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 e...