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.

项目概要/摘要 最近的突破性实验使用单一中和单克隆抗体（nmAb）来减少 埃博拉病毒（EBOV）感染者的死亡率凸显了此类药物在治疗中的重要性 传染病的治疗。 2019 年 8 月，安东尼·福奇博士宣布管理 mAb114 已将 EBOV 感染患者的死亡率从 70% 降低至约 35%。埃博拉病毒感染 不再被认为是一种统一的致命疾病。与埃博拉病毒感染类似，野生型黄热病病毒 (wtYFV) 感染导致住院患者病毒载量高，死亡率高达 50%。一次 感染，目前没有可用的治疗方法。虽然 YFV17D 疫苗总体上有效，但 一些潜在的严重副作用会减少其覆盖范围。不幸的是，世界卫生组织 (WHO) 报告了约 100 例因大规模疫苗接种运动而造成的严重不良反应 在巴西，阻止许多人接种疫苗。尽管疫苗接种运动 尽管免疫接种计划启动，但免疫覆盖率仍然很低，使大量人面临风险。大部分的 包括美国在内的世界很容易受到蚊子传播疾病的影响，两种蚊子的出现就表明了这一点 相关黄病毒登革热 (DENV) 和寨卡病毒 (ZIKV)。 在 Mabloc LLC，通过与 Watkins、Kallas 和 Burton 实验室以及 Adimab LLC 的合作， 我们组装了大量黄病毒特异性中和单克隆抗体 (nmAb)。 事实上，沃特金斯实验室已经证明这些单克隆抗体可用于预防和预防 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已经 证明可以通过使用 nmAb 混合物来预防印度恒河猴的 ZIKV 感染 或单个 nmAb。此外，沃特金斯和伯顿实验室还表明，这种鸡尾酒可以减少 感染 ZIKV 的怀孕猕猴的病毒载量达到不可检测的水平。这些数据表明，对于 第一次，用 nmAb 进行暴露后治疗可以减少相关非黄病毒复制 人类灵长类动物（NHP）模型。 在该应用的第一阶段，我们计划从现有的 mAb 池中识别至少 5 种 nmAb，用于 使用叙利亚金仓鼠的体外测定和体内筛选进行 wtYFV 治疗。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。接下来我们将测试其功效 治疗 wtYFV 感染猴子的最佳三种 nmAb。 在完成快速通道一期/二期申请后，我们计划至少有一个商业化 可以有效抑制 wtYFV 攻击的病毒复制的可行混合物或单一 nmAb NHP，从而使它们免于 wtYFV 感染的后遗症，即死亡。