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

针对流感感染的年度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通过产生持久的类型特异性抗体来获得保护。 中和IgG抗血凝素（HA）抗体，其结合分子相似的流感亚型。这 这种现象被称为抗体介导的异亚型免疫（amHSI）， 季节性流感疫苗接种成功。MF59是一种最近被批准用于季节性的角鲨油佐剂。 ≥65岁的个体接种流感疫苗。我们的初步数据表明，MF 59增加了 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加B细胞介导的amHSI的机制 免疫球蛋白重链DNA和蛋白库水平。目的1：检验MF59 佐剂增加了流感后IgG库的广度、深度和分子序列多样性 预防针目的2：建立并验证异亚型的年龄依赖分枝过程模型 佐剂流感疫苗诱导的免疫覆盖率。目标3：建模和识别机制 负责MF59佐剂流感疫苗诱导的抗HA IgG库进化和amHSI 在人类疫苗接受者中产生。该提案涉及公共卫生中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，以增加交叉菌株反应性 的IgG抗HA抗体的所得混合物。它还解决了科学方法的重大差距， 在生发中心内重建由超加速体细胞突变产生的IG序列谱系 反应.我们将创建年龄相关的分支过程模型，这将提供机械的洞察力， 佐剂和皮内接种如何改变抗体介导的HSI的分子多样性。这些 在目标1中，将首先使用用MF59佐剂流感疫苗接种的小鼠开发模型， 然后在目标2中扩展到人类受试者。如果成功，这项工作将提供一个总体框架， 模拟参与amHSI生成的分子过程。

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.