Pathogen-adaptable active and passive immunization platforms based on adenovirus.

基于腺病毒的病原体适应性主动和被动免疫平台。

• 批准号: 8043573
• 负责人: Gustavo F. Palacios
• 金额: $ 21.14万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8043573
• 关键词: Active immunity; Address; Adenovirus Vector; Adenoviruses; Alphavirus; Animals; Antibodies; Antibody-mediated protection; Antigens; Bacillus anthracis; Binding; Bioterrorism; Capsid; Capsid Proteins; Cellular Immunity; Chikungunya virus; Chimeric Proteins; Code; Combined Vaccines; Dependovirus; Development; Engineering; Gene Expression; Genes; Genetic; Human; Human Adenoviruses; Immune response; Immunity; Immunoglobulin G; Infection prevention; Intramuscular; Intranasal Administration; Kinetics; Mediating; Molecular Profiling; Monoclonal Antibodies; Morbidity - disease rate; Mutation; Nipah Virus; Passive Immunity; Passive Immunization; Population; Production; Property; Proteins; Serotyping; Site; Technology; Testing; Therapeutic; Time; Transgenes; Vaccines; Viral; Viral Antigens; Virulent; Virus; adeno-associated viral vector; base; biodefense; chikungunya; comparative; cost; experience; gene transfer vector; in vivo; meetings; mortality; mutant; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; pathogen; protective efficacy; response; subcutaneous; therapeutic vaccine; vaccine candidate; vaccine development; vector; vector vaccine; vector-based vaccine

The large number of pathogens with potential for use in an act of bioterrorism and the inability to predict the particular pathogen threat dictates the need for a therapeutic platform that can be adapted in response to particular biothreats. In this context, the ideal biodefense therapeutic platform should have the following properties: (1) rapid adaptation, allowing simple alterations as the pathogen threat changes; (2) ease of manufacture in large quantities at reasonable cost; (3) no pre-existing immunity in the population; and (4) induction of rapid and sustained protection with a single administration. To meet these criteria, we have developed a versatile strategy to elicit protective immunity based on adenovirus (Ad) and adeno-associated virus (AAV) gene transfer vectors expressing either pathogen-specific antigens or pathogen-neutralizing antibodies. For antigen delivery, Ad and AAV gene transfer vectors have demonstrated efficacy as vaccines against a variety of pathogens. For antibody delivery, the different kinetic expression profiles of Ad (rapid, but short, 1 to 21 days) and AAV (slower, but persistent; from 1 wk to years) gene transfer vectors can be exploited for short-term protection, long-term protection or a combination when the vectors are coadministered. To circumvent issues of pre-existing immunity against common Ad and AAV serotypes, we will focus on the use of non-human primate-derived Ad (AdC7) and AAV (AAVrh.10) serotypes that do not circulate in the human population, and for which humans do not have pre-existing immunity. This proposal addresses the efficacy of this technology for Chikungunya virus (CHIKV) and Nipah virus (NiV), two emerging pathogens for which no therapeutics exist. The proposed specific aims include (1) the development of AdC7- and AAVrh.10-based vaccine vectors for induction of acquired immune responses with an analysis of the relevant cellular immunity profiles elicited by each vector; (2) the production of AdC7- and AAVrh.10-based vectors expressing CHIKV or NiV-neutralizing monoclonal antibodies with a comparison of IgG site-directed mutants to evaluate the mechanism of antibody-mediated protection; and (3) an assessment of combinations of the vaccine vectors for rapid and sustained protective efficacy against virulent CHIKV or NiV challenge following a single co-administration.

大量病原体可能被用于生物恐怖主义行为，并且无法预测 特定的病原体威胁决定了需要一个可以适应的治疗平台 特定的生物威胁。在此背景下，理想的生物防御治疗平台应具备以下特点 特性：（1）快速适应，允许随着病原体威胁的变化进行简单的改变； (2) 方便性 以合理的成本进行大批量生产； (3) 人群中不存在预先存在的免疫力；和（4） 通过单次给药即可诱导快速且持续的保护。为了满足这些标准，我们有 开发了一种基于腺病毒（Ad）和腺相关蛋白的通用策略来引发保护性免疫 表达病原体特异性抗原或病原体中和性病毒（AAV）基因转移载体 抗体。对于抗原递送，Ad 和 AAV 基因转移载体已证明作为疫苗的功效 对抗多种病原体。对于抗体递送，Ad 的不同动力学表达谱（快速，但 短，1 至 21 天）和 AAV（较慢，但持久；从 1 周到数年）基因转移载体可以 当载体共同施用时，可用于短期保护、长期保护或组合保护。 为了规避针对常见 Ad 和 AAV 血清型的现有免疫力问题，我们将 重点关注非人类灵长类动物来源的 Ad (AdC7) 和 AAV (AAVrh.10) 血清型的使用，这些血清型不 在人群中传播，并且人类对其没有预先存在的免疫力。这个提议 阐述了该技术对基孔肯雅病毒 (CHIKV) 和尼帕病毒 (NiV) 两种病毒的功效 尚无治疗方法的新出现的病原体。拟议的具体目标包括（1） 开发基于 AdC7 和 AAVrh.10 的疫苗载体，用于诱导获得性免疫反应 分析每个载体引发的相关细胞免疫特征； (2) AdC7-的产生 和基于 AAVrh.10 的载体，表达 CHIKV 或 NiV 中和单克隆抗体 比较 IgG 定点突变体以评估抗体介导的保护机制；和（3） 评估疫苗载体组合的快速和持续的保护功效 单次共同给药后的毒性 CHIKV 或 NiV 挑战。