Deciphering the Molecular Mechanisms of Response to COVID Vaccine in Kidney Transplant Recipients

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PROJECT SUMMARY / ABSTRACT Solid organ transplant recipients have increased morbidity and mortality in response to infection with SARS- CoV-2, the virus responsible for COVID19. While the general population has greatly benefited from the rapid development of several vaccines that are protective against the development of severe infection, the transplant recipient population has sub-optimal responses to similar vaccination regimens. Herein, we build on our published and preliminary data on the cellular and serological responses to SARS-CoV-2 mRNA vaccination in both liver and kidney transplant recipients. Liver transplant recipients are significantly more likely to respond to a two-dose regimen with both viral specific T cells and seroconversion when compared with kidney transplant recipients. Interestingly, although both seroconversion efficiency and T cell activation are affected by the levels of immunosuppression, the organ transplanted (liver versus kidney) has an independent effect on the humoral and cellular responses. However, an in depth, mechanistic evaluation of these adaptive immune responses is lacking. We hypothesize that there are intrinsic differences in immune function, irrespective of the degree of immunosuppression, between liver and kidney transplant recipients. This proposal builds on an already productive collaboration between the laboratories of Jonathan Maltzman and Paolo Cravedi. The overall goal of this work is to use cryopreserved samples to mechanistically understand the features that characterize effective immune response to SARS-CoV-2 vaccination in kidney transplant recipients. To address this goal, we propose the following specific aims: Aim 1: Assess the differences in T cell phenotype and function between solid organ transplant (SOT) recipients that are SARS-CoV-2 vaccine responders versus non-responders; Aim 2: Determine differences in innate and adaptive immune cell populations between vaccine responders versus non-responders by measuring chromatin accessibility and gene expression. This project builds upon the productive collaboration between the Maltzman and Cravedi laboratories and leverages their expertise. Success of this high-risk proposal has the potential to comprehensively delineate the immune responses in both kidney and liver transplant recipients upon SARS- CoV-2 vaccination, a point of critical importance to define biomarkers of response and envision strategies to improve response (high reward).