Human monoclonal antibodies (huMAbs) for medically important arboviruses

在NIAID A、B和C类优先病原体的虫媒病毒中，有经批准的疫苗可用 仅适用于日本脑炎病毒、森林脑炎病毒和黄热病病毒。另外， 由于越来越多的报道称，即使是高效的YFV17D疫苗的使用也正在重新评估 接种疫苗后的严重不良事件，特别是在免疫功能低下的患者中。确实有 目前还没有批准用于虫媒病毒疾病的其他预防或治疗策略。因此，我们建议 人(HU)和人源化小鼠(MUHU)虫媒病毒特异性单抗的应用研究 作为抗病毒预防或治疗试剂的抗体(单抗)。初步研究，包括我们在 进展报告如下，表明单抗可以作为有效的预防和治疗药物。 脑炎西尼罗河和委内瑞拉马脑炎病毒(VEEV)在小鼠模型中的感染。 基于这些结果，我们假设抗病毒单抗可以使用HU-OR预防和/或治疗 MuHuMAbs也将成功地用于嗜内脏、A和C类虫媒病毒登革热(DENV)和 黄热病(YFV)。我们将继续评估HuMAb对VEEV的保护和治疗能力 在我们的第一个赠款期间开发，并将使用两种方法来开发YFV和DENV2反应 HuMAb或MuHuMAb。1)使用新的细胞融合伙伴，MFP-2或MFP-2D细胞，以准备人类 使用感染免疫者的人外周血B细胞或人B细胞的杂交瘤 来自病毒免疫的人源化小鼠。2)基因重组保护性小鼠的可变区 具有人类免疫球蛋白恒定区的单抗。它们的保护和治疗能力 单抗将通过外周病毒攻击杂交小鼠(VEEV)或近交系小鼠进行测试 干扰素应答(YFV和DENV2)。具体目标如下：1.继续塑造人物形象 人和人源化VEEV反应性单抗和MAP的保护和治疗能力评估 人类抗VEEV曲目。2.研制针对YFV和DENV2 E蛋白的HuMAb和MuHuMAb。 3.用YFV17D疫苗建立干扰素缺陷型YF外周攻击动物模型 AG129小鼠。4.鉴定YFV和DENV2反应性MuHuMAbs和HuMAbs的能力 在AG129小鼠模型中预防或治疗YFV和DENV2感染并使用HuMAb进行定位 人抗E蛋白抗体库。该项目符合RMRCE综合研究的重点 将与RPS 3.1和1.7以及Core C直接交互。

Of the arboviruses that are NIAID Category A, B and C Priority Pathogens, approved vaccines are available only for Japanese encephalitis virus, tick-borne encephalitis virus, and yellow fever virus (YFV). Additionally, use of even the highly effective YFV17D vaccine is now being re-evaluated due to increasing reports of severe adverse events following vaccination, particularly in immunocompromised patients. There are currently no other prophylactic or therapeutic strategies approved for arbovirus diseases. Thus, we propose to investigate the utility of human (Hu) and humanized murine (MuHu) arbovirus-specific monoclonal antibodies (MAbs) as antiviral prophylactic or therapeutic reagents. Initial studies, including those in our Progress Report below, indicate that MAbs can be effective prophylactic and therapeutic agents for the encephalitic West Nile and Venezuelan equine encephalitis viruses (VEEV) in mouse models of infection. Based on these results we hypothesize that antiviral MAb prophylaxis and/or therapy using Hu- or MuHuMAbs will also be successful for the viscerotropic, Category A and C arboviruses dengue (DENV) and yellow fever (YFV). We will continue to assess the protective and therapeutic capacities of HuMAb for VEEV developed during our first grant period and will use two approaches to develop YFV and DENV2-reactive HuMAb or MuHuMAb. 1) Use new cell fusion partners, MFP2 or MFP2D cells, to prepare human hybridomas using either human peripheral blood B-cells from infection-immune persons, or human B-cells from virus-immunized, humanized mice. 2) Genetically recombine the variable regions of protective murine MAbs with the constant regions of human immunoglobulin. Protective and therapeutic capacity of these MAbs will be tested by peripheral virus challenge of outbred mice (VEEV) or inbred mice deficient in their interferon response (YFV and DENV2). Specific aims are as follows: 1. Continue characterization and assessment of protective and therapeutic capacities of human or humanized VEEV-reactive MAbs and map the human anti-VEEV repertoire. 2. Develop HuMAbs and MuHuMAbs specific for YFV and DENV2 Eproteins. 3. Develop a new peripheral challenge animal model for YF using YFV17D vaccine in interferondeficient AG129 mice. 4. Characterize the ability of the YFV- and DENV2-reactive MuHuMAbs and HuMAbs to protect from or treat YFV and DENV2 infections in the AG129 mouse model and use the HuMAbs to map the human anti-E protein antibody repertoire. This project fits within the RMRCE Integrated Research Focus on Viral Therapeutics and will interact directly with RPs 3.1 and 1.7 and Core C.