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

大量可能用于生物恐怖主义行为的病原体，以及无法预测 特定的病原体威胁决定了对治疗平台的需求，该平台可以适应 特殊的生物栖息地。在这种背景下，理想的生物防御治疗平台应该具备以下几个方面 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)人口中没有预先存在的免疫力；和(4) 通过一次给药诱导快速和持续的保护。为了达到这些标准，我们有 开发了一种基于腺病毒(Ad)和腺相关病毒(Ado-Association)的多功能策略来诱导保护性免疫 表达病原特异性抗原或中和病原的AAV基因转移载体 抗体。在抗原传递方面，Ad和AAV基因转移载体已被证明是有效的疫苗 对抗各种病原体。对于抗体递送，不同的Ad(快速，但 短，1到21天)和AAV(较慢，但持续；从1周到几年)基因转移载体可以 用于短期保护、长期保护或当病媒共同管理时的组合。 为了绕过对常见的Ad和AAV血清型的预先存在的免疫问题，我们将 重点使用非人类灵长类来源的Ad(AdC7)和AAV(AAVRh.10)血清型 在人类群体中循环，而人类对此并不具有预先存在的免疫力。这项建议 阐述了这项技术对基孔肯雅病毒(CHIKV)和尼帕病毒(NIV)的有效性，这两种病毒 没有治疗方法的新出现的病原体。建议的具体目标包括：(1) 诱导获得性免疫应答的AdC7和AAVRh.10疫苗载体的研制 并分析了每个载体诱导的相关细胞免疫图谱；(2)AdC7- 和基于AAVRh.10的表达CHIKV或NIV中和抗体的载体 比较免疫球蛋白定点突变体以评价抗体介导的保护机制； 疫苗载体组合的快速和持续保护效果的评估 在单一联合管理下进行致命的CHIKV或NIV挑战。

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.