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: 7670893
• 负责人: Gustavo F. Palacios
• 金额: $ 17.65万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670893
• 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.

有可能在生物恐怖行为中使用的大量病原体，并且无法预测 特定的病原体威胁决定了可以根据响应的治疗平台的需求 特定的生物治疗。在这种情况下，理想的BiodeFense治疗平台应具有以下内容 特性：（1）快速适应，随着病原体威胁的变化而允许简单的改变； （2）轻松 以合理的成本大量制造； （3）人口中没有预先存在的免疫力； （4） 单个管理诱导快速和持续的保护。为了满足这些标准，我们有 制定了一种多功能策略，以基于腺病毒（AD）并与腺相关的保护性免疫 病毒（AAV）基因转移载体，表达病原体特异性抗原或病原体中和化 抗体。对于抗原递送，AD和AAV基因转移载体已显示为疫苗的功效 针对各种病原体。对于抗体递送，AD的不同动力学表达谱（快速，但 简而 当对向量共同采用时，利用用于短期保护，长期保护或组合。 为了规避预先存在针对普通AD和AAV血清型的免疫力的问题，我们将 专注于使用非人类灵长类动物衍生的AD（ADC7）和AAV（AAVRH.10）血清型的使用 在人口中流通，人类没有先前的免疫力。这个建议 解决了该技术对Chikungunya病毒（CHIKV）和NIPAH病毒（NIV）的功效，两个 不存在治疗剂的新兴病原体。拟议的具体目的包括（1） 开发基于ADC7-和AAVRH.10的疫苗向量，以诱导获得的免疫反应 通过分析每个载体引起的相关细胞免疫特征； （2）ADC7-的生产 和AAVRH.10的矢量表达CHIKV或NIV中和单与单克隆抗体 比较IgG位置指导突变体以评估抗体介导的保护机制； （3） 评估疫苗向量的组合，以快速和持续的保护功效 一次共同给药后，有毒的Chikv或NIV挑战。