Stimulating innate immunity to protect against Ebola virus infection

刺激先天免疫力以预防埃博拉病毒感染

• 批准号: 10325941
• 负责人: George Norbert Cox
• 金额: $ 30万
• 依托单位: BOLDER BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-02 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325941
• 关键词: Animals; Antibiotics; Antibodies; Biological Availability; Bioterrorism; Blood Cells; Burkholderia; Categories; Category A pathogen; Cells; Clinical; Contracts; DNA Sequence Alteration; Data; Dendritic Cells; Development; Disease Outbreaks; Dose; Drug Kinetics; Ebola; Ebola virus; Emergency Situation; Emerging Communicable Diseases; Filovirus; Future; Government; Grant; Half-Life; Health Personnel; Homologous Gene; Hour; Human; Immune response; Immune system; Immunity; In Vitro; Infection; Interferon Type II; Intramuscular; Intraperitoneal Injections; Intravenous infusion procedures; Marburgvirus; Measures; Medicine; Methods; Modeling; Morbidity - disease rate; Mus; Mutation; Myeloid Cells; National Institute of Allergy and Infectious Disease; National Security; Natural Immunity; Patients; Pharmacology; Plasma; Production; Property; Prophylactic treatment; Protein Engineering; Proteins; Public Health; Reproducibility; Resistance; Resistance development; Running; Safety; Subcutaneous Injections; Testing; Time; Tularemia; Vaccines; Virus; Virus Diseases; Weight Gain; analog; arm; chemokine; comparative efficacy; cytokine; effective therapy; emergency service responder; first responder; high risk; improved; in vivo; intraperitoneal; macrophage; manufacturing process; mortality; nonhuman primate; novel; novel therapeutics; pathogen; pathogenic bacteria; pathogenic microbe; pathogenic virus; phase 2 study; pre-exposure prophylaxis; preclinical study; prevent; prophylactic; scale up; subcutaneous; viral resistance; weapons; Animals; Antibiotics; Antibodies; Biological Availability; Bioterrorism; Blood Cells; Burkholderia; Categories; Category A pathogen; Cells; Clinical; Contracts; DNA Sequence Alteration; Data; Dendritic Cells; Development; Disease Outbreaks; Dose; Drug Kinetics; Ebola; Ebola virus; Emergency Situation; Emerging Communicable Diseases; Filovirus; Future; Government; Grant; Half-Life; Health Personnel; Homologous Gene; Hour; Human; Immune response; Immune system; Immunity; In Vitro; Infection; Interferon Type II; Intramuscular; Intraperitoneal Injections; Intravenous infusion procedures; Marburgvirus; Measures; Medicine; Methods; Modeling; Morbidity - disease rate; Mus; Mutation; Myeloid Cells; National Institute of Allergy and Infectious Disease; National Security; Natural Immunity; Patients; Pharmacology; Plasma; Production; Property; Prophylactic treatment; Protein Engineering; Proteins; Public Health; Reproducibility; Resistance; Resistance development; Running; Safety; Subcutaneous Injections; Testing; Time; Tularemia; Vaccines; Virus; Virus Diseases; Weight Gain; analog; arm; chemokine; comparative efficacy; cytokine; effective therapy; emergency service responder; first responder; high risk; improved; in vivo; intraperitoneal; macrophage; manufacturing process; mortality; nonhuman primate; novel; novel therapeutics; pathogen; pathogenic bacteria; pathogenic microbe; pathogenic virus; phase 2 study; pre-exposure prophylaxis; preclinical study; prevent; prophylactic; scale up; subcutaneous; viral resistance; weapons

Abstract. Filoviruses such as Ebola and Marburg viruses are Category A pathogens (pathogens that provide the highest risk to national security and public health) on NIAID's list of emerging infectious diseases due to their ease of dissemination, high mortality rates, and potential use as bioterrorism weapons. There is a need for fast acting, easy to use, and more effective medicines to protect against and improve survival from Ebola virus infection. Vaccines in development require at least 10 days for subjects to develop immunity and thus are not useful for treating newly infected patients or protecting non-vaccinated healthcare providers and first responders in an emergency outbreak situation. Antibiotics and antibody cocktails under study require intravenous infusion and resistance may develop through random or directed virus mutation. An alternative and potentially synergistic approach for protecting against Ebola virus infection is to stimulate the innate arm of the host immune system to resist viral infection. Macrophages and dendritic cells typically are the first cells infected by Ebola virus. Upon entry, the virus replicates and expresses proteins that interfere with the host cell's ability to block viral infection. The virus also causes host cells to secrete proinflammatory cytokines and chemokines that attract other myeloid cells to propagate the infection and results in a dysfunctional immune response unable to control the virus. Interferon gamma (IFNG) quickly (within hours) activates macrophages and dendritic cells so that they resist infection by Ebola and other viruses, as well as infection by several Category A facultative intracellular bacterial pathogens such as Tularemia and Burkholderia. Thus, IFNG has the potential to be an effective therapy against several deadly bioterrorism threats. However, IFNG has a very short in vivo half-life, poor bioavailability, required intraperitoneal injection for efficacy in preclinical studies, and has a narrow efficacy window, all of which limit the protein's utility as an Ebola therapy. We created a long- acting human IFNG analog (PEG IFNG) that has superior bioavailability and a longer half-life following subcutaneous injection and significantly greater efficacy than IFNG in animals. We hypothesize PEG-IFNG will be significantly more effective than IFNG at preventing morbidity and mortality from Ebola virus infection both as a protectant for pre-exposure prophylaxis and as a mitigator for post-exposure prophylaxis. We will test this hypothesis by comparing efficacy of a murine PEG IFNG homolog and murine IFNG administered pre and post infection for reducing morbidity and mortality from lethal Ebola virus infection in mice, as measured by survival, weight gain and clinical sickness scores. These studies will lead to an effective treatment that confers protection within hours and which can be administered easily (subcutaneous injection) to patients who recently contracted Ebola virus, as well as to first responders and healthcare providers in an emergency outbreak situation. Stimulating innate immunity using PEG IFNG will protect against Ebola virus and multiple other intracellular Category A pathogens such as Tularemia and Burkholderia that replicate within macrophages.

抽象的。埃博拉病毒和马堡病毒等丝病毒是病原体类别（提供的病原体 国家安全和公共卫生的最高风险）NIAID由于 他们易于传播，高死亡率和潜在用作生物恐怖武器。有需要 快速表演，易于使用和更有效的药物，以防止和改善埃博拉病毒的生存 病毒感染。发育中的疫苗至少需要10天才能使受试者发展免疫，因此 对于治疗新感染的患者或保护非接种疫苗的医疗保健提供者，首先是无用的 在紧急爆发情况下的响应者。正在研究的抗生素和抗体鸡尾酒需要 静脉输注和耐药性可能通过随机或定向病毒突变而发展。替代方案 防止埃博拉病毒感染的潜在协同方法是刺激先天臂 宿主免疫系统可抵抗病毒感染。巨噬细胞和树突状细胞通常是第一个细胞 被埃博拉病毒感染。进入后，病毒复制并表达干扰宿主的蛋白质 细胞阻断病毒感染的能力。该病毒还会导致宿主细胞分泌促炎性细胞因子和 吸引其他髓样细胞传播感染并导致功能障碍免疫的趋化因子 反应无法控制病毒。干扰素伽玛（IFNG）迅速（在几个小时内）激活巨噬细胞 和树突状细胞，以便它们抵抗埃博拉病毒和其他病毒的感染，以及几个感染 A类细胞内细菌病原体，例如Tuarlemia和Burkholderia。因此，IFNG具有 有效的疗法，以应对几种致命的生物恐怖威胁。但是，IFNG非常 简短的体内半衰期，生物利用度差，需要腹膜内注射才能在临床前研究中的功效，并且需要 具有一个狭窄的功效窗口，所有这些窗口都限制了蛋白质的用途作为埃博拉治疗。我们创造了一个长期的 具有优越的生物利用度和更长的半衰期的人类IFNG类似物（钉IFNG） 皮下注射和比动物中的IFNG明显更大的功效。我们假设PEG-IFNG将会 比IFNG在防止埃博拉病毒感染的发病率和死亡率方面更有效 作为暴露前预防的保护剂，作为暴露后预防的缓解剂。我们将测试这个 假设通过比较鼠钉同性恋和鼠IFNG的疗效。 通过生存测量，可降低小鼠致命埃博拉病毒感染的发病率和死亡率的感染 体重增加和临床疾病得分。这些研究将导致一种有效的治疗方法 在几个小时内进行保护，并且可以轻松给予（皮下注射）对最近的患者 在紧急爆发中，埃博拉病毒以及第一反应者和医疗保健提供者 情况。使用PEG IFNG刺激先天免疫会预防埃博拉病毒和多个其他 细胞内类别的病原体，例如巨噬细胞中复制的Tularemia和Burkholderia。