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Principal Investigator: ADRIANA WEINBERG
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $704,735
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
People with immunocompromising conditions, including end stage renal disease (ESRD) and renal
transplantation, are at increased risk of developing severe infections. Vaccination is the preferred mode of
protection against infections but people with the highest risk of infectious morbidity tend to have poor responses
to vaccines. The recombinant zoster vaccine (RZV) showed excellent efficacy in healthy adults ≥50 years of age
and lower immunogenicity and efficacy in transplant recipients. The goal of this study is to define the immunologic
and metabolomic profiles associated with decreased magnitude and persistence of immune responses to RZV
in people with ESRD before and after transplantation. We will use plasma and PBMC collected in a study of RZV
in ESRD sponsored by GlaxoSmithKline, in which participants receive the standard 2-dose RZV immunization
regimen while awaiting renal transplantation and are then followed for 31 months. Transplanted participants on
stable immunosuppression are randomized to receive a 3rd dose of RZV or not and are followed for 12 additional
months. Responses of these immunocompromised hosts are compared with responses of healthy adults ≥50
years of age, who received RZV in previous studies. Research questions will be addressed in the following Aims:
Aim 1. Identify immunologic and metabolomic correlates of reduced persistence of immune responses
to RZV in people with ESRD. We will compare adaptive and innate memory responses to RZV in 50 ESRD
and 50 healthy older adults using flow cytometric and single cell immunogenomic approaches and identify factors
associated with persistence. Using systems and computational immunology approaches, we will identify pre-
vaccination phenotypic, functional, and genomic immune cell profiles, and inflammatory and metabolomic
characteristics associated with decreased responses to RZV in people with ESRD. Associations of inflammatory
factors and/or metabolites with characteristics that hamper the immune responses to RZV will be verified in vitro.
Aim 2. Define the effect of renal transplantation and of a 3rd dose of vaccine on immune responses to
RZV. We will compare adaptive and innate memory responses to a 3rd dose of RZV administered to 30 transplant
recipients with responses to the standard RZV regimen in 50 healthy and 50 ESRD older adults using flow
cytometry and single cell immunogenomics. We will analyze the T-cell repertoire to define the effect of induction
regimens and of the 3rd dose of RZV on the persistence of RZV-expanded T cell clones. We will determine pre-
vaccination immunologic and metabolomic profiles associated with responses to the 3rd dose of RZV in transplant
recipients.
Impact. This study will identify actionable inflammatory and/or metabolomic factors and immunogenomic
characteristics associated with decreased responses to RZV in people with ESRD with and without
transplantation and will determine if a 3rd dose of RZV can mitigate the negative effect of transplantation on the
persistence of immune responses to RZV. We will leverage prior NIH- and GlaxoSmithKline-funded studies.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><AIDS><Acceleration><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Address><Adult><Adult Human><Adverse drug effect><Affect><Age><Age Years><Anti-Rejection Therapy><Blood Plasma><COVID-19 virus><COVID19 virus><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Characteristics><Chickenpox Virus><Clinical Trials><Clone Cells><CoV-2><CoV2><Defect><Disease><Disorder><Dose><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Filtration><Filtration Fractionation><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Genomics><Goals><Grippe><HHV-3><HHV3><Herpes Zoster><Herpes zoster Virus><Herpes zoster disease><Herpesvirus Type 3><Herpesvirus varicellae><Iatrogenesis><Immune><Immune response><Immunes><Immunity><Immunization><Immunochemical Immunologic><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunogenomics><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunosuppressive Therapy><Impairment><In Vitro><Infection><Inflammation><Inflammatory><Influenza><Intermediary Metabolism><Investigators><Kidney><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><Knowledge><Memory><Metabolic Processes><Metabolism><Morbidity><Morbidity - disease rate><NIH><National Institutes of Health><Ocular Herpes zoster Virus><PBMC><Participant><Peripheral Blood Mononuclear Cell><Persons><Phenotype><Plasma><Plasma Serum><Predisposition><Primary Immunodeficiency><Randomized><Recombinants><Regimen><Renal Grafting><Renal Transplantation><Renal Transplants><Research><Research Personnel><Research Resources><Researchers><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><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 CoV 2><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 related corona virus 2><Shingles><Susceptibility><System><T cell response><T-Cells><T-Lymphocyte><Therapeutic immunosuppression><Training><Transplant Recipients><Transplantation><United States National Institutes of Health><VZ Virus><Vaccination><Vaccines><Varicella-Zoster Virus><Wuhan coronavirus><Zona><Zoster><Zoster Vaccine><adulthood><ages><artificial immunosuppression><cell mediated immune response><congenital immune deficiency><congenital immunodeficiency><coronavirus disease 2019 virus><coronavirus disease-19 virus><drug-related adverse effects><flow cytophotometry><genetic immune defect><genetic immune deficiency><genetic immunodeficiency><hCoV19><herpes zona><high risk><host response><iatrogenic><iatrogenically><iatrogenicity><immune senescence><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunogenicity><immunoresponse><immunosenescence><immunosuppressed patient><immunosuppression therapy><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><inborn errors in immunity><inborn errors of immunity><inborn immunodeficiency><inherited immune defect><inherited immune deficiency><inherited immunodeficiency><kidney tx><metabolism measurement><metabolomics><metabonomics><nCoV2><older adult><older adulthood><post-transplant><post-transplantation><posttransplant><posttransplantation><primary immune defect><primary immune deficiency><randomisation><randomization><randomly assigned><renal><response><social role><thymus derived lymphocyte><transplant><transplant patient>