Modeling Mechanisms of Adjuvanted Influenza Vaccine Induced IgG Repertoire Diversity and Heterosubtypic Immunity

每年针对流感感染进行的免疫接种是最大的协调国际公共卫生之一。 努力。目前的流感疫苗接种策略主要是通过产生持久的特定类型的疫苗来获得保护 中和与分子上相似的流感亚型结合的抗血凝素(HA)抗体。这 这一现象被称为抗体介导的异种亚型免疫(AmHSI)，这是导致 成功接种季节性流感疫苗。MF59是最近批准用于季节性的一种角鲨油佐剂。 ≥65岁的个人接种流感疫苗。我们的初步数据表明，MF59增加 小鼠、雪貂和人类受试者的AMHSI。因此，本项目的主要目标是阐明和模拟 MF59佐剂季节性流感疫苗增强B细胞介导的AMHSI的机制 免疫球蛋白重链DNA和蛋白质谱水平。目标1：检验MF59的假设 佐剂增加流感后免疫球蛋白谱系的广度、深度和分子序列多样性 接种疫苗。目的2：建立和验证异亚型年龄相关的分枝过程模型 流感佐剂疫苗免疫接种率。目标3：建立模型并确定机制 负责MF59佐剂流感疫苗诱导的抗-HA免疫球蛋白谱系进化和AMHSI 人类疫苗接受者中的一代。这项提案解决了公共卫生中的一个非常重要的问题，即如何 使用疫苗佐剂优化流感疫苗的保护，提高跨毒株的反应性 得到的免疫球蛋白和抗HA抗体的混合物。它还解决了在科学方法方面的一个重大差距 生发中心超加速体细胞突变产生的免疫球蛋白序列谱系的重建 反应。我们将创建年龄相关的分支过程模型，该模型将提供对 佐剂和皮内接种如何改变抗体介导的人类免疫缺陷病毒的分子多样性。这些 在AIM 1中，将首先使用接种MF59佐剂流感疫苗的小鼠建立模型，并 如果成功，这项工作将提供一个通用的框架 对产生amHSI的分子过程进行模拟。

Annual immunization against influenza infection is one of the largest coordinated international public health efforts. Current flu vaccination strategies primarily elicit protection by the generating long lasting type-specific neutralizing IgG anti-hemagglutinin (HA) antibodies that bind to molecularly similar influenza subtypes. This phenomenon is termed antibody mediated heterosubtypic immunity (amHSI), and a major reason for the success of seasonal influenza vaccination. MF59 is a squaline-oil adjuvant recently approved for seasonal influenza vaccination in indivduals ≥65 years of age. Our preliminary data suggests that MF59 increases amHSI in mice, ferrets and human subjects. Thus the primary goal of this Project is to elucidate and model the mechanisms of by which MF59 adjuvanted seasonal influenza vaccine increase B cell mediated amHSI at the immunoglobulin heavy chain DNA and protein repertoire level. Aim 1: To test the hypothesis that MF59 adjuvant increases the breadth, depth and molecular sequence diversity in the IgG repertoire after influenza vaccination. Aim 2: To build and validate an age-dependent branching process model of heterosubtypic immunity coverage induced by adjuvanted influenza vaccine. Aim 3: To model and identify the mechanisms responsible for MF59 adjuvanted influenza vaccine induced anti-HA IgG repertoire evolution and amHSI generation in human vaccine recipients. This proposal addresses a highly significant issue in public health, how to optimize the protection of the influenza vaccine using vaccine adjuvants to increase the cross-strain reactivity of the resulting mixture of IgG anti-HA antibodies. It also addresses a significant gap in scientific methods for reconstructing Ig sequence lineages resulting from hyperaccellerated somatic mutation within germinal center reactions. We will create age dependent branching process models that will provide mechanistic insight into how the adjuvant and intradermal vaccination alter the molecular diversity of antibody-mediated HSI. These models will be first developed using mice vaccinated with MF59 adjuvanted influenza vaccine in Aim 1, and then extended to human subjects in Aim 2. If successful, this work will provide a general framework for modeling the molecular processes involved in the generation of amHSI.