Griffith B Perkins, Australia has been granted the Young Investigator Congress Scientific Award
mTOR inhibitors promote highly functional T cell immunity in kidney transplant recipients vaccinated against COVID-19
Griffith Perkins1,2,3, Matthew Tunbridge3, Tania Salehi3, Cheng Sheng Chai1, Christopher M Hope1,4,5, Pablo Garcia-Valtanen1,6, Julian J Singer8,9, Plinio R Hurtado1,3, Stuart Turville7, Pravin Hissaria1,2,3, Branka Grubor-Bauk1,6, Simon C Barry1,4,5, Steven J Chadban8,9, Toby Coates AO1,3.
1University of Adelaide, Adelaide, Australia; 2SA Pathology, Adelaide, Australia; 3Royal Adelaide Hospital, Adelaide, Australia; 4Robinson Research Institute, Adelaide, Australia; 5Women's and Children's Hospital, North Adelaide, Australia; 6Basil Hetzel Institute for Translational Health Research, Woodville, Australia; 7Kirby Institute, Sydney, Australia; 8Royal Prince Alfred Hospital, Sydney, Australia; 9University of Sydney, Sydney, Australia
Introduction: 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. Inhibition of mechanistic target of rapamycin (mTOR) has been found to enhance the formation of memory T cells following vaccination of non-human primates.
Methods: KTRs and age-matched healthy controls (HC) were recruited from a transplant centre in South Australia to undergo a 2-dose vaccination schedule with BNT162b2 or ChAdOx1. KTRs were receiving standard-of-care (SOC) triple therapy (tacrolimus, mycophenolate mofetil, prednisolone; n=15), sirolimus-inclusive (n=15), or everolimus-inclusive (n=11) protocols. Patients on mTORi-inclusive protocols were most commonly receiving sirolimus or everolimus, mycophenolate mofetil, and prednisolone. Following 2 vaccine doses, spike-specific IgG and T cell responses (by IFNγ 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. Function and phenotype of antigen-specific T cells were further interrogated by flow cytometry.
Results: KTRs on mTORi-inclusive protocols demonstrated improved humoral immunity, with 46.7% and 63.6% seroconversion rates in the sirolimus and everolimus groups, respectively, compared with 26.3% in the SOC group. This was mirrored by improved serological neutralisation of live SARS-CoV-2 virus (ancestral strain) by patients on mTOR inhibitors. Serological neutralisation of the Omicron variant was achieved by 20% of KTRs on sirolimus, but by none in the SOC nor everolimus groups. Remarkably, sirolimus use was associated with a median antiviral T cell response 55-fold greater than SOC therapy, and 5-fold greater than HCs. SARS-CoV-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. While the phenotype of antigen-specific memory T cells from KTRs on SOC therapy was skewed relative to healthy individuals, this abnormality was corrected in the sirolimus group.
Conclusions: These data support a randomised controlled trial of immunosuppression modification with sirolimus as a strategy to directly improve vaccine responses in KTRs.
Funded by The Hospital Research Foundation Group, South Australia. The following reagent was obtained through BEI Resources, NIAID, NIH: Peptide Array, SARS-Related Coronavirus 2 Spike (S) Glycoprotein, NR-52402.
