Broadly Neutralizing Antibodies Against Human Pathogenic Old World Arenaviruses

针对人类致病性旧世界沙粒病毒的广泛中和抗体

• 批准号: 9223671
• 负责人: Luis Martinez-Sobrido
• 金额: $ 24.81万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223671
• 关键词: Adverse effects; Africa; Alpha Cell; Amino Acids; Antibodies; Antibody Response; Antigenic Variation; Antigens; Antiviral Agents; Area; Arenaviridae; Arenaviridae Infections; Arenavirus; Arenavirus Infections; Aseptic Meningitis; Binding; Biological Assay; Clinical; Collection; Dengue; Development; Disease; Disease Outbreaks; Distant; Dose; Drug Targeting; Epitope Mapping; Epitopes; Exhibits; Follow-Up Studies; Foundations; GP2 gene; GTPBP1 gene; Generations; Genetic Drift; Glycoproteins; Goals; HIV; Human; Immunocompromised Host; Immunotherapeutic agent; In Vitro; Individual; Infection; Influenza; Knowledge; Label; Lassa Fever; Lassa virus; Lujo virus; Lymphocytic choriomeningitis virus; Morbidity - disease rate; Mus; Mutation; Old World Arenaviruses; Passive Immunotherapy; Pathogenicity; Patients; Pharmaceutical Preparations; Plasmids; Population; Procedures; Property; Public Health; Recombinants; Reporting; Resistance; Ribavirin; Risk; Seroprevalences; Serum; Southern Africa; Spain; Structure; Survivors; Testing; Therapeutic; Time; Transfection; Transplantation; Travel; Universities; Vaccines; Variant; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Walking; base; biodefense; clinically significant; combat; cross reactivity; design; epidemiology study; genetic approach; human monoclonal antibodies; in vivo; metropolitan; mortality; mouse model; neglect; neutralizing antibody; novel; pathogen; prevent; prophylactic; public health relevance; response; reverse genetics; tool

 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.

 描述（由申请人提供）：几种沙粒病毒，主要是西非的拉沙病毒（LASV），会引起人类出血热（HF）疾病，该病具有高发病率和死亡率，HF沙粒病毒在其流行地区代表了一个重要的公共卫生问题。此外，世界范围内分布的原型沙粒病毒淋巴细胞性脉络膜脑膜炎病毒（LCMV）是一种被忽视的临床上重要的人类病原体。包括 LASV 和 LCMV 在内的人类沙粒病毒感染带来的可信生物防御威胁，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标签外使用利巴韦林而加剧，而利巴韦林仅部分有效。广泛中和抗体 (BNAb) 已从 HIV 和流感等表现出高度抗原变异性的病毒感染中恢复的个体中分离出来，这些 BNAb 可以防止抗原不同的病毒株的感染，并且因此，它们为被动免疫治疗提供了强大的工具。此外，有关这些 BNAb 与其高度保守的靶表位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，从而提供广谱保护。我们建议首先评估来自 14 名不同拉沙热 (LF) 幸存者的 103 种 LASV 糖蛋白 (GP) 特异性人单克隆抗体 (hMAb)（由 Robinson 博士提供）。杜兰大学）因其针对一系列不同的旧世界沙粒病毒（OWA）（包括 LASV 和 LCMV 的遗传远缘毒株）的交叉反应性（目标 1）和中和活性范围（目标 2），我们将鉴定 GP 亚基。通过进行抗体结合竞争测定并表征对选定的 BNhMAb 中和具有抗性的选定病毒变体，确定选定的 OWA BNhMAb 识别的 LASV GP 的特定氨基酸残基（目的3). 最后，我们将检查具有最佳体外中和特性的选定 OWA BNhMAb 的体内中和活性和治疗价值（目标 4） OWA BNhMAb 的鉴定和表征是免疫治疗潜在开发的第一步，也是必要的一步。为了治疗 LF 和其他由 OWA 引起的人类疾病，目前尚无疫苗且现有的抗病毒药物疗效有限，此外，还需要鉴定这些药物所针对的表位。 BNhMAb 将为产生能够诱导类似沙粒病毒 BNhMAb 反应的免疫原提供有价值的信息，用于开发针对引起心力衰竭的人类 OWA 的通用疫苗，以及鉴定针对以下定义的结构和活性的广谱抗沙粒病毒药物：这些 BNhMAb 识别的高度保守的表位。