to: (a) cease MMF, start rapamycin 2mg daily and reduce tacrolimus by 50% (‘Switch’); or (b) remain on existing immunosuppression (‘control’). Participants received a third dose of COVID-19 mRNA vaccine, and functional antibody and T cell responses were assessed four weeks later by live virus neutralization and IFNγ ELISpot assay, respectively. Results: Fifty-four patients were screened and all were randomized to switch (n=28) or control (n=26). Three participants from each group were withdrawn, leaving 25(89%) switch and 23(88%) control participants for outcome analyses. The proportion of KTRs who exhibited protective neutralization titers was not different between groups: Switch (10/25, 40%) versus control (9/21, 43%), p=0.85. T cell responses (IFNγ spot-forming units) increased following vaccination in both groups (p < 0.05), with no difference in the magnitude of change between groups (p = 0.89). There was no significant difference in the frequency of any adverse events between groups (switch 27% vs control 9%, p = 0.10), no significant change in estimated GFR, and no episodes of transplant rejection or proteinuria in either group over the course of the trial. Conclusion: Switching KTRs from MMF to rapamycin prior to COVID-19 booster vaccination was feasible and well-tolerated, however did not produce a beneficial effect on antibody or T cell responses. Further investigation of the potential for mToRI switch to enhance vaccine responses in KTRs is warranted.

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