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.
These proposed studies will identify unique innate, adaptive B and T cell immune signatures to a challenge dose of live virus rubella vaccine in order to understand the most important components that determine inter- individual variations in innate and adaptive immune responses. Such immune signatures can predict immune responses, and advance our understanding of drivers of variations in rubella vaccine response.
|Lambert, Nathaniel D; Haralambieva, Iana H; Kennedy, Richard B et al. (2015) Polymorphisms in HLA-DPB1 are associated with differences in rubella virus-specific humoral immunity after vaccination. J Infect Dis 211:898-905|
|Lambert, Nathaniel D; Pankratz, V Shane; Larrabee, Beth R et al. (2014) High-throughput assay optimization and statistical interpolation of rubella-specific neutralizing antibody titers. Clin Vaccine Immunol 21:340-6|
|Kennedy, Richard B; Ovsyannikova, Inna G; Lambert, Nathaniel D et al. (2014) The personal touch: strategies toward personalized vaccines and predicting immune responses to them. Expert Rev Vaccines 13:657-69|
|Kennedy, Richard B; Ovsyannikova, Inna G; Haralambieva, Iana H et al. (2014) Genome-wide SNP associations with rubella-specific cytokine responses in measles-mumps-rubella vaccine recipients. Immunogenetics 66:493-9|
|Haralambieva, Iana H; Salk, Hannah M; Lambert, Nathaniel D et al. (2014) Associations between race, sex and immune response variations to rubella vaccination in two independent cohorts. Vaccine 32:1946-53|
|Haralambieva, Iana H; Lambert, Nathaniel D; Ovsyannikova, Inna G et al. (2014) Associations between single nucleotide polymorphisms in cellular viral receptors and attachment factor-related genes and humoral immunity to rubella vaccination. PLoS One 9:e99997|
|Lambert, Nathaniel D; Haralambieva, Iana H; Ovsyannikova, Inna G et al. (2014) Characterization of humoral and cellular immunity to rubella vaccine in four distinct cohorts. Immunol Res 58:1-8|
|Poland, Gregory A; Ovsyannikova, Inna G; Kennedy, Richard B et al. (2014) A systems biology approach to the effect of aging, immunosenescence and vaccine response. Curr Opin Immunol 29:62-8|
|Kennedy, Richard B; Ovsyannikova, Inna G; Haralambieva, Iana H et al. (2014) Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination. Hum Genet 133:1407-17|
|Ovsyannikova, Inna G; Salk, Hannah M; Larrabee, Beth R et al. (2014) Single-nucleotide polymorphism associations in common with immune responses to measles and rubella vaccines. Immunogenetics 66:663-9|
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