Broadly Neutralizing Antibodies Against Human Pathogenic Old World Arenaviruses

 描述（由申请方提供）：几种沙粒病毒，主要是西非的拉沙病毒（LASV），可引起人类出血热（HF）疾病，并伴有高发病率和死亡率。HF沙粒病毒在其流行地区代表重要的公共卫生问题。此外，全球分布的原型沙粒病毒淋巴细胞脉络丛脑膜炎病毒（LCMV）是一个被忽视的临床重要的人类病原体。此外，包括LASV和LCMV在内的几种沙粒病毒是可靠的生物防御威胁。由于缺乏FDA许可的疫苗以及目前的抗沙粒病毒治疗仅限于部分有效的利巴韦林的标签外使用，人类沙粒病毒感染引起的公共卫生问题加剧。广泛中和抗体（BNAb）已从感染HIV和流感等抗原变异性高的病毒后恢复的个体中分离出来。这些BNAb可以保护免受抗原性趋异病毒株的感染，因此它们为被动免疫治疗提供了有力的工具。此外，关于这些BNAb与其高度保守的靶表位及其中和机制的相互作用的信息可以促进新型通用疫苗和抗病毒药物的设计和开发，这些疫苗和药物可以赋予针对沙粒病毒的广谱保护。我们建议首先评估来自14个不同拉沙热（LF）幸存者的103个LASV糖蛋白（GP）特异性人单克隆抗体（hMAbs）（由杜兰大学的罗宾逊博士提供），用于其对不同旧世界沙粒病毒（OWA）集合的交叉反应性（目标1）和中和活性范围（目标2）包括LASV和LCMV的遗传上远相关的菌株。然后，我们将通过进行抗体结合竞争测定和表征对所选BNhMAb中和具有抗性的所选病毒变体，鉴定所选OWA BNhMAb识别的LASV GP的GP亚基和特异性氨基酸残基（目的3）。最后，我们将检查具有最佳体外中和特性的所选OWA BNhMAb的体内中和活性和治疗价值（目的4）。OWA BNhMAb的鉴定和表征构成了潜在开发免疫治疗剂以治疗LF和其他OWA诱导的人类疾病的第一步和必要步骤，这些疾病的疫苗不可用，并且现有的抗病毒药物疗效有限。此外，这些BNhMAb靶向表位的鉴定将为产生能够诱导类似沙粒病毒BNhMAb应答的免疫原提供有价值的信息，用于开发针对HF引起的人OWA的通用疫苗，以及鉴定靶向这些BNhMAb识别的高度保守表位所定义的结构和活性的广谱抗沙粒病毒药物。

 DESCRIPTION (provided by applicant): Several arenaviruses, chiefly Lassa virus (LASV) in West Africa, cause hemorrhagic fever (HF) disease in humans that is associated with high morbidity and mortality. HF arenaviruses represent an important public health problem in their endemic regions. In addition, the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected clinically important human pathogen. Moreover, several arenaviruses, including LASV and LCMV, represent credible biodefense threats. Public health concerns posed by human arenavirus infections are aggravated by the lack of FDA-licensed vaccines and current anti-arenaviral therapy being limited to the off-label use of ribavirin that is only partially effective. Broadly neutralizing antibodies (BNAb) have been isolated from individuals who recovered from infection with viruses that exhibit a high degree of antigenic variability like HIV and influenza. These BNAb can protect against infection by antigenically divergent viral strains, and therefore they provide a powerful tool for passive immunotherapy. Moreover, information regarding the interaction of these BNAb with their highly conserved target epitopes and their mechanisms of neutralization can facilitate the design and development of novel universal vaccines and antiviral drugs that could confer broad-spectrum protection against arenaviruses. We propose first to evaluate a panel of 103 LASV glycoprotein (GP)-specific human monoclonal antibodies (hMAbs) derived from 14 different Lassa fever (LF) survivors (provided by Dr. Robinson at Tulane University) for their cross-reactivity (Aim 1) and range of neutralizing activities (Aim 2) against a collection of different Old World Arenavirus (OWA) including genetically distantly related strains of LASV and LCMV. We will then identify the GP subunits and specific amino acid residues of LASV GP recognized by selected OWA BNhMAbs by conducting antibody binding competition assays and characterizing selected viral variants resistant to neutralization by the selected BNhMAbs (Aim 3). Finally, we will examine the in vivo neutralizing activity and therapeutic value of selected OWA BNhMAbs with optimal in vitro neutralization profiles (Aim 4). The identification and characterization of OWA BNhMAbs constitutes a first and necessary step for the potential development of immunotherapeutics to treat LF and other OWA-induced disease in humans for which vaccines are not available and existing antivirals are of limited efficacy. Additionally, the identification of the epitopes targeed by these BNhMAbs will provide valuable information for the generation of immunogens able to induce similar arenavirus BNhMAb responses for the development of universal vaccines against HF-causing human OWA, as well as the identification of broad-spectrum anti-arenavirus drugs targeting the structures and activities defined by the highly conserved epitopes recognized by these BNhMAbs.