Systems analyses of induction and maintenance of immunity to SARS-CoV-2 vaccination in kidney transplant recipients receiving mycophenolate mofetil immunotherapy - PROJECT SUMMARY/ABSTRACT Immunocompromised patients, including those requiring immunosuppressive therapy following organ transplantation, are at high risk for severe disease from SARS‐CoV‐2. As SARS-CoV-2 rapidly transitions from a pandemic virus to endemic status, like influenza, seasonal vaccinations against emerging variants will likely become the primary tool for limiting morbidity and mortality. While the efficacy of vaccination against SARS-CoV- 2 has been very promising, specific populations have been identified who are at increased risk of failing to develop protective immunity. Immunocompromised populations respond poorly to SARS-CoV-2 vaccination, particularly solid organ transplant (SOT) recipients receiving immunosuppressive therapy. Within SOT recipients, the type and dose of immunosuppressive therapy have further been shown to impact vaccine efficacy. Patients receiving mycophenolate mofetil (MMF) immunotherapy, which functions by preventing B and T cell proliferation/activation, as well as leukocyte recruitment, have the poorest humoral and cellular response post- vaccination for SARS-CoV-2. Preliminary evidence suggests that discontinuing MMF before vaccination improves humoral responses in SOT recipients. This project will test the hypothesis that coordinated innate and adaptive dysregulation pre-vaccination driven by MMF immunosuppressive therapy diminishes the quality, quantity, and durability of cellular and humoral immunity to SARS-CoV-2 in kidney transplant recipients. In Aim 1, we will characterize the impact of MMF on the generation, quality, and maintenance of adaptive immune responses to SARS-CoV-2 vaccination in SOT recipients. We will use validated assays to quantify and functionally profile humoral and cellular immunity to SARS-CoV-2. In Aim 2, we will define the pre-vaccine immunological determinants of a protective host immune response to SARS-CoV-2 vaccination in kidney transplant recipients and identify the mechanisms of MMF-diminished immunity. We will use systems biological tools to comprehensively profile, at the single-cell level, the peripheral immune system prior to vaccination. In Aim 3, we will determine how pre-vaccine MMF reduction impacts the host immune response to SARS-CoV-2 booster vaccination in kidney transplant recipients. Together, these data will provide a comprehensive, mechanistic understanding of how MMF immunotherapy dysregulates the immune system in SOT recipients and how this dysregulation impacts the induction and durability of protective immunity against SARS-CoV-2. This knowledge will allow the development of targeted strategies to correct or circumvent MMF-driven immune dysregulation, thereby permitting efficacious responses to SARS-CoV-2, and other vaccines, in SOT recipients and other at-risk populations.
