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: 10082044
• 负责人: Jonah B. Sacha
• 金额: $ 29.96万
• 依托单位: MABLOC, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-02 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082044
• 关键词: Adverse effects; Biotechnology; Brazil; Cessation of life; Characteristics; Collaborations; Collection; Culicidae; Data; Death Rate; Dengue; Dengue Virus; Development; Diagnosis; Diagnostic tests; Disease; Disease Outbreaks; Ebola; Ebola virus; Flavivirus; Flavivirus Infections; 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; Pharmaceutical Preparations; Phase; Play; Prevention; Reporting; Research Institute; Research Personnel; Risk; Role; Testing; Time; Tissues; Universities; Vaccinated; Vaccination; Vaccines; Viral Load result; Virion; Virus; Virus Diseases; Virus Replication; World Health Organization; Yellow Fever; Yellow Fever Virus Infection; Yellow fever virus; ZIKA; ZIKV infection; Zika Virus; base; cross reactivity; efficacy testing; experimental study; human tissue; in vitro Assay; in vivo; infectious disease treatment; mortality; neutralizing monoclonal antibodies; nonhuman primate; novel; novel drug class; pregnant; prevent; public health emergency; screening; side effect; success; virus envelope

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.

项目摘要/摘要 最近的突破性实验使用单一中和单抗(NmAb)来减少 埃博拉病毒(EBOV)感染者的死亡率突显了这类药物在 传染病的治疗。2019年8月，安东尼·福奇博士宣布 MAb114使EBOV感染患者的死亡率从70%降至约35%。流行性出血热病毒感染 不再被认为是一种致命的疾病。类似于EBOV感染，野生型黄热病病毒 WtYFV感染导致高病毒载量，住院患者的死亡率高达50%。一次 感染，目前还没有可用的治疗方法。虽然YFV17D疫苗通常是有效的，但它 一些潜在的严重副作用，降低了其覆盖面。不幸的是，世界卫生组织 (世卫组织)报告了大约100例因大规模接种疫苗运动而产生的严重不良反应 在巴西，劝阻许多人接种疫苗。即使疫苗接种活动 自启动以来，免疫覆盖率仍然很低，使相当数量的人处于危险之中。大多数 世界，包括美国，很容易受到蚊子传播的疾病的影响，这从两种蚊子传播疾病的出现中可见一斑 与登革热(DENV)和寨卡病毒(ZIKV)相关的黄病毒。 在Mabloc LLC，通过我们与Watkins、Kallas和Burton实验室以及Adimab LLC的合作， 我们已经收集了大量黄病毒特异性中和单抗(NmAbs)。 事实上，沃特金斯实验室已经证明，这些单抗可以用于预防和 治疗黄病毒感染。沃特金斯和伯顿实验室，以及最近的其他实验室， 证明印度猕猴可以通过使用nmAb鸡尾酒来预防ZIKV感染 或一种单一的nmAb。此外，沃特金斯和伯顿的实验室也表明，这种鸡尾酒可以减少 ZIKV感染的怀孕猕猴体内的病毒载量达到无法检测到的水平。这些数据表明，对于 第一次，接触后使用nmAbs治疗可以减少黄病毒在相关的非 人类灵长类(NHP)模型。 在此应用程序的第一阶段，我们计划从我们现有的mAb池中识别至少五个nmAb，用于 WtYFV治疗叙利亚金黄地鼠的体外试验和体内筛选。在第二阶段，我们会 使用我们最好的YFV特异性nmAb进行组织交叉反应研究。然后我们将测试它的疗效 治疗wtYFV感染猴的最佳三种核单抗。 在完成这个快速通道第一阶段/第二阶段的申请后，我们计划至少有一个商业 活的鸡尾酒或单个nmAb可以有效地抑制wtYFV挑战的病毒复制 NHPS，从而使他们免于wtYFV感染的后遗症，即死亡。