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

摘要 项目摘要/摘要最近使用单一中和单抗(NmAb)降低埃博拉病毒(EBOV)感染者死亡率的开创性实验突出了这类药物在治疗传染病方面的重要性。2019年8月，Anthony Fuci博士宣布，应用mAb114已将EBOV感染患者的死亡率从70%降至约35%。EBOV感染不再被认为是一种完全致命的疾病。与EBOV感染类似，野生型黄热病病毒(WtYFV)感染会导致高病毒载量，住院患者的死亡率高达50%。一旦感染，目前没有可用的治疗方法。虽然YFV17D疫苗总体上是有效的，但它有一些潜在的严重副作用，从而减少了其覆盖面。不幸的是，世界卫生组织(WHO)报告了大约100例因巴西大规模疫苗接种活动而产生的严重不良反应，阻止了许多人接种疫苗。尽管开展了疫苗接种运动，但免疫覆盖率仍然很低，使相当数量的人处于危险之中。世界上大多数地区，包括美国，都很容易受到蚊子传播疾病的影响，两种相关的黄病毒登革热(DENV)和寨卡病毒(ZIKV)的出现就表明了这一点。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(NmAbb)。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。Watkins和Burton实验室以及最近的其他实验室已经证明，印度猕猴可以通过使用nmAb鸡尾酒或单一nmAb来预防ZIKV感染。此外，Watkins和Burton的实验室还表明，这种鸡尾酒可以将感染ZIKV的怀孕猕猴的病毒载量降低到无法检测到的水平。这些数据首次证明，在相关的非人灵长类动物(NHP)模型中，暴露后使用nmAbs治疗可以减少黄病毒的复制。在这项应用的第一阶段，我们计划从我们现有的mAb库中至少鉴定出五株用于wtYFV治疗的nmAb，使用体外分析和叙利亚金黄地鼠的体内筛选。在第二阶段，我们将使用我们最好的YFV特异性nmAb进行组织交叉反应研究。然后，我们将测试最好的三种nmAb对感染wtYFV的猴子的治疗效果。在这个快速通道I/II阶段应用完成后，我们计划至少有一种商业上可行的鸡尾酒或单一的nmAb，可以有效地抑制wtYFV挑战的NHP中的病毒复制，从而使它们免于wtYFV感染的后遗症，即死亡。

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.