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

大量的病原体有可能用于生物恐怖主义行为，而且无法预测 特定的病原体威胁决定了对治疗平台的需要， 特别的生物威胁在这种情况下，理想的生物防御治疗平台应具备以下条件 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）易于 以合理的成本大量生产;（3）人群中没有预先存在的免疫力;以及（4） 通过单次给药诱导快速和持续的保护。为了满足这些标准，我们 开发了一种基于腺病毒（Ad）和腺相关病毒的多功能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抗原的病毒（AAV）基因转移载体 抗体的对于抗原递送，Ad和AAV基因转移载体已经证明作为疫苗的功效 对抗各种病原体对于抗体递送，Ad的不同动力学表达谱（快速，但快速，但快速）是不同的。 短，1至21天）和AAV（较慢，但持续;从1周至数年）基因转移载体可以是 用于短期保护、长期保护或当共同施用载体时的组合。 为了避免针对常见Ad和AAV血清型的预先存在的免疫问题，我们将 集中于使用非人灵长类动物来源的Ad（AdC 7）和AAV（AAVrh.10）血清型， 在人群中传播，并且人类对其没有预先存在的免疫力。这项建议 解决了该技术对基孔肯雅病毒（CHIKV）和尼帕病毒（NiV）的有效性， 新出现的病原体，没有治疗方法存在。建议的具体目标包括：（1） 用于诱导获得性免疫应答的基于AdC 7和AAVrh.10的疫苗载体的开发 分析每种载体引起的相关细胞免疫谱;（2）AdC 7- 和基于AAVrh.10的表达CHIKV或NiV中和单克隆抗体的载体， 比较IgG定点突变体以评估抗体介导的保护机制;以及（3） 评估疫苗载体的组合对以下疾病的快速和持续保护效力： 在单次共施用后，用毒性CHIKV或NiV攻击。

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.