Concurrent vaccination of kidney transplant recipients and close household cohabitants against COVID-19

Perkins, Griffith B.; Tunbridge, Matthew; Salehi, Tania; Chai, Cheng Sheng; Kireta, Svjetlana; Johnston, Julie K; Penko, Daniella; Nitschke, Jodie; Yeow, Arthur Eng Lip; Al-Delfi, Zahraa; Drogemuller, Chris; García-Valtanen, Pablo; Masavuli, Makutiro G.; Hope, Christopher; Singer, Julian; Aggarwal, Anupriya; Stella, Alberto Ospina; Turville, Stuart; Hurtado, Plinio R; Barry, Simon C.; Hissaria, Pravin; Grubor‐Bauk, Branka; Chadban, Steven J.; Coates, P. Toby

doi:10.1016/j.kint.2022.02.015

Cited by 9 publications

(12 citation statements)

References 10 publications

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“…Inadequate response to vaccination is a major problem facing immunocompromised KTRs, underscored by the 24% mortality rate early in the COVID-19 pandemic ( 1 ), and by the limited protection afforded this group by standard COVID-19 vaccination strategies ( 3 ). A number of strategies have been employed to try to improve protective immunity in KTRs, which predominantly focus on enhancing or maintaining humoral immunity to SARS-CoV-2, including multiple vaccine boosters ( 5, 6, 10, 11, 52-54 ), as well as ring vaccination ( 13, 55 ), convalescent plasma and immunoglobulin ( 56, 57 ), and prophylactic monoclonal antibody therapy ( 58, 59 ). While repetitive booster vaccinations have shown benefit ( 4, 7, 11, 54 ), there are limitations to this strategy ( 60–62 ), and a subgroup of KTRs, particularly those receiving higher doses of the anti-metabolite mycophenolate (mycophenolate mofetil, MMF or mycophenolic acid, MPA), remain seronegative ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

“…Vaccine boosters have been found to increase antibody titers in those with poor responses to primary vaccination, but virus neutralizing titers remain suboptimal in the majority of patients after a third or fourth dose, and a subgroup of patients remain seronegative ( 10–12 ). Indirect approaches to protect KTRs through ring vaccination may be beneficial in the immediate-term ( 13 ), however a strategy to directly boost immunity in immunosuppressed individuals is urgently needed ( 14 ). Such a strategy would likely center on transient modification of immunosuppression, and must strike the balance of enhancing vaccine immunogenicity and efficacy without increasing the risk of transplant rejection.…”

Section: Introductionmentioning

confidence: 99%

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mTOR inhibition improves the formation of functional T cell memory following COVID-19 vaccination of kidney transplant recipients

Perkins

Tunbridge

Chai

et al. 2023

Preprint

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Inadequate immune response to vaccination is a long-standing problem faced by immunosuppressed kidney transplant recipients (KTRs), requiring novel strategies to improve vaccine efficacy. In this study, the potential of mechanistic target of rapamycin inhibitors (mTORi) to improve T cell responses to COVID-19 vaccination was investigated. Following primary vaccination with adenoviral (ChAdOx1) or mRNA (BNT162b2) COVID-19 vaccines, KTRs receiving rapamycin demonstrated T cell responses greater than those of healthy individuals, characterized by increased frequencies of vaccine-specific central memory, effector memory and TEMRA T cells, in both the CD4+ and CD8+ compartments. Relative to standard-of-care triple therapy, mTORi-based therapy was associated with a 12-fold greater functional T cell response to primary vaccination of KTRs. The use of rapamycin to augment T cell responses to COVID-19 booster (third dose) vaccination was next investigated in a randomized, controlled trial. Immunosuppression modification with rapamycin was feasible and well-tolerated, but did not improve vaccine-specific T cell responses in this cohort. To understand the parameters for effective use of rapamycin as a vaccine adjuvant, mice were treated with rapamycin before primary or booster vaccination with ancestral and/or Omicron COVID-19 vaccines. Supporting the findings from KTRs, significant enhancement of functional and stem-like memory T cell responses was observed when rapamycin was administered from the time of primary, rather than booster, vaccination. Collectively, a positive effect of mTOR inhibitors on vaccine-induced T cell immunity against COVID-19 in humans was demonstrated.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mTOR inhibition improves the formation of functional T cell memory following COVID-19 vaccination of kidney transplant recipients

Perkins

Tunbridge

Chai

et al. 2023

Preprint

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“…However, immunocompromised populations such as KTRs were excluded from initial vaccine trials. KTRs exhibit suboptimal vaccine responses and are inadequately protected by current standard two-and threedose vaccine regimes [4,5].…”

Section: Background and Rationale {6a}mentioning

confidence: 99%

“…3 SA Pathology, Adelaide, South Australia, Australia. 4 Department of Renal Medicine, Kidney Centre, Royal Prince Alfred Hospital, Sydney, Australia. 5 Kidney Node, Charles Perkins Centre, University of Sydney, Sydney, Australia.…”

Section: Abbreviationsmentioning

confidence: 99%

Rapamycin and inulin for booster vaccine response stimulation (RIVASTIM)—rapamycin: study protocol for a randomised, controlled trial of immunosuppression modification with rapamycin to improve SARS-CoV-2 vaccine response in kidney transplant recipients

Tunbridge

Perkins

Singer

et al. 2022

Trials

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Kidney transplant recipients are at an increased risk of severe COVID-19-associated hospitalisation and death. Vaccination has been a key public health strategy to reduce disease severity and infectivity, but the effectiveness of COVID vaccines is markedly reduced in kidney transplant recipients. Urgent strategies to enhance vaccine efficacy are needed.Methods: RIVASTIM-rapamycin is a multicentre, randomised, controlled trial examining the effect of immunosuppression modification prior to a third dose of COVID-19 vaccine in kidney transplant recipients who have failed to develop protective immunity to a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to either remain on standard of care immunosuppression with tacrolimus, mycophenolate, and prednisolone (control) or cease mycophenolate and commence sirolimus (intervention) for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm who develop protective serological neutralisation of live SARS-CoV-2 virus at 4-6 weeks following a third COVID-19 vaccination. Secondary outcomes include SARS-CoV-receptor binding domain IgG, vaccine-specific immune cell populations and responses, and the safety and tolerability of sirolimus switch.

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“…Registry data have suggested reduced mortality risk from Covid-19 infection for vaccinated kidney transplant recipients when compared to unvaccinated patients. 49,50 Furthermore, the protection conferred by vaccination among transplant candidates and recipients can be enhanced by accelerated or fourth booster doses messenger RNA vaccines 51,52 , even the fifth dose 53 , and ring vaccination 54 (priority and booster dosing of close household contacts of kidney transplant recipients).…”

Section: Challenge 2: Should Vaccination Of Kidney Transplant Candida...mentioning

confidence: 99%

Ethical Issues in Kidney Transplant and Donation During COVID-19 Pandemic

Chow

Maggiore

Dor

2022

Seminars in Nephrology

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Concurrent vaccination of kidney transplant recipients and close household cohabitants against COVID-19

Cited by 9 publications

References 10 publications

mTOR inhibition improves the formation of functional T cell memory following COVID-19 vaccination of kidney transplant recipients

mTOR inhibition improves the formation of functional T cell memory following COVID-19 vaccination of kidney transplant recipients

Rapamycin and inulin for booster vaccine response stimulation (RIVASTIM)—rapamycin: study protocol for a randomised, controlled trial of immunosuppression modification with rapamycin to improve SARS-CoV-2 vaccine response in kidney transplant recipients

Ethical Issues in Kidney Transplant and Donation During COVID-19 Pandemic

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