Combining AD Epitope Vaccine with Innate Immunity

描述(申请人提供)：临床前和临床数据表明，安全有效的AD免疫疗法的开发需要抗A？抗体，同时避免促炎佐剂和自身反应性T细胞，它们被认为是应对AN1792临床试验在AD患者中发生的不良事件(脑膜脑炎)的罪魁祸首。我们的原型肽表位疫苗(PepVac)和DNA表位疫苗(DepVac)是由三个拷贝的自身B细胞表位A？1-11和一个混杂的外源T细胞表位PADRE与强大的抗炎分子佐剂巨噬细胞衍生趋化因子(CCL22)连接而成的。我们的三方DepVac方法在转基因AD小鼠模型中诱导了强大的抗-A抗体滴度。不幸的是，AN1792临床试验的应答者数量很少，对AN1792疫苗有反应的人的效价通常也很低。因此，未来的临床试验需要解决老年人中免疫衰老的流行问题，以确保疫苗的安全性和成功。为了克服人们对老年人对主动免疫的有效免疫反应能力有限的严重担忧，我们建议利用预先存在的记忆CD4+T辅助(Th)细胞，这些细胞是在传统公共卫生疫苗接种计划和/或各种病原体感染时产生的。因此，在我们的新方法中，我们设计了包含多个Th表位的改良PepVac和DepVac，这些表位有望激活记忆Th细胞，然后提供Th刺激表达A？1-11，B细胞表位Ig受体的B细胞。这些第三代候选疫苗被指定为MPepVac和MDepVac，以表明使用多个Th表位。因此，这项更新建议的目标是：1)证明老年动物模型中预先存在的记忆CD4+Th细胞诱导快速而强劲的抗A？抗体反应的可行性；2)在Tg2576小鼠和兔子中检测MDepVac和/或MPepVac的安全性和有效性，与啮齿动物相比，这是一个很好的更大的动物模型，以证明扩大DNA免疫的可行性；3)比较目前用于人类临床试验的电穿孔系统的DNA免疫肌肉内和皮内DNA免疫的可行性。最终，我们相信，我们的基于DNA和蛋白质的AD表位候选疫苗的进一步完善将有助于在AD非常早期或最好是通过验证的AD生物标记物识别的临床前阶段的个体转化为人类临床试验。公共卫生相关性：阿尔茨海默病是美国痴呆症的主要原因，其特征是进行性认知能力下降，影响记忆力、语言、判断力、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增加，神经元普遍丧失。在目前的项目中，我们建议生产安全有效的表位疫苗，以防止/减少早期诊断为阿尔茨海默病症状前期患者的阿尔茨海默病病理的发展。

DESCRIPTION (provided by applicant): Pre-clinical and clinical data suggest that the development of a safe and effective A¿-immunotherapy for AD requires anti- A¿ antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which are believed to be responsible for the adverse events (meningoenchephalitis) that occurred in response to the AN1792 clinical trial in AD patients. Our prototype Peptide epitope Vaccine (PepVac) and DNA epitope Vaccine (DepVac) were designed with three copies of the self-B cell epitope of A¿, A¿1-11, in tandem with a promiscuous foreign T cell epitope, PADRE, linked to the powerful anti-inflammatory molecular adjuvant, macrophage derived chemokine (CCL22). Our tripartite DepVac approach induced robust anti-A¿ antibody titers in transgenic mouse models of AD. Unfortunately, the AN1792 clinical trial also suffered from a low number of responders and generally low titers in those that did respond to the AN1792 vaccine. Thus future clinical trials need to address the prevalence of immunosenescence in the elderly to insure both the safety and the success of the vaccine. In order to overcome serious concerns regarding the limited ability of the elderly to mount an effective immune response to active immunization, we propose to take advantage of pre-existing memory CD4+T helper (Th) cells that were generated in response to conventional public health vaccination programs and/or infections with various pathogens. Thus in our new approach we have engineered modified PepVac and DepVac that contain Multiple Th epitopes that are expected to activate memory Th cells, which will then provide Th stimulation of B cells expressing Ig receptors for the A¿1-11, B cell epitope. These third generation vaccine candidates have been designated MPepVac and MDepVac to indicate the use Multiple Th epitopes. Thus, the goals of this renewal proposal are: 1) to demonstrate the feasibility of pre-existing memory CD4+Th cells in aged animal models to induce a rapid and robust anti- A¿ antibody response; 2) to examine the safety and efficacy of MDepVac and/or MPepVac in Tg2576 mice and rabbits, which represent an excellent larger animal model compared to rodent to show feasibility to scale up DNA immunization; 3) to compare intramuscular versus intradermal DNA immunization using electroporation system that is currently being used in human clinical trials for other vaccine applications. Ultimately we believe that the further refinement our AD DNA- and protein-based epitope vaccine candidates will facilitate translation to human clinical trials in either very early AD, or preferably to preclinical stage individuals identified by validated AD biomarkers. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease is the major cause of dementia in the US and characterized by 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. In current project we propose to generate safe and effective epitope vaccine that may prevent/reduce development of Alzheimer's disease pathology in pre-symptomatic people diagnosed with early-stage AD.