Combining AD Epitope Vaccine with Innate Immunity

AD表位疫苗与先天免疫相结合

• 批准号: 8274897
• 负责人: Michael G Agadjanyan
• 金额: $ 43.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-25 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274897
• 关键词: AN-1792; Active Immunization; Address; Adjuvant; Adverse event; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antibody Formation; Antigen Presentation Pathway; Antigens; Ants; Asses; B-Lymphocyte Epitopes; B-Lymphocytes; Biological Markers; CCL22 gene; CD4 Positive T Lymphocytes; Clinical Data; Clinical Research; Clinical Trials; Complement 3d; DNA; DNA Vaccines; DNA delivery; Dementia; Deposition; Development; Diagnosis; Dose; Elderly; Electrodes; Electroporation; Engineering; Epitopes; Funding; Future; Generations; Goals; Health; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Human; Immune response; Immunization; Immunologic Tests; Immunotherapy; Impaired cognition; Individual; Infection; Intradermal Tests; Intramuscular; Intramuscular Injections; Judgment; Langerhans cell; Language; Link; Mannans; Medical; Memory; Methods; Molecular; Monitor; Mus; Natural Immunity; Neurites; Neurofibrillary Tangles; Oryctolagus cuniculus; Pathology; Patients; Peptides; Plasma Cells; Prevalence; Production; Proteins; Public Health; Recombinant Proteins; Recombinant Vaccines; Recombinants; Regimen; Risk; Rodent; Route; Safety; Senile Plaques; Skin; Staging; Supplementation; System; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Tg2576; Therapeutic; Therapeutic Effect; Time; Transgenic Mice; Translations; Treatment Efficacy; Vaccinated; Vaccination; Vaccines; Viral; aged; aluminum sulfate; autoreactive T cell; base; cell mediated immune response; design; efficacy testing; flexibility; gene gun; immunogenic; immunogenicity; immunosenescence; lymph nodes; macrophage-derived chemokine; memory CD4 T lymphocyte; mouse model; neuron loss; novel strategies; particle; pathogen; pre-clinical; preclinical study; prevent; programs; prototype; receptor; response; scale up; success; vaccine candidate; vaccine safety

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.

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 A¿ - AD 免疫治疗需要抗 A¿抗体，同时避免促炎佐剂和自身反应性 T 细胞，它们被认为是针对 AD 患者的 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)。 ）被设计为具有 A¿ 的自身 B 细胞表位的三个副本, A? 1-11，与混杂的外源 T 细胞表位 PADRE 串联，与强大的抗炎分子佐剂巨噬细胞衍生趋化因子 (CCL22) 结合，我们的三方 DepVac 方法诱导了强大的抗 A¿不幸的是，AN1792 临床试验的反应者数量也很少，而且对 AN1792 疫苗有反应的人抗体滴度普遍较低，因此未来的临床试验需要解决免疫衰老的普遍问题。为了克服对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) 细胞是针对传统公共卫生疫苗接种计划和/或各种病原体感染而产生的，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，然后为表达 A 的 Ig 受体的 B 细胞提供 Th 刺激1-11，B 细胞表位。这些第三代候选疫苗已被指定为 MPepVac 和 MDepVac，以表明使用多个 Th 表位。因此，该更新提案的目标是：1) 证明预先存在的记忆 CD4+ Th 的可行性。衰老动物模型中的细胞诱导快速而强大的抗 A¿抗体反应；2) 检查 MDepVac 和/或 MPepVac 在 Tg2576 小鼠和兔子中的安全性和有效性，与啮齿类动物相比，这是一种出色的大型动物模型，以显示扩大 DNA 免疫的可行性；3) 比较肌肉内和皮内 DNA 免疫使用电穿孔系统进行免疫，该系统目前正用于其他疫苗应用的人体临床试验，最终我们相信，基于 AD DNA 和蛋白质的候选表位疫苗的进一步完善将有助于转化。非常早期的 AD 人类临床试验，或者最好是通过经过验证的 AD 生物标志物识别的临床前阶段个体。 公共健康相关性：阿尔茨海默氏病是美国痴呆症的主要原因，其特点是进行性认知衰退，影响记忆、语言和判断力。 ，时间和地点的定向等。病理学上，淀粉样斑块、神经原纤维缠结、营养不良的神经突的存在增加，并且神经元普遍丧失。生产安全有效的表位疫苗，可以预防/减少诊断为早期 AD 的症状前人群发生阿尔茨海默病病理。