This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Our central purpose is to investigate variability in host genes predicting variation in antibody responses and adverse reactions to Anthrax Vaccine Adsorbed (AVA). The proposed study of population immunogenetics and associations with immune response to AVA represents a collaboration with the Anthrax Vaccine Research Program (AVRP) at the Centers for Disease Control and Prevention and the ongoing CDC-sponsored anthrax vaccine clinical trial (Anthrax Vaccine Adsorbed: Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction - AVA000). Access to the AVA000 cohort represents an unparalleled opportunity to explore host factors influencing vaccine responses. It will extend work by us and others highlighting the role of both HLA and non-HLA genetic factors in host responses to vaccines. Research Area 1 (RA1) will concentrate largely on anthrax vaccine recipients in the ongoing trial. We will select genes believed likely to influence vaccine outcomes, identify genetic variants in these genes, and search for associations of the polymorphisms with levels of antibody to anthrax protective antigen and with adverse reactions. Research Area 2 (RA2) involves two subprojects, one in the AVA vaccinees and one in the healthy controls. In these two subprojects, to determine whether the promising associations of genetic variations with responses of trial participants actually reflect genetically determined differences in protein expression and function, we will characterize the functional significance of variants in genes related to B cell proliferation, physiology, surface marker expression and antibody production. Because of the nature and complexity of this project, we have defined three distinct subprojects with individual leaders. The subprojects may begin at different times but will eventually proceed concurrently.Different members of the research team will lead the separate research areas and subprojects, as follows:Subproject 1: Genetic Determinants of Vaccine Response (associated with RA1 in vaccinees)P.I.: Scott Parker, M.D.Co-Investigator: Richard A. Kaslow, M.D., M.P.H.Subproject 2: Immune Cell Profiles in Vaccine Response (associated with RA2)P.I.: Robert H. Carter, M.D.Co-Investigator: James (Jianming) TangSubproject 3: Determinants of Immunologic Responsiveness (associated with RA2)P.I.: Jeffrey C. Edberg, Ph.D.This application covers the submission of Subproject 3.
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