Evaluation of Safe and Immunogenic Dose of AD Vaccine in aged non-human primates: Prelude to Phase 1 Preventive Vaccinations

AD 疫苗在老年非人灵长类动物中的安全和免疫原性剂量评估：第一阶段预防性疫苗接种的前奏

• 批准号: 10433497
• 负责人: Michael G Agadjanyan
• 金额: $ 41.95万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433497
• 关键词: Active Immunotherapy; Adjuvant; Administrative Supplement; Aducanumab; Alzheimer disease prevention; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Antibodies; Antibody titer measurement; B-Lymphocyte Epitopes; B-Lymphocytes; Behavioral; Biochemistry; Biological Assay; Biological Markers; Biological Process; Blood; Brain; C-reactive protein; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Cyclic GMP; Data; Disease; Disease Progression; Disease model; Dose; Early Intervention; Early treatment; Emergency Situation; Enzyme-Linked Immunosorbent Assay; Evaluation; Female; Future; Genetic Polymorphism; Goals; Helper-Inducer T-Lymphocyte; Human; Immune system; Immunization; Immunize; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Inflammation; Injections; Interferon Type II; Intramuscular; Longevity; Macaca fascicularis; Memory; Methods; Monitor; Monkeys; Monoclonal Antibodies; Mus; Onset of illness; Paper; Passive Immunotherapy; Pathologic; Pathologic Processes; Pathology; Peripheral Blood Mononuclear Cell; Phase; Preventative vaccination; Preventive; Preventive treatment; Production; Publishing; Recombinant Proteins; Reporting; Research; Risk; Safety; Site; Testing; Therapeutic; Time; TimeLine; Toxic effect; Toxicology; Vaccine Clinical Trial; Vaccines; adaptive immunity; age group; aged; autoreactive T cell; autoreactivity; base; first-in-human; immunogenic; immunogenicity; male; meetings; mouse model; multidisciplinary; multiple omics; non-demented; nonhuman primate; novel; pathogen; phase I trial; pre-clinical; prevent; programs; response; synergism; targeted treatment; tau Proteins; tau aggregation; tau-1; therapy development; treatment strategy; vaccine development; vaccine trial

Project Summary Immunotherapy is still considered a very promising therapeutic strategy for AD prevention when certain conditions are met. Data from various immunotherapeutic studies support our long- standing tenet that immunogenic AD vaccines could at least delay disease progression when they target both Aβ and Tau pathological molecules at an early stage of the disease before AD manifestation or even in asymptomatic healthy people at risk of AD. Recently FDA announced emergency accelerated approval of mAb Aducanumab for treatment of early AD. However, it is impractical to use very expensive mAbs as a preventive treatment of healthy subjects due to the need for frequent (monthly) administration of high concentrations (700-800mg per IV injection) of this immunotherapeutic. In contrast, almost all effective vaccines are effective when they are used as a preventive treatment. Accordingly, in this administrative supplement to U01 AG060965, we propose to test the overall safety and immunogenicity of a dual vaccine (DUVAC) targeting Aβ and Tau in non-human primates that more closely resemble the human immune system. These data will support the submission of INDs to the FDA for future clinical trials that will allow us to treat asymptomatic healthy subjects at risk to MCI with extremely immunogenic Aβ and tau vaccines based on the same and very immunogenic MultiTEP platform and novel adjuvant AdvaxCpG. Our proprietary vaccine platform can stimulate adaptive immunity, providing broad coverage of human MHC polymorphisms and activating both naive Th cells and pre-existing memory Th cells generated in response to conventional vaccines and/or infections with various pathogens during one's lifespan without the activation of harmful autoreactive T cells. These "non-self" Th cells should activate B cells and induce the production of therapeutically potent antibodies specific to pathological Aβ and Tau in humans, similar to that in non-human primates. Completing studies in aged monkeys along with data from AG060965 safety/toxicology studies in diseased mice should strongly support our IND submission for the first-in-human preventive dual Aβ/tau vaccine with healthy people at risk of MCI or earlier based on research blood, CSF, brain biomarkers.

项目摘要 免疫疗法仍然被认为是预防阿尔茨海默病的一种非常有前途的治疗策略 满足某些条件。来自各种免疫治疗研究的数据支持我们的长期- 坚持的原则是，免疫原性AD疫苗至少可以延缓疾病的进展，当它们 在AD之前的疾病早期阶段同时靶向Aβ和Tau病理分子 甚至在无症状的健康人群中表现为阿尔茨海默病。FDA最近宣布 紧急加速批准单抗Aducanumab用于治疗早期AD。然而，它是 使用非常昂贵的单抗作为健康受试者的预防性治疗是不切实际的，因为 需要经常(每月)服用高浓度(每次静脉注射700-800毫克) 这种免疫疗法。相比之下，几乎所有有效的疫苗在使用时都是有效的 作为一种预防性治疗。因此，在U01 AG060965的这一行政副刊中，我们 建议测试针对β的双重疫苗的整体安全性和免疫原性 和Tau在非人类灵长类动物中更接近于人类的免疫系统。这些 数据将支持将IND提交给FDA进行未来的临床试验，这将使我们能够 用极具免疫原性的A、β和tau治疗有轻度脑梗塞风险的无症状健康患者 基于同一高度免疫原性多TEP平台和新型佐剂的疫苗 AdvaxCpG。我们的专有疫苗平台可以刺激适应性免疫，提供广泛的 人类MHC基因多态及激活初始Th细胞和预先存在的Th细胞的覆盖率 在常规疫苗和/或感染各种不同疾病时产生的记忆Th细胞 在没有激活有害的自身反应性T细胞的情况下，在人的一生中感染病原体。这些 “非我”Th细胞应激活B细胞并诱导产生治疗效应 人类中针对病理性Aβ和Tau的抗体，与非人类灵长类动物中的类似。 完成对老年猴子的研究以及AG060965安全/毒理学研究的数据 患病小鼠应大力支持我们的IND提交的人类首例预防性双重试验 一种基于血液、脑脊液、脑研究的针对有心肌梗塞风险或更早风险的健康人的β/tau疫苗 生物标志物。