Solid organ transplant(SOT)recipients receive immunosuppressive drugs(ISDs)and are susceptible to developing severe COVID-19.Here,we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group ...Solid organ transplant(SOT)recipients receive immunosuppressive drugs(ISDs)and are susceptible to developing severe COVID-19.Here,we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients(n=136)treated with different ISDs.We demonstrate that a combination of a calcineurin inhibitor(CNI),mycophenolate mofetil(MMF),and prednisone(Pred)treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response.Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection.To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients,we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor(TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta,Delta,Gamma,and Omicron variants.This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.展开更多
基金We would like to acknowledge the contribution of the Singapore National University Centre for Organ Transplantation team members who helped recruit patients:AV,AL,and WKK.We thank all voluntary blood donors for their donations.We would like to thank the members of AB’s lab for their insights and critique.Finally,we would also like to thank Dr.Yongxu Lu and Prof.Geoffrey L.Smith from the Department of Pathology,University of Cambridge,U.K.,for supplying the vaccinia virus-expressing Spike and Nucleocapsid proteins.This study was supported by research funding from the Singapore Ministry of Health’s National Medical Research Council MOH-000019(MOH-StaR17Nov-001)to Antonio BertolettiPart of this work was also supported by the A*ccelerate GAP-funded project(ACCL/19-GAP064-R20H-H)from the Agency of Science+1 种基金Technology and Research(A*STAR),the Singapore National Medical Research Council COVID-19 Research Fund(COVID19RF-011)a Start-up University Grant from the Ministry of Education(Singapore)to Laurent Renia.YSG was supported by a Career Development Fund award by A*STAR(SC35/22-805100).
文摘Solid organ transplant(SOT)recipients receive immunosuppressive drugs(ISDs)and are susceptible to developing severe COVID-19.Here,we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients(n=136)treated with different ISDs.We demonstrate that a combination of a calcineurin inhibitor(CNI),mycophenolate mofetil(MMF),and prednisone(Pred)treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular response.Such defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough infection.To then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients,we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor(TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta,Delta,Gamma,and Omicron variants.This strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.
