Immunotherapeutics Against Other Filovirus Threats

丝状病毒是NIAID/CDC A类生物防御性病原体，可导致严重和快速发展的出血热，对人类的致死率为50%-90%。目前还没有FDA批准的丝状病毒感染疫苗或疗法。在丝状病毒中，扎伊尔埃博拉病毒(EBOV)的特征最为广泛。然而，苏丹埃博拉病毒(SUDV)和马尔堡病毒(MARV)的暴发频率一直在增加，可能与EBOV一样致命。此外，致病的本迪布乔埃博拉病毒(BDBV)在2012年重新出现，致命性增加。免疫疗法最近被证明在非人灵长类动物(NHP)中提供了对EBOV攻击的暴露后保护。对于MARV，来自免疫的NHP的恢复期血清可以提供类似的保护，这表明对所有丝状病毒的免疫治疗在人类将是容易的。一条强大的针对EBOV的单抗(MAbb)管道已经存在，并将在项目1中开发，但SUDV和MARV mAbs的管道不太完整。没有一种单一的SUDV或MARV单抗或单抗鸡尾酒疗法在NHPS中得到评估。目前，尚无中和性BDBV单抗。项目2的目标是填补丝状病毒治疗性单抗组合中的这些空白。在联盟研究人员中，总共有216株抗SUDV或MARV的鼠源单抗可用，但尚未完全表征；我们将开发这些单抗，并评估它们在啮齿动物模型和NHP中的保护作用。此外，我们将从乌干达暴发疫情感染的人类幸存者中识别新的SUDV和MARV单抗，特别是2012年的疫情。该联盟的调查人员史无前例地接触到了SUDV和MARV感染的四个独立的幸存者队列，并在最近证明了幸存者的外周血液中存在中和单抗。此外，我们还将鉴定和鉴定新的抗BDBV单抗和广谱抗丝病毒单抗。初步的ELISA研究表明，仅接触一种丝状病毒的幸存者的外周血中存在与SUDV、BDBV和(某些情况下)EBOV的包膜糖蛋白(GP)具有交叉反应的抗体。我们将使用人类杂交瘤和抗体噬菌体展示技术来筛选丝状病毒感染幸存者的淋巴细胞，以寻找新的BDBV和交叉中和丝病毒单抗。最有希望的候选人将在啮齿动物和非人类灵长类动物挑战模型中进一步评估。这项工作的终点将是针对这些未被研究和重新出现的丝状病毒的mAb的强大管道。

The filoviruses are NIAID/CDC Category A biodefense pathogens that cause severe and rapidly progressing hemorrhagic fever with 50-90% human lethality. There are currently no FDA-approved vaccines or therapies for filovirus infection. Among the filoviruses, the Zaire Ebola virus species (EBOV) has been most extensively characterized. However, outbreaks ofthe Sudan Ebola virus species (SUDV) and Marburg virus (MARV) have been occurring with increased frequency and can be just as lethal as EBOV. Further, the pathogenic Bundibugyo Ebola virus species (BDBV) re-emerged in 2012 with increased lethality. Immunotherapy was recently demonstrated to provide post-exposure protection to EBOV challenge in nonhuman primates (NHPs). For MARV, convalescent sera from immunized NHPs can provide similar protection, suggesting that immunotherapy for all filoviruses will be tractable in humans. A robust pipeline of monoclonal antibodies (mAbs) targeting EBOV exists and will be developed in Project 1, but the pipeline for SUDV and MARV mAbs is less complete. Not a single SUDV or MARV mAb or mAb cocktail therapy has been evaluated in NHPs. Currently, there are no neutralizing BDBV mAbs. The goal of Project 2 is to fill these gaps in the filovirus therapeutic mAb portfolio. Among consortium investigators, a total of 216 murine mAbs against SUDV or MARV are available but have not been completely characterized; we will develop these mAbs and evaluate them for protection in rodent models and NHPs. In addition, we will identify new SUDV and MARV mAbs from human survivors of infection from outbreaks in Uganda, especially those in 2012. The consortium investigators have unprecedented access to four separate survivor cohorts of SUDV and MARV infection, and have demonstrated recently that neutralizing mAbs exist in peripheral blood of survivors. In addition, we will identify and characterize new anti-BDBV and broadly reactive anti-filovirus mAbs. Preliminary ELISA studies indicate that antibodies with cross-reactivity for the envelope glycoprotein (GP) from SUDV, BDBV and (in some cases) EBOV exist in peripheral blood of survivors who have been exposed to only a single filovirus species. We will use human hybridoma and antibody phage display technologies to screen the lymphocytes of survivors of filovirus infection for new BDBV and cross neutralizing filovirus mAbs. The most promising candidates will be further evaluated in rodent and nonhuman primate challenge models. The end-point of this work will be a robust pipeline of mAbs for these understudied and re-emerging filoviruses.