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Principal Investigator: ELAINE F REED
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $605,731
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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disease rate><Organ Transplantation><Organ Transplants><PBMC><Patients><People at risk><Peripheral><Peripheral Blood Mononuclear Cell><Persons><Persons at risk><Pharmaceutical Preparations><Phase><Plasma><Plasma Serum><Population><Populations at Risk><Renal Grafting><Renal Transplantation><Renal Transplants><Research><Reticuloendothelial System, Serum, Plasma><Risk><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 antibody><SARS-CoV-2 booster><SARS-CoV-2 immunity><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine booster><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Seasons><Secondary Immunization><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome related corona virus 2><Solid><Systems Analyses><Systems Analysis><T cell response><T-Cell Proliferation><Testing><Therapeutic immunosuppression><Transplant Recipients><Vaccination><Vaccines><Variant><Variation><Virus><White Blood Cells><White Cell><Wuhan coronavirus><adaptive immune response><antibody against COVID-19><antibody against SARS-CoV-2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody titering><antibody to COVID-19><antibody to SARS-CoV-2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><antibody-based immunity><artificial immunosuppression><biological systems><booster against COVID-19><booster against SARS-CoV-2><booster vaccination><computational modeling><computational models><computer based models><computerized modeling><coronavirus disease 2019 antibody><coronavirus disease 2019 immunity><coronavirus disease 2019 vaccination><coronavirus disease 2019 virus><coronavirus disease-19 virus><developmental><drug/agent><enroll><hCoV19><high risk><host response><immune response to vaccination><immune response to vaccines><immune suppressive agent><immune suppressor><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunity against COVID-19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunization strategy><immuno therapy><immunoresponse><immunosuppressed patient><immunosuppression therapy><immunosuppressive substance><immunosuppressor><improved><kidney tx><methylation pattern><mortality><mycophenolate mofetil><mycophenolic acid morpholinoethyl ester><nCoV2><organ allograft><organ graft><organ transplant patient><organ transplant recipient><organ xenograft><pandemic><pandemic disease><pandemic virus><prediction algorithm><predictive signature><prevent><preventing><recruit><response><severe acute respiratory syndrome coronavirus 2 antibody><tool><transplant patient><vaccinate against COVID-19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccination strategy><vaccine associated immune response><vaccine efficacy><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccine response><vaccine responsiveness><vaccine-induced response><white blood cell><white blood corpuscle>