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

基本信息

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
项目类别：
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

项目摘要

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。埃博拉病毒和马尔堡病毒等丝状病毒属于 A 类病原体（提供 NIAID 的新发传染病清单中对国家安全和公共卫生构成最高风险的疾病它们易于传播、死亡率高，并有可能被用作生物恐怖主义武器。有需要寻找起效快、易于使用且更有效的药物来预防埃博拉病毒并提高生存率病毒感染。开发中的疫苗至少需要 10 天才能让受试者产生免疫力，因此对于治疗新感染的患者或保护未接种疫苗的医疗保健提供者没有用处，首先紧急疫情爆发情况下的响应者。研究中的抗生素和抗体混合物需要静脉输注和耐药性可能通过随机或定向病毒突变而产生。替代方案和预防埃博拉病毒感染的潜在协同方法是刺激免疫系统的先天臂宿主免疫系统抵抗病毒感染。巨噬细胞和树突细胞通常是最早的细胞感染埃博拉病毒。一旦进入，病毒就会复制并表达干扰宿主的蛋白质细胞阻止病毒感染的能力。该病毒还会导致宿主细胞分泌促炎细胞因子吸引其他骨髓细胞传播感染并导致免疫功能失调的趋化因子反应无法控制病毒。 γ 干扰素 (IFNG) 快速（数小时内）激活巨噬细胞和树突状细胞，从而抵抗埃博拉病毒和其他病毒的感染，以及多种病毒的感染 A 类兼性细胞内细菌病原体，例如土拉菌病和伯克霍尔德杆菌。因此，IFNG 有可能成为对抗几种致命生物恐怖主义威胁的有效疗法。然而，IFNG 有一个非常体内半衰期短，生物利用度差，临床前研究需要腹腔注射才能发挥功效，以及功效窗口很窄，所有这些都限制了该蛋白质作为埃博拉疗法的效用。我们创建了一个长期的作用人 IFNG 类似物 (PEG IFNG)，具有卓越的生物利用度和更长的半衰期皮下注射，在动物中的疗效明显优于 IFNG。我们假设 PEG-IFNG 将在预防埃博拉病毒感染的发病率和死亡率方面比 IFNG 显着更有效作为暴露前预防的保护剂和暴露后预防的缓解剂。我们将测试这个通过比较小鼠 PEG IFNG 同源物和小鼠 IFNG 前后施用的功效来验证假设感染可降低小鼠致命埃博拉病毒感染的发病率和死亡率（以生存率衡量），体重增加和临床疾病评分。这些研究将带来一种有效的治疗方法数小时内即可获得保护，并且可以轻松地对最近患有此病的患者进行（皮下注射）感染埃博拉病毒，以及紧急疫情爆发时的急救人员和医疗保健提供者情况。使用 PEG IFNG 刺激先天免疫将预防埃博拉病毒和多种其他病毒细胞内 A 类病原体，如土拉菌病和伯克霍尔德杆菌，在巨噬细胞内复制。