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，这些佐剂和自身反应性T细胞被认为是导致AD患者中AN 1792临床试验应答中发生的不良事件（脑膜炎）的原因。我们的原型肽表位疫苗（PepVac）和DNA表位疫苗（DepVac）被设计为具有三个拷贝的自身B细胞表位A <$，A <$1 -11，与混杂的外源T细胞表位PADRE串联，PADRE与强大的抗炎分子佐剂巨噬细胞衍生的趋化因子（CCL 22）连接。我们的三方DepVac方法在AD转基因小鼠模型中诱导了稳健的抗A？抗体滴度。不幸的是，AN 1792临床试验的应答者数量也很少，并且对AN 1792疫苗有应答的应答者的滴度通常较低。因此，未来的临床试验需要解决老年人免疫衰老的普遍性，以确保疫苗的安全性和成功性。为了克服严重的问题，老年人的能力有限，安装一个有效的免疫反应，主动免疫，我们建议利用预先存在的记忆CD 4+辅助性T细胞（Th）细胞，产生响应于传统的公共卫生疫苗接种计划和/或感染各种病原体。因此，在我们的新方法中，我们已经工程化了含有预期激活记忆Th细胞的多Th表位的修饰的PepVac和DepVac，所述记忆Th细胞然后将为表达A B细胞表位的IG受体的B细胞提供Th刺激。这些第三代疫苗候选物已被命名为MPepVac和MDepVac以指示使用多Th表位。因此，该更新提案的目标是：1）证明预先存在的记忆性CD 4 +Th细胞在老年动物模型中诱导快速和稳健的抗A？抗体应答的可行性; 2）检查MDepVac和/或MPepVac在Tg 2576小鼠和兔中的安全性和功效，与啮齿动物相比，Tg 2576小鼠和兔代表了极好的较大动物模型，以显示扩大DNA免疫的可行性; 3）使用电穿孔系统比较肌内与皮内DNA免疫，所述电穿孔系统目前用于其他疫苗应用的人类临床试验。最终，我们相信，我们的基于AD DNA和蛋白质的表位疫苗候选物的进一步改进将有助于在非常早期的AD中转化为人类临床试验，或者优选地转化为通过经验证的AD生物标志物鉴定的临床前阶段个体。

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.