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

描述(申请人提供)：我们和其他人已经证明，在临床前和临床环境中，诱导β-淀粉样多肽(AB)抗体对阿尔茨海默病具有治疗效果。这种方法目前被病理性自身反应性的激发所阻碍。为了克服这个问题，我们开发了几种限制病理免疫的策略。例如，我们研制了一种由免疫优势的AB42自身B细胞肽与外源CD4+Th细胞表位融合而成的表位疫苗，并证明这种疫苗可以诱导高滴度的抗AB抗体，而不会产生针对AB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，正如我们在两种不同的AD小鼠模型(APP/TG2576和3xTg-AD)中所显示的那样。在证明了在没有病理自身反应的情况下选择性地诱导对AB的有益抗体反应的可行性后，我们决定将这些研究扩展到更适用于临床的系统。在与我们的合作研究人员的合作下，我们使用流感病毒平台将AB42(AB1-10)的免疫优势B细胞表位输送到宿主体内。在我们的初步数据中，我们已经产生了一种流感-AB1-10疫苗，它可以诱导强大的抗AB和抗流感抗体，并减少免疫3xTg-AD小鼠大脑中的AB沉积。因此，在本提案的前三个翻译目标中，我们计划了解(I)重组Flu-AB1-10疫苗在3xTg-AD小鼠中的免疫原性和有效性，这些小鼠没有AD样病理(目标1)，以及早期(目标2)和晚期(目标3)AD样病理。本研究的最后目的4旨在探讨该疫苗产生抗AB抗体的免疫学机制，并鉴定参与这一过程的抗病毒记忆Th细胞的特异性。因此，在这项研究的最后，我们将了解控制AB1-10和流感特异性抗体产生的细胞和分子机制。这项提议的长期目标将是开发出一代安全有效的双重(Flu-AB)疫苗，这种疫苗可能会防止无症状人群的AD病理发展，同时保护他们免受流感感染。公共卫生相关性：阿尔茨海默病是美国痴呆症的主要原因，其特征是潜伏性发病和进行性认知能力下降，影响记忆、语言、判断、对时间和地点的定向等。病理上，淀粉样斑块、神经原纤维缠结、营养不良的神经突起和神经元的全面丧失的存在增加。已经证明，在临床前和临床环境中，诱导针对β-淀粉样肽的抗体对阿尔茨海默病具有治疗效果。这一途径目前被病理性自身反应性T辅助细胞的激发所阻碍。为了克服这个问题，我们和其他人正在开发几种限制病理免疫的策略。在目前的项目中，我们建议开发安全有效的双重疫苗，基于流感病毒载体和来自β-淀粉样多肽的免疫优势B细胞表位，可以预防/减少早期AD患者的阿尔茨海默病病理发展，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.