Broadly Neutralizing Antibodies Against Human Pathogenic Old World Arenaviruses

 描述(申请人提供)：几种阿拉伯病毒，主要是西非的拉萨病毒(LASV)，在人类中引起出血热(HF)疾病，与高发病率和死亡率有关。出血热病毒在其流行地区是一个重要的公共卫生问题。此外，分布于世界各地的原型性淋巴细胞性脉络膜脑膜炎病毒(LCMV)是一种被忽视的临床重要人类病原体。此外，包括LASV和LCMV在内的几种阿拉伯病毒是可信的生物防御威胁。由于缺乏FDA许可的疫苗，以及目前的抗ARA病毒治疗仅限于标签外使用仅部分有效的利巴韦林，加剧了对人类ArenaVirus感染造成的公共卫生关切。广谱中和抗体(BNab)是从感染了艾滋病毒和流感等具有高度抗原性变异的病毒后康复的人身上分离出来的。这些bNab可以抵抗抗原性不同的病毒株的感染，因此它们为被动免疫治疗提供了强有力的工具。此外，关于这些bNab与其高度保守的靶表位的相互作用及其中和机制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，这些疫苗和抗病毒药物可以提供对Arena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)特异性人类单抗(HMAb)(由杜兰大学的Robinson博士提供)，以了解它们对一组不同的旧大陆阿拉伯病毒(OWA)的交叉反应性(AIM 1)和中和活性范围(AIM 2)，其中包括遗传上关系遥远的LASV和LCMV毒株。然后，我们将通过进行抗体结合竞争分析和鉴定耐中和所选BNhMAbs的所选病毒变体，来鉴定选定的OWA BNhMAbs识别的LASV GP的GP亚基和特定氨基酸残基(目标3)。最后，我们将检验选定的具有最佳体外中和曲线的OWA BNhMAb的体内中和活性和治疗价值(目标4)。OWA BNhMAbs的鉴定和鉴定是潜在的免疫疗法发展的第一步，也是必要的一步，用于治疗由OWA引起的人类疾病，这些疾病没有疫苗可用，现有的抗病毒药物效果有限。此外，这些BNhMAb所针对的表位的鉴定将为产生能够诱导类似的ArenaVirus BNhMAb反应的免疫原的产生以及针对这些BNhMAb所识别的高度保守的表位所定义的结构和活性的广谱抗ArenaVirus药物的鉴定提供有价值的信息。

 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.