Immunogenicity & efficacy of chimeric flu virus expressing Ab42 B cell epitope

描述（由申请人提供）：我们和其他人已经证明，诱导β-淀粉样蛋白（AB）肽的抗体在临床前和临床环境中都赋予阿尔茨海默病的治疗效果。这种方法目前受到病理性自身反应性诱发的阻碍。为了克服这个问题，我们已经开发了几种策略来限制病理性免疫。例如，我们产生了由AB 42的小免疫显性自身B细胞肽与外源CD 4 +Th细胞表位融合组成的表位疫苗，并证明这种疫苗诱导高滴度的抗AB抗体，而不产生对AB特异性的潜在有害的自身反应性T细胞。重要的是，这些抗体具有治疗活性，如我们在两种不同的AD小鼠模型（APP/Tg 2576和3xTg-AD）中所示。在证明了在没有病理性自身反应性的情况下选择性诱导对AB的有益抗体应答的可行性后，我们决定将这些研究扩展到更临床适用的系统。与我们的合作研究者合作，我们已经使用流感病毒平台将AB 42（AB 1 -10）的免疫显性B细胞表位递送到宿主中。在我们的初步数据中，我们已经产生了一种流感-AB 1 -10疫苗，该疫苗诱导了强大的抗AB和抗流感抗体，并减少了免疫3xTg-AD小鼠大脑中的AB沉积物。因此，在本提案的前三个翻译目的中，我们计划了解（i）重组流感-AB 1 -10疫苗在无AD样病理（目的1）以及具有早期（目的2）和晚期（目的3）AD样病理的3xTg-AD小鼠中的免疫原性和有效性。本研究的最后一个目的4是探索该疫苗产生抗AB抗体的免疫学机制，并鉴定参与该过程的抗病毒记忆Th细胞的特异性。因此，在本研究结束时，我们将了解控制AB 1 -10和流感特异性抗体产生的细胞和分子机制。该提案的长期目标将是开发出安全有效的双重（流感-AB）疫苗，可以预防症状前人群中AD病理的发展，同时保护他们免受流感感染。公共卫生相关性：阿尔茨海默氏病是美国痴呆症的主要原因，其特征在于潜伏发作和进行性认知下降，影响记忆、语言、判断、时间和地点定向等。病理上，淀粉样蛋白斑块、神经纤维缠结、营养不良性神经突和神经元的普遍损失增加。已经证明，诱导针对β-淀粉样肽的抗体在临床前和临床环境中都赋予阿尔茨海默病的治疗效果。这种方法目前受到病理性自身反应性T辅助细胞诱导的阻碍。为了克服这个问题，我们和其他人正在开发几种策略来限制病理性免疫。在当前的项目中，我们提出了基于流感病毒载体和来自β-淀粉样蛋白肽的免疫显性B细胞表位的安全有效的双重疫苗，其可以预防/减少诊断为早期AD的症状前人群中阿尔茨海默病病理的发展，同时保护他们免受流感感染。

DESCRIPTION (provided by applicant): We and others have demonstrated that induction of antibodies to the beta-amyloid (AB) peptide endows therapeutic effects in Alzheimer's disease both in pre-clinical and clinical settings. This approach is currently hampered by elicitation of pathological autoreactivity. In order to overcome this problem we have developed several strategies to limit pathological immunity. For example, we generated an epitope vaccine composed of small immunodominant self B cell peptide of AB42 fused with a foreign CD4+Th cell epitope and demonstrated that such vaccine induced high titers of anti-AB antibodies without generation of potentially harmful autoreactive T cells specific to AB. Importantly, these antibodies were therapeutically active, as we showed in two different mouse models of AD (APP/Tg 2576 & 3xTg-AD). After having demonstrated feasibility of selectively inducing a beneficial antibody response to AB in absence of pathological autoreactivity, we decided to expand these studies to a more clinically applicable system. In collaboration with our co-investigator, we have used the influenza virus platform for delivery of immunodominant B cell epitopes of AB42 (AB1-10) into the host. In our preliminary data we have generated a flu-AB1-10 vaccine that induces robust anti-AB and anti-influenza antibodies and reduces AB-deposits in the brains of immune 3xTg-AD mice. Thus, in the first three translational Aims of this proposal we plan to learn about (i) immunogenicity and efficacy of recombinant flu- AB1-10 vaccine in 3xTg-AD mice without AD-like pathology (Aim 1), as well as with early (Aim 2) and late (Aim 3) AD-like pathology. The last Aim 4 of this study is designed to explore immunological mechanism/s of generation of anti-AB antibodies by this vaccine and identify specificity of anti-viral memory Th cells involved in this process. Thus, at the end of this study we will learn about cellular and molecular mechanisms governing the generation of antibodies specific to both AB1-10 and influenza. The long-term goal of this proposal will be a generation of the safe and effective dual (flu-AB) vaccine that may prevent development of AD pathology in pre-symptomatic people, protecting them from the flu infection at the same time. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease is the major cause of dementia in the US and is characterized by an insidious onset and progressive cognitive decline that impacts memory, language, judgment, orientation to time and place, etc. Pathologically there is an increase in the presence in amyloid plaques, neurofibrillary tangles, dystrophic neurites and a general loss of neurons. It was demonstrated that induction of antibodies to the beta-amyloid peptide endows therapeutic effects in Alzheimer's disease both in pre-clinical and clinical settings. This approach is currently hampered by elicitation of pathological autoreactive T helper cells. In order to overcome this problem we and others are developing several strategies to limit pathological immunity. In current project we are proposing to generate the safe and effective dual vaccine, based on influenza viral vector and immunodominant B cell epitope from beta-amyloid peptide that may prevent/reduce development of Alzheimer's disease pathology in pre-symptomatic people diagnosed with early-stage AD, protecting them from the flu infection at the same time.