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

每年针对流感感染的免疫接种是最大规模的国际公共卫生协调行动之一 努力。目前的流感疫苗接种策略主要通过产生持久的类型特异性来获得保护 中和 IgG 抗血凝素 (HA) 抗体，与分子相似的流感亚型结合。这个 这种现象被称为抗体介导的异亚型免疫（amHSI），这是造成这种现象的主要原因。 季节性流感疫苗接种取得成功。 MF59 是一种角鲨烷油佐剂，最近被批准用于季节性 年龄≥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，该项目的主要目标是阐明并建模 MF59 佐剂季节性流感疫苗增加 B 细胞介导的 amHSI 的机制 免疫球蛋白重链 DNA 和蛋白质库水平。目标 1：检验 MF59 的假设 佐剂增加了流感后 IgG 库的广度、深度和分子序列多样性 疫苗接种。目标 2：建立并验证异亚型的年龄依赖性分支过程模型 佐剂流感疫苗诱导的免疫覆盖。目标 3：建模并识别机制 负责 MF59 佐剂流感疫苗诱导的抗 HA IgG 库进化和 amHSI 人类疫苗接种者的一代。该提案解决了公共卫生领域的一个非常重要的问题，即如何 使用疫苗佐剂提高交叉毒株反应性，优化流感疫苗的保护 产生的 IgG 抗 HA 抗体混合物。它还解决了科学方法中的重大差距 重建生发中心内超加速体细胞突变产生的 Ig 序列谱系 反应。我们将创建与年龄相关的分支过程模型，该模型将提供机制洞察 佐剂和皮内疫苗接种如何改变抗体介导的 HSI 的分子多样性。这些 目标 1 中将首先使用接种 MF59 佐剂流感疫苗的小鼠开发模型，并且 然后扩展到目标 2 中的人类受试者。如果成功，这项工作将为 对 amHSI 生成所涉及的分子过程进行建模。

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.