PROJECT SUMMARY/ABSTRACT This application is a request for funding of a vaccine immunogenetics research program focused on identifying critical genetic determinants of long-term mumps vaccine-induced immunity by examining associations be- tween gene polymorphisms and variations in immune response to mumps vaccine. Our laboratory has done significant work delineating the effect of gene polymorphisms on mumps, measles, rubella, influenza and smallpox immune responses, and reported new findings demonstrating that HLA, TLR, viral receptor, cyto- kine/cytokine receptor, vitamin A/D receptor, and a variety of other immune gene SNPs significantly influence humoral and cell-mediated immune (CMI) responses following these vaccines. Our research demonstrates that variations in immune responses to measles and rubella vaccines are multigenic and not a single dominant al- lele model, and that the genetic contribution to such variations in immune responses can be quantified. In- formed by insights from these studies over almost 2 decades, and given the public health importance of con- tinued mumps outbreaks in the US, Europe, Pacific Island states, and Asia, we now turn our attention to understanding genetic associations with mumps vaccine-induced immune responses. The most thorough and efficient study for such purposes is a comprehensive discovery/replication genome-wide association study (GWAS), followed by functional studies to validate which gene polymorphisms and pathways have the largest or most critical impact on variations in immunity among immunized subjects, and the mechanism(s) through which these effects occur, supporting a new paradigm by which future efforts in vaccine development could occur. In this application, we propose studies supporting a new directed paradigm of ?Discover ? Replicate ? Validate ? Apply,? which we have called vaccinomics. Our studies focus on the first two steps of the paradigm. Our Specific Aims are to 1) perform a two-stage, discovery/replication, genome-wide association study to identify novel genetic associations between SNPs and inter-individual variations in humoral and cellular im- mune response to mumps vaccine; and 2) to validate our already-replicated TLR4 SNP associations and newly identified associations from Aim 1 through functional studies that will define the direct effects and/or down- stream immunologic consequences of the identified polymorphisms. These aims will allow us to comprehen- sively define how inter-individual variations in immune responses to mumps vaccine are influenced by gene polymorphisms. The justification for this approach comes from our data demonstrating that the heritability of mumps vaccine humoral immunity is 40%, and is an appropriate target for immunogenetic studies. Despite the public health implications, there are no population-based studies identifying associations between mumps vac- cine immune response and genome-wide SNPs and validating the functional characteristics of those polymor- phisms. Our study is carefully designed to be rigorous and produce robust, unbiased, and reproducible results.