Learning from the Ebola success: Can a mAb also save lives after yellow fever infection?

借鉴埃博拉病毒的成功经验：单克隆抗体也能拯救黄热病感染后的生命吗？

• 批准号: 10669613
• 负责人: David I Watkins
• 金额: $ 97.87万
• 依托单位: MABLOC, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669613
• 关键词: Adverse effects; Biotechnology; Brazil; Cessation of life; Characteristics; Collaborations; Collection; Culicidae; Data; Death Rate; Dengue Virus; Development; Diagnosis; Diagnostic tests; Disease; Disease Outbreaks; Ebola; Ebola virus; Flavivirus; Flavivirus Infections; Hospitalization; Immunization; In Vitro; Incidence; Individual; Infection; Laboratories; Learning; Macaca; Macaca mulatta; Mass Vaccinations; Mesocricetus auratus; Modeling; Monkeys; Monoclonal Antibodies; Mosquito-borne infectious disease; Mutation; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Play; Populations at Risk; Prevention; Rapid diagnostics; Reporting; Research Institute; Research Personnel; Role; Testing; Time; Tissues; Universities; Vaccination; Vaccinee; Vaccines; Viral Load result; Virion; Virus; Virus Diseases; Virus Replication; World Health Organization; Yellow Fever; Yellow Fever Virus Infection; Yellow fever virus; ZIKV infection; Zika Virus; cross reactivity; disease transmission; efficacy testing; experimental study; human tissue; in vitro Assay; in vivo; infectious disease treatment; mortality; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; novel drug class; pregnant; prevent; public health emergency; public health relevance; screening; side effect; success; virus envelope

Abstract PROJECT SUMMARY/ABSTRACT The recent groundbreaking experiment using a single neutralizing monoclonal antibody (nmAb) to reduce the death rate in Ebola virus (EBOV)-infected individuals highlights the importance of this class of drug in the treatment of infectious disease. In August 2019, Dr. Anthony Fauci announced that administration of mAb114 had reduced the death rate from 70% to approximately 35% in EBOV-infected patients. EBOV infection is no longer considered a uniformly fatal disease. Similar to EBOV infection, wild-type yellow fever virus (wtYFV) infection results in high viral loads and a death rate of up to 50% in hospitalized patients. Once infected, there is no current treatment available. While the YFV17D vaccine is generally efficacious, it has some potentially severe side effects which diminish its coverage. Unfortunately, the World Health Organization (WHO) reported approximately 100 cases of severe adverse effects due to mass vaccination campaigns in Brazil, dissuading many people from receiving the vaccine. Even though vaccination campaigns were launched, immunization coverage remains low, leaving a significant number of people at risk. Most of the world, including the U.S., is vulnerable to mosquito-transmitted diseases, as shown by the emergence of two related flaviviruses dengue (DENV) and Zika (ZIKV). At Mabloc LLC, through our collaborations with the Watkins, Kallas and Burton laboratories, and Adimab LLC, we have assembled a large collection of flavivirus-specific neutralizing monoclonal antibodies (nmAbs). Indeed, the Watkins laboratory has already shown that these mAbs can be used for the prevention and treatment of flavivirus infections. The Watkins and Burton laboratories, and more recently others, have demonstrated that ZIKV infection can be prevented in Indian rhesus macaques by using either a nmAb cocktail or a single nmAb. Additionally, the Watkins and Burton laboratories have also shown that this cocktail can reduce viral load to undetectable levels in ZIKV-infected pregnant macaques. These data demonstrated, for the first time, that post-exposure treatment with nmAbs can reduce flavivirus replication in a relevant non- human primate (NHP) model. In Phase I of this application, we plan to identify at least five nmAbs from our existing pool of mAbs for wtYFV treatment using in vitro assays and in vivo screening in Syrian golden hamsters. In Phase II, we will perform tissue cross reactivity studies using our best YFV-specific nmAbs. We will then test the efficacy of the best three nmAbs in treating wtYFV-infected monkeys. After the completion of this Fast-Track Phase I/II application, we plan to have at least a commercially viable cocktail or a single nmAb that can efficaciously suppress viral replication in wtYFV-challenged NHPs, and thereby save them from the sequelae of wtYFV infection, namely death.

抽象的 项目摘要/摘要最近使用单个中和单克隆抗体（NMAB）降低埃博拉病毒（EBOV）感染的个体的死亡率的突破性实验突出了这类药物在治疗传染病中的重要性。 2019年8月，Anthony Fauci博士宣布，在EBOV感染的患者中，MAB114的管理已从70％降低到约35％。 EBOV感染不再被认为是统一的致命疾病。与EBOV感染相似，野生型黄热病病毒（WTYFV）感染导致高病毒负荷和住院患者的死亡率高达50％。感染后，目前将没有可用的治疗方法。虽然YFV17D疫苗通常是有效的，但它具有一些潜在的严重副作用，从而降低了其覆盖范围。不幸的是，由于巴西大规模疫苗接种运动，世界卫生组织（WHO）报告了大约100例严重不良影响，劝阻许多人接受该疫苗。即使发起了疫苗接种运动，免疫承保范围仍然很低，使许多人处于危险之中。包括美国的大多数地方，包括美国，容易受到蚊子传播的疾病的影响，如两个相关的黄病毒登革热（DENV）和Zika（Zikv）的出现所示。在Mabloc LLC，通过与Watkins，Kallas和Burton Laboratories以及Adimab LLC的合作，我们组装了大量的Flavivivurus特异性中和中和中和的单网抗体（NMABS）。确实，沃特金斯实验室已经表明，这些mAB可用于预防和治疗黄病毒感染。沃特金斯（Watkins）和伯顿（Burton）实验室以及最近的实验室已经证明，通过使用NMAB鸡尾酒或单个NMAB，可以在印度恒河猕猴中预防ZIKV感染。此外，沃特金斯和伯顿实验室还表明，这种鸡尾酒可以将病毒载量降低到ZIKV感染的怀孕猕猴中无法检测到的水平。这些数据首次证明了使用NMAB的暴露后治疗可以减少相关非人类灵长类动物（NHP）模型中的黄病毒复制。在本应用的第一阶段，我们计划使用现有的mAB库中的至少五个NMAB，用于使用体外测定和叙利亚金仓鼠的体内筛查进行WTYFV处理。在第二阶段，我们将使用我们最好的YFV特异性NMAB进行组织交叉反应性研究。然后，我们将测试最好的三个NMAB在处理WTYFV感染的猴子方面的功效。在此快速轨道I/II阶段应用程序完成后，我们计划至少拥有一家商业上可行的鸡尾酒或单个NMAB，该鸡尾酒可以有效地抑制WTYFV挑战的NHP中的病毒复制，从而从WTYFV感染的续集中保存它们。