Poly-ICLC Prophylaxis Treatment of Ebola Virus Infection

在埃博拉病毒自然或故意暴发期间，暴露期间预防是保护高暴露风险目标人群的一种潜在有效方法。这项建议中提出的临床前小鼠数据表明，在疫情控制的情况下，聚ICLC可以提供高安全边际的保护。Poly-ICLC(Hiltonol(TM))是一种稳定的、临床安全和有效的、但相对简单的dsRNA病毒模拟物，其天然和适应性宿主免疫反应的广泛激活导致在刺激长期特定体液和细胞免疫的情况下立即处于非特异性抗病毒状态。它表现出广泛的抗病毒保护，无论是肌肉内还是鼻腔内给药，使其成为国家生物防御武器库中潜在的有价值的制剂。 总体目标：加快开发dsRNA病毒模拟聚ICLC(Hiltonol(TM))，作为一种安全、有效和后勤简单的预防和早期治疗人类埃博拉病毒感染的方法。具体目的：a)在已建立的小鼠攻击模型中，确定Poly-ICLC预防和治疗埃博拉病毒感染的最佳剂量和方案，并进一步阐明其作用机制和对病毒载量以及天然免疫和获得性免疫元件的影响；B)在已建立的非人灵长类(食蟹猴)攻击模型中，利用小鼠研究确定的最佳给药方案，确认PolyICLC预防和治疗埃博拉病毒感染的安全性和有效性。 C)根据FDA的具体指导，开发Poly-ICLC的GMP制造方法。

Peri-exposure prophylaxis is a potentially effective method of protecting targeted populations at high risk of exposure during a natural or intentional outbreak of Ebola virus. Preclinical murine data presented in this proposal indicates that poly-ICLC could provide such protection with a high safety margin in an epidemic containment situation. Poly-ICLC (Hiltonol(TM)) is a stabilized, clinically safe and active, yet relatively simple dsRNA viral-mimic whose broad activation of both innate and adaptive host immune responses results in an immediate non-specific antiviral state in the context of stimulation of longer-term specific humoral and cellular immunity. Its demonstrated broad antiviral protection when delivered either intramuscularly or intranasally make it a potentially valuable agent for inclusion in the Nation's biodefense armamentarium. General Aims: To accelerate the development of the dsRNA viral-mimic poly-ICLC (Hiltonol(TM)) as a safe, effective and logistically simple prophylaxis and early treatment for ebola virus infection in humans. Specific Aims: A) To determine the optimal dose and schedule of poly-ICLC for prophylaxis and treatment of Ebola virus infection in an established murine challenge model, and to further elucidate its mechanism of action and effect on viral load and on elements of innate and adaptive immunity B) To confirm the safety and efficacy of poly-ICLC in prophylaxis and treatment of ebola virus infection in a well-established non-human primate (cynomolgous) challenge model, utilizing the optimal dose schedules determined in the murine studies. C) To develop GMP manufacturing methods for Poly-ICLC, in compliance with specific FDA guidance.