This application is for renewed funding for years 6-10 of R01 AI48793. Our long-term objective is to determine the genetic mechanisms influencing the immune response to live viral vaccines and to answer the question of how and to what degree differences in immune responses that depends upon the immunogenetics of the individual determine the outcome of immunization with live viral vaccines. Because of the central role of cytokines as intercellular protein messengers, and their receptors, in the immune response cascade, the role of cytokine and cytokine receptor gene polymorphisms will be a primary focus of this application, and we will focus on the influence of these polymorphisms on measures of humoral and cellular immune response to a live viral vaccine - rubella - as a model with which to explore the influence of immunogenetics on the variability of vaccine response. To accomplish these goals, we propose the following specific aims: 1) To test the hypothesis that significant associations exist between polymorphisms of specific cytokine genes (IFNa, (3, y, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12A, IL-12B, TNFa and GM-CSF) and rubella immune responses (neutralizing antibody level and markers of cell-mediated immunity), 2) To test the hypothesis that significant associations exist between polymorphisms of specific cytokine receptor genes (IL-2RA, IL-2RB, IL-2RG, IL-4R, IL-6R, IL-6ST, IL-10RA, IL-10RB, IL-12RB1, IL-12RB2, IFNAR1, IFNAR2, IFNGR1, IFNGR2, TNFRSF1A, TNFRSF1B, CSF2RA and CSF2RB), and rubella immune responses, 3) To test the hypothesis that significant associations exist between secreted cytokine protein levels (IFNa, (3, y, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p35 and p40), TNFa and GM-CSF) after ex vivo rubella stimulation and rubella immune responses, and 4) To verify the associations between class I and II HLA genes and rubella immune responses found in our previous study and to assess potential effects of gene-gene interactions on these immune responses within a new validation cohort. The application is innovative as it examines the effect of immunogenetics on variability of vaccine response. The significance of this information is that it will provide a framework for estimating the contribution of HLA variability on variability of immune responses as well as provide knowledge significant to the development of new viral vaccines (HIV, HPV, Hepatitis C, and others) in a genetically heterogeneous population. Relevance to Public Health: This grant proposes to study the genes that influence and determine the human immune response to rubella vaccine. The knowledge gained from these studies will enable us to design new strategies and new vaccines to protect human health against viral diseases. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI048793-06
Application #
7048017
Study Section
Special Emphasis Panel (ZRG1-HOP-Q (90))
Program Officer
Cassetti, Cristina
Project Start
2001-02-01
Project End
2011-02-28
Budget Start
2006-03-15
Budget End
2007-02-28
Support Year
6
Fiscal Year
2006
Total Cost
$443,997
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Voigt, Emily A; Haralambieva, Iana H; Larrabee, Beth L et al. (2018) Polymorphisms in the Wilms Tumor Gene Are Associated With Interindividual Variations in Rubella Virus-Specific Cellular Immunity After Measles-Mumps-Rubella II Vaccination. J Infect Dis 217:560-566
Haralambieva, Iana H; Gibson, Michael J; Kennedy, Richard B et al. (2017) Characterization of rubella-specific humoral immunity following two doses of MMR vaccine using proteome microarray technology. PLoS One 12:e0188149
Haralambieva, Iana H; Ovsyannikova, Inna G; Kennedy, Richard B et al. (2017) Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine. Hum Genet 136:421-435
Ovsyannikova, Inna G; Larrabee, Beth R; Schaid, Daniel J et al. (2017) Immunoglobulin GM and KM genes and measles vaccine-induced humoral immunity. Vaccine 35:5444-5447
Ovsyannikova, Inna G; Schaid, Daniel J; Larrabee, Beth R et al. (2017) A large population-based association study between HLA and KIR genotypes and measles vaccine antibody responses. PLoS One 12:e0171261
Schaid, Daniel J; Haralambieva, Iana H; Larrabee, Beth R et al. (2017) Heritability of vaccine-induced measles neutralizing antibody titers. Vaccine 35:1390-1394
Voigt, Emily A; Ovsyannikova, Inna G; Haralambieva, Iana H et al. (2016) Genetically defined race, but not sex, is associated with higher humoral and cellular immune responses to measles vaccination. Vaccine 34:4913-4919
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; Strebel, Peter; Orenstein, Walter et al. (2015) Rubella. Lancet 385:2297-307
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

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