Poly-ICLC Prophylaxis Treatment of Ebola Virus Infection

暴露期预防是一种潜在的有效方法，可在埃博拉病毒自然或故意爆发期间保护暴露风险高的目标人群。本提案中提供的临床前小鼠数据表明，聚ICLC可以在流行病控制情况下提供高安全裕度的保护。Poly-ICLC（Hiltonol（TM））是一种稳定的、临床上安全和有活性的、但相对简单的dsRNA病毒模拟物，其先天性和适应性宿主免疫应答的广泛激活导致在刺激长期特异性体液和细胞免疫的情况下立即的非特异性抗病毒状态。它被证明是广泛的抗病毒保护时，无论是肌肉内或鼻内交付使它成为一个潜在的有价值的代理列入国家的生物防御医疗设备。 总体目标：加速开发双链RNA病毒模拟聚ICLC（Hiltonol（TM）），作为人类埃博拉病毒感染的安全、有效且后勤简单的预防和早期治疗方法。具体目标：A）为了在建立的鼠攻击模型中确定聚-ICLC用于预防和治疗埃博拉病毒感染的最佳剂量和时间表，并进一步阐明其作用机制和对病毒载量以及对先天性和适应性免疫要素的影响B）证实聚-ICLC在预防和治疗已确立的非人灵长类动物中埃博拉病毒感染中的安全性和有效性（食蟹猴）激发模型，利用鼠研究中确定的最佳剂量方案。 C）根据FDA的具体指导原则，制定聚ICLC的GMP生产方法。

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.