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

项目总结/摘要 最近的突破性实验使用单一的中和单克隆抗体（nmAb），以减少 埃博拉病毒（EBOV）感染者的死亡率凸显了这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， mAb114将EBOV感染患者的死亡率从70%降低到约35%。ebov感染 不再被认为是一种致命的疾病。与EBOV感染类似，野生型黄热病病毒 （wtYFV）感染导致高病毒载量和住院患者高达50%的死亡率。一旦 感染，目前没有治疗方法。虽然YFV 17D疫苗通常是有效的，但它具有 一些潜在的严重的副作用，这减少了它的覆盖范围。不幸的是，世界卫生组织 (WHO)报告了大约100例由于大规模疫苗接种运动而产生的严重不良反应 在巴西，许多人都不愿接种疫苗。尽管疫苗接种运动 尽管已经启动，但免疫覆盖率仍然很低，使大量人口面临风险。大部分 世界，包括美国，很容易受到蚊子传播的疾病的影响，正如两种蚊子的出现所表明的那样， 相关的黄病毒登革热（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， 我们已经收集了大量的黄病毒特异性中和单克隆抗体（nmAbs）。 事实上，沃特金斯实验室已经表明，这些单克隆抗体可用于预防和治疗 黄病毒感染的治疗。沃特金斯和伯顿实验室，以及最近的其他实验室， 证明了可以通过使用nmAb混合物在印度恒河猴中预防ZIKV感染， 或单一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 在ZIKV感染的怀孕猕猴中将病毒载量降低到检测不到的水平。这些数据表明，对于 第一次，暴露后治疗与nmAbs可以减少黄病毒复制在相关的非- 人灵长类动物（NHP）模型。 在本申请的第一阶段，我们计划从我们现有的mAb库中鉴定至少五种nmAb，用于 在叙利亚金黄仓鼠中使用体外测定和体内筛选的wtYFV治疗。在第二阶段，我们将 使用我们最好的YFV特异性nmAbs进行组织交叉反应性研究。然后我们将测试 治疗wtYFV感染猴的最佳三种nmAb。 在此快速通道I/II期申请完成后，我们计划至少有一个商业 在wtYFV攻击的小鼠中，可以有效抑制病毒复制的活的鸡尾酒或单一nmAb NHP，从而使他们免于wtYFV感染的后遗症，即死亡。

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.