Influence of Naive Lymphocyte Repertoire Size on Vaccination Efficancy

描述（由申请人提供）：人类对感染和免疫的免疫反应-通过现代免疫学方法和系统生物学进行分析。乙型肝炎亚单位疫苗通过诱导抗体预防病毒感染，在数百万人体内诱导免疫。然而，不同个体对乙肝表面抗原（HBS）成分的抗体反应差异非常大，有些个体完全没有反应。我们认为，这种可变性提供了一个千载难逢的机会，以了解人类免疫应答疫苗的多样性和识别免疫应答相关。该应用的中心假设是免疫前库中幼稚抗原特异性B细胞和/或CD4+辅助性T细胞的数量决定了抗体反应的大小。我们将使用一种超灵敏的方法来检验这一假设，我们开发了一种超灵敏的方法来检测疫苗接种前后人类HBS特异性B细胞和HBS肽-主要组织相容性复合体ii特异性CD4+辅助性T细胞。本提案的目标是开发用于全面分析人类hbs特异性幼稚T细胞和B细胞所需的试剂，然后使用这些工具来确定疫苗接种后抗体滴度的大范围是否由免疫前库的变化来解释。这种创新的方法可以提供疫苗反应的最终生物标志物——疫苗特异性淋巴细胞本身——并为如何改进疫苗以保护所有个体提供方向。

DESCRIPTION (provided by applicant): The human immune response to infection and immunization - Profiling via modern immunological methods and systems biology. The Hepatitis B subunit vaccine induces immunity in millions of people by inducing antibodies that prevent viral infection. However, the variability in the antibody response to the Hepatitis B surface antigen (HBS) component of the vaccine in different individuals is remarkably large and some individuals fail to respond altogether. We propose that this variability provides a golden opportunity to understand the diversity of human immune responses to vaccination and identify immune response correlates. The central hypothesis of this application is that the number of naive antigen-specific B cells and/or CD4+ helper T cells in the pre-immune repertoire dictates the magnitude of the antibody response. We will test this hypothesis using an ultra sensitive method that we developed to detect HBS-specific B cells and HBS peptide-Major Histocompatibilty Complex II-specific CD4+ helper T cells in humans before and after vaccination. The goals of this proposal are to develop the reagents needed for comprehensive analysis of the HBS-specific naive T and B cells in humans and then use these tools to determine whether or not the great range in postvaccination antibody titer is explained by variations in the pre-immune repertoire. This innovative approach could provide the ultimate biomarker of vaccine response - the vaccine-specific lymphocytes themselves - and provide direction as to how the vaccine could be improved to protect all individuals. PUBLIC HEALTH RELEVANCE: These studies are relevant because they have the potential to explain why certain people do not develop specific antibodies after receiving the Hepatitis B subunit vaccine. Our theory is that these individuals lack the relevant lymphocytes before vaccination. If this theory is correct, then these individuals should develop antibodies if vaccinated with a different Hepatitis B subunit. Therefore, these studies have the potential to predict who will not respond to this important vaccine and suggest a solution to this problem.