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.

项目总结