This application is a request for continued funding of 5RO1 AI033144 for Years 19-23 of a highly productive measles vaccine (MV) immunogenetics research program. Measles remains an epidemic virus in much of the world, leading to millions of infections and 164,000 deaths each year, and the current vaccine results in a failure rate of 2-10% after two doses. For 2011, the US has had 211 cases, more than in any year of the last decade. Our research is focused on identifying critical genetic determinates of immunity by examining associations between heterogeneity in humoral and cellular immune responses to MV and gene polymorphisms. Importantly, our research demonstrates that humoral and cellular immune responses to MV are significantly associated with HLA alleles and SNPs in candidate immune response genes, but these associations do not explain all of the variance in immune responses seen within the population. We will comprehensively identify the genetic determinants that explain our finding that the heritability of MV- induced humoral immunity is nearly 90%. To do so, we propose a state-of-the-art genome-wide association study (GWAS) design, followed by replication studies in independent cohorts, and finally validation studies to determine the functional consequences of replicated SNPs. The data from our study will support a new vaccinomics """"""""Discover-Replicate-Validate-Apply"""""""" paradigm for new vaccine development by defining how variations in MV immune responses are determined by gene polymorphisms. To accomplish these goals, we propose the following Specific Aims: 1) Discover: To perform a GWAS to identify novel genetic associations between SNPs, multigenic interactions, and gene networks/pathways and markers of humoral (neutralizing antibody) and cell-mediated (IFN-g ELISPOT) immunity to MV, 2) Replicate: To replicate a prioritized set of the strongest associations from both our GWAS (Aim 1) and candidate gene SNPs from our currently funded grant in an independent, population-based cohort of subjects, and 3) Validate: To determine the direct effects and/or downstream functional consequences on immune outcomes of selected replicated genetic variants. This application is innovative and significant in that it will: examin the effect of gene polymorphisms on the heterogeneity of measles vaccine immune responses, provide data that may explain mechanisms for these variations in MV immune responses, and provide data to support a novel paradigm of Discover-Replicate- Validate-Apply for new vaccine development. These studies will provide specific knowledge for understanding measles immunity, as well as provide a model framework for estimating the genetic contribution to variations in immune responses to a viral vaccine. Lastly, our work may provide knowledge important to the development of new viral vaccines-particularly against measles-by understanding genetic restrictions that prevent protective immune responses to vaccine.

Public Health Relevance

to Public Health: This grant will develop comprehensive information on the contribution and influence of genetic variants on measles vaccine-induced immune responses. These data will support a novel paradigm enabling the future design of new measles vaccines to protect public health and could also be used to inform vaccine development against other viral infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Cassetti, Cristina
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Mayo Clinic, Rochester
United States
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Poland, Gregory A; Whitaker, Jennifer A; Poland, Caroline M et al. (2016) Vaccinology in the third millennium: scientific and social challenges. Curr Opin Virol 17:116-25
Haralambieva, Iana H; Zimmermann, Michael T; Ovsyannikova, Inna G et al. (2016) Whole Transcriptome Profiling Identifies CD93 and Other Plasma Cell Survival Factor Genes Associated with Measles-Specific Antibody Response after Vaccination. PLoS One 11:e0160970
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
Haralambieva, Iana H; Simon, Whitney L; Kennedy, Richard B et al. (2015) Profiling of measles-specific humoral immunity in individuals following two doses of MMR vaccine using proteome microarrays. Viruses 7:1113-33
Whitaker, Jennifer A; Ovsyannikova, Inna G; Poland, Gregory A (2015) Adversomics: a new paradigm for vaccine safety and design. Expert Rev Vaccines 14:935-47
Haralambieva, Iana H; Kennedy, Richard B; Ovsyannikova, Inna G et al. (2015) Variability in Humoral Immunity to Measles Vaccine: New Developments. Trends Mol Med 21:789-801
Ovsyannikova, Inna G; Salk, Hannah M; Larrabee, Beth R et al. (2015) Single nucleotide polymorphisms/haplotypes associated with multiple rubella-specific immune response outcomes post-MMR immunization in healthy children. Immunogenetics 67:547-61
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

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