Combining AD Epitope Vaccine with Innate Immunity

描述（由申请人提供）：临床前和临床数据表明，开发一种安全有效的AD a -免疫疗法需要抗a -抗体，同时避免促炎佐剂和自身反应性T细胞，这被认为是AD患者在AN1792临床试验中发生的不良事件（脑膜脑炎）的原因。我们的原型肽表位疫苗（PepVac）和DNA表位疫苗（DepVac）是用3个拷贝的A¿，A¿1-11的自身b细胞表位，与混杂的外源T细胞表位PADRE串联设计的，PADRE与强大的抗炎分子佐剂巨噬细胞衍生趋化因子（CCL22）相连。我们的三方DepVac方法在AD转基因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也很低，而且对AN1792疫苗有应答者的滴度普遍较低。因此，未来的临床试验需要解决老年人免疫衰老的患病率，以确保疫苗的安全性和成功。为了克服老年人对主动免疫产生有效免疫反应的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，这些细胞是在常规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，我们设计了改良的PepVac和DepVac，它们含有多个Th表位，有望激活记忆Th细胞，然后为A¿1-11 B细胞表位表达Ig受体的B细胞提供Th刺激。这些第三代候选疫苗被命名为MPepVac和MDepVac，以表明使用多个Th表位。因此，这一更新建议的目标是：1)证明在老年动物模型中预先存在的记忆CD4+Th细胞诱导快速和强大的抗a¿抗体反应的可行性；2)研究MDepVac和/或MPepVac在Tg2576小鼠和家兔身上的安全性和有效性，Tg2576小鼠和家兔与啮齿动物相比是一个很好的大动物模型，证明了扩大DNA免疫的可行性；3)比较肌内和皮内DNA免疫使用电穿孔系统，目前正在用于其他疫苗应用的人体临床试验。最终，我们相信进一步完善我们的基于DNA和蛋白质的阿尔茨海默病表位候选疫苗将有助于在早期阿尔茨海默病的人类临床试验中，或者最好是通过验证的阿尔茨海默病生物标志物识别的临床前阶段个体。公共卫生相关性：阿尔茨海默病是美国痴呆症的主要病因，其特点是认知能力逐渐下降，影响记忆、语言、判断、时间和地点定位等。病理表现为淀粉样斑块、神经原纤维缠结、神经突营养不良和神经元的普遍丧失。在目前的项目中，我们建议生产安全有效的表位疫苗，可以预防/减少早期AD症状前患者的阿尔茨海默病病理发展。

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.