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: 10422995
• 负责人: David I Watkins
• 金额: $ 99.94万
• 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/10422995
• 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; Rapid diagnostics; 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; 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 最近使用单一中和单克隆抗体 (nmAb) 降低埃博拉病毒 (EBOV) 感染者死亡率的突破性实验凸显了此类药物在治疗传染病中的重要性。 2019 年 8 月，安东尼·福奇博士宣布，使用 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普遍致命的疾病。与 EBOV 感染类似，野生型黄热病病毒 (wtYFV) 感染会导致住院患者病毒载量高，死亡率高达 50%。一旦感染，目前没有可用的治疗方法。虽然 YFV17D 疫苗通常有效，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，世界卫生组织 (WHO) 报告称，巴西的大规模疫苗接种活动导致约 100 例严重不良反应，导致许多人不愿接种疫苗。尽管开展了疫苗接种运动，但免疫覆盖率仍然很低，使大量人面临风险。包括美国在内的世界大部分地区都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，通过使用 nmAb 混合物或单一 nmAb 可以预防印度恒河猴感染 ZIKV。此外，沃特金斯和伯顿实验室还表明，这种鸡尾酒可以将感染 ZIKV 的怀孕猕猴的病毒载量降低至不可检测的水平。这些数据首次证明，在相关非人灵长类动物 (NHP) 模型中，使用 nmAb 进行暴露后治疗可以减少黄病毒复制。在该应用的第一阶段，我们计划使用体外测定和叙利亚金仓鼠体内筛选，从我们现有的 mAb 库中鉴定至少 5 种 nmAb，用于 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。然后我们将测试三种最好的 nmAb 在治疗 wtYFV 感染的猴子中的功效。在完成这一快速通道I / II期应用后，我们计划至少拥有一种商业上可行的鸡尾酒或单一nmAb，可以有效抑制wtYFV攻击的NHP中的病毒复制，从而使它们免于wtYFV感染的后遗症，即死亡。