ABSTRACT
Purpose: Kidney transplant recipients (KTR) have inadequate responses to 2-dose COVID vaccination schedules and are at increased risk of severe COVID-19. Formation of T cell memory following vaccination is regulated by mTOR complex 1. mTOR inhibitors have been used in pre-clinical models to boost vaccine-elicited cytotoxic T cell memory responses. In observational studies, KTR receiving mTOR inhibitors had improved serological neutralisation and SARS-CoV-2 reactive T cell responses to 2 doses of COVID-19 vaccine, including cytotoxic T cells and circulating T follicular helper cells. We performed a clinical trial in stable KTR using sirolimus as a substitute for mycophenolate prior to a 3rd dose of COVID-19 vaccine to enhance COVID-19 vaccine responses. Method(s): KTR receiving tacrolimus, mycophenylate and corticosteroid with inadequate response to 2 doses of a COVID vaccine (defined by anti-RBD IgG <100U/ mL) and no history of COVID infection were recruited from 2 Australian transplant centres. Patients were randomised in a 1:1 ratio to continue mycophenolate maintenance or switch to sirolimus (trough level target 6 ng/mL). All patients received a 3rd dose of BNT162b2 COVID-19 vaccine and had immunological responses measured 4-6 weeks later. Result(s): 54 patients were randomised to sirolimus switch (n = 28), or control (n = 26). Patients were 70% male, mean age 57.5 years (SD10.4), with mean graft age 6.2 years (SD 5.4). Mean serum trough concentrations of sirolimus and tacrolimus were 6.4 and 6.1 respectively. There have been no safety or tolerability issues in the sirolimus cohort with stable serum creatinine (mean 117.8 vs 119.3, p=0.6), and mild increase in urinary ACR (mean 5.4 vs 17.4, p=0.1). Final results including immunological testing will be collated March 2022. Conclusion(s): Sirolimus switch is safe and well-tolerated. This trial will determine whether the strategy of mTOR inhibitor therapy peri-vaccination can optimise vaccine immune responses against COVID-19 in KTR.
ABSTRACT
Purpose: Kidney transplant recipients (KTR) commonly exhibit inadequate responses to 2-dose COVID-19 vaccination schedules and remain at increased risk of severe COVID-19. Gut dysbiosis is common among KTRs and has been associated with poor vaccine responses. We hypothesised that a dietary fibre supplement may correct dysbiosis and enhance responses to a third dose of COVID-19 vaccine in KTRs. Method(s): KTRs who had received 2 doses of a COVID-19 vaccine were recruited from 2 transplant programs in Australia. KTRs with an inadequate response (defined by anti-RBD <100U/mL) were randomised to receive inulin (fibre) or maltodextran (control), 10g dissolved in 200ml water twice daily for 4 weeks prior to, and 4 weeks after a 3rd vaccine, at which time vaccine response was measured by anti-RBD titre, vaccine-specific B and T cell responses, and changes in the gut microbiome. Patients and investigators were blinded to treatment assignment. COVID-19 infection was excluded by measurement of anti-nucleocapsid antigen. Result(s): Of 85 KTRs screened, 71 had baseline anti-RBD<100U/mL and were randomised to inulin (n=37) or control (n=34). Participants were 33% female, mean age 59 yrs (SD 11), with mean eGFR 56 ml/min/1.73m2 (SD 24.8), and were most commonly receiving tacrolimus, mycophenolate and prednisolone. All participants received a third dose of a mRNA COVID-19 vaccine after receiving a dietary supplement for 4 weeks. Week 8 assessment of vaccine response, supplement tolerability and change in microbiome are ongoing. Four participants tested positive for COVID-19 during the study. Conclusion(s): Gut dysbiosis is one potential contributor to the poor COVID-19 vaccine responses exhibited by KTRs. This trial will determine whether a simple dietary fibre supplement is well tolerated and effective in correcting gut dysbiosis and restoring vaccine responsiveness. Improved vaccine responses are urgently required to better protect KTRs from ongoing morbidity and mortality from COVID-19.
ABSTRACT
Purpose: Kidney transplant recipients (KTRs) are highly vulnerable to severe COVID-19, however are poorly protected by vaccination. Additional vaccine doses have achieved limited improvements in serological neutralisation or T cell response. A novel strategy to boost vaccine response is needed. Method(s): KTRs (n=80) and healthy cohabitants (HCs;n=80) were recruited from a transplant centre in South Australia to undergo a 2-dose vaccination schedule with BNT162b2 or ChAdOx1. KTRs were most commonly receiving the standard-of-care (SOC) triple therapy: tacrolimus, mycophenolate mofetil, prednisolone. Following 2 vaccine doses (median 21 days;IQR 21-24), spike-specific IgG and T cell responses (by IFNgamma ELISpot) were measured to assess vaccine immunogenicity, and live virus neutralisation and anti-receptor binding domain (RBD) IgG (Elecsys, Roche) were evaluated as correlates of protection from infection and disease. In an extended cohort comparing SOC (n=15) and sirolimus-inclusive (n=15) protocols, function and phenotype of antigen-specific T cells were further interrogated by flow cytometry. Result(s): Vaccine immunogenicity was profoundly reduced in KTRs, with a >1,000- fold lower median anti-spike IgG titre, and >10-fold lower median antiviral T cell response relative to HCs. Thresholds for protective anti-RBD IgG (100 U/mL) and serological neutralisation (50% neutralisation at a serum dilution of 1/40) were achieved by 6.7% and 10.9% of KTRs, respectively, and by 100% of cohabitants. In an extended cohort, patients on mTOR inhibitors (mTORi;sirolimus or everolimus) achieved 4-fold higher rates of serological neutralisation than those on SOC therapy (34.6% vs 7.9%). Remarkably, sirolimus use was associated with a median antiviral T cell response 55-fold greater than SOC therapy, and 5-fold greater than HCs. SARSCoV- 2-specific CD4+ and CD8+ T cells in these patients were highly polyfunctional and formed robust central memory out to 3 months post second vaccine dose. Conclusion(s): These data underscore priority vaccination of cohabitants as an effective strategy to protect KTRs, and support a randomised controlled trial of immunosuppression modification with sirolimus as a strategy to directly improve vaccine responses in KTRs.