Understanding inter-individual variations in immune responses to live viral vaccines is critical to understanding how viral vaccines induce protective immune responses, informs new rational vaccine design, and allows identification of new correlates of vaccine immunogenicity and efficacy. The studies supported by this grant during the current funding cycle have shown that: 1) specific HLA alleles and haplotypes as well as specific SNPs and multigenic SNP interactions significantly influence rubella vaccine immune reponses; 2) these HLA alleles and SNPs have now been replicated/confirmed; and 3) some of these SNPs influence both rubella and measles vaccine immune responses-potentially identifying key genetic determinates shared across multiple viral families. These studies account for approximately 15% of the inter-individual variation in humoral response to rubella vaccine, where the heritability of rubella vaccine immune response is nearly 50%, thus key drivers of immune response variation are not yet understood. In this proposal, we take a systems-level approach to identifying the key compoents, and their interactions, that together most influence innate and adaptive immune response variability to rubella vaccine. To do so, we propose the following Specific Aims: 1) To perform a systems biology-level study to identify predictors of innate immune responses ("innate immune signature") after live in vitro rubella virus stimulation among cohorts of non/low and high responders to rubella vaccine; 2) To perform a systems biology-level study to identify novel predictors of adaptive B cell antibody immune responses ("adaptive B cell immune signature") to live rubella virus vaccination among cohorts of non/low and high rubella vaccine responders; 3) To perform a systems biology-level study to identify novel predictors of T cell immune responses ("adaptive T cell immune signature") to live rubella virus vaccination among cohorts of non/low and high rubella vaccine responders; and 4) To determine the direct effects and mechanisms by which the above identified components result in variations in innate and adaptive B and T cell immune responses to rubella vaccination. These data will lead to identifying unique immune signatures that predict innate and adaptive immune responses.