This application is for renewed funding for years 14-18 of 2R01 AI33144. Our broad 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 heterogeneity in immune responses depends upon polymorphisms of immune response genes. Measles kills over 500,000 children annually. Because of the primary role of measles virus receptors (SLAM and CD46) in virus entry, Toll-like receptors (TLRs) in stimulating both innate and adaptive immune responses, and cytokines as intercellular protein messengers in the immune response cascade, gene polymorphisms of these receptors and cytokines will be the focus of this application. Having previously examined the role of HLA genes, we now focus on the influence of these additional gene polymorphisms on measures of humoral and cell-mediated immunity (CMI) to a live viral vaccine 'measles'as a probe and model to further explore the influence of immunogenetics on vaccine response variability. To accomplish these goals, we propose to test the following hypotheses: 1) Significant associations exist between polymorphisms of measles virus receptor genes (SLAM and CD46) and variations in humoral and CMI responses to measles vaccine, 2) Significant associations exist between polymorphisms of a prioritized set of Toll-like receptor genes (TLR 2,3,4,5,6,7,8, and 9) and their associated intracellular signaling molecules, and humoral and CMI responses to measles vaccine, 3-4) Significant associations exist between polymorphisms of a prioritized set of cytokine genes (IFN1, 2, 3, IL-12, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12A, IL-12B, TNF1 and GM-CSF) and selected corresponding cytokine receptor genes (IL-1R1, IL-1R2, IL-1RN, IL-2RA, IL-2RB, IL- 2RG, IL-4RA, IL-5RA, IL-6R, IL-6ST, IL-10RA, IL-10RB, IL-12RB1, IL-12RB2, IFNAR1, IFNAR2, IFNGR1, IFNGR2, TNFRSF1A, TNFRSF1B, CSF2RA and CSF2RB), and humoral and CMI responses to measles vaccine and 5) Significant associations exist between selected prototypic Th1 (IL-2, IL-12(p40), IFN3), Th2 (IL- 4, IL-10), and innate/inflammatory (IFN1) secreted cytokine protein levels and humoral and CMI responses to measles vaccine. This application is innovative in examining the effect of immune response gene polymorphisms on the heterogeneity of measles vaccine immune responses in a population. These studies will also provide specific knowledge for understanding measles immunity, as well as provide a model framework for estimating the contribution of immune response gene polymorphisms on the heterogeneity of 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. In turn, it may be possible in the near future to engineer viral vaccine candidates that can overcome such restrictions.

Public Health Relevance

This application studies genes that influence and determine the human immune response to measles vaccine. This knowledge will allow a better understanding of how measles immunity develops after vaccination and why a range of immune responses occurs. Globally, measles kills over 500,000 children annually, and small outbreaks continue to occur in the U.S.

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, G A; Ovsyannikova, I G; Kennedy, R B (2018) Personalized vaccinology: A review. Vaccine 36:5350-5357
Haralambieva, Iana H; Kennedy, Richard B; Simon, Whitney L et al. (2018) Differential miRNA expression in B cells is associated with inter-individual differences in humoral immune response to measles vaccination. PLoS One 13:e0191812
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
Schaid, Daniel J; Haralambieva, Iana H; Larrabee, Beth R et al. (2017) Heritability of vaccine-induced measles neutralizing antibody titers. Vaccine 35:1390-1394
Poland, Gregory A; Whitaker, Jennifer A; Poland, Caroline M et al. (2016) Vaccinology in the third millennium: scientific and social challenges. Curr Opin Virol 17:116-125
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
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

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