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（由适用提供）：西非的几种体育病毒，主要是西非的LASSA病毒（LASV），引起人类的出血热（HF）疾病，与高发病率和死亡率有关。 HF竞技病毒代表了其内在区域中一个重要的公共卫生问题。此外，全球原型体育症病毒病毒病毒（LCMV）是一种被忽视的临床上重要的人类病原体。此外，包括LASV和LCMV在内的几个体育疾病病毒代表了可信的生物幻想威胁。人类体内病毒感染引用的公共卫生问题是由于缺乏FDA许可的疫苗而汇总的，目前的抗嗜酸病毒疗法仅限于非标签的利巴韦林使用，这仅是部分有效的。广泛中和抗体（BNAB）已从从存在高度抗原变异性的病毒中恢复过的个体中分离出来，例如HIV和HIV和影响。这些BNAB可以通过抗原发散病毒菌株预防感染，因此为被动免疫疗法提供了强大的工具。此外，有关这些BNAB与其高度保守的靶向鉴定的相互作用及其神经化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允许对舞台病毒进行广谱保护。我们首先建议评估一个由103个LASV糖蛋白（GP）特定的人类单克隆抗体（HMAB）得出的小组，该抗体（HMAB）源自14种不同的LASSA热（LF）冲浪者（LF）冲浪者（由Tulane University的Robinson博士提供），用于跨反应性（AIM 1）和范围（AIM AIM AIM的范围）（AIL的范围）（AIL）的范围（AIL）（AIL）的范围（AIL（AIL）的范围（AIL）（AID）（AIL）（AIL）（AIL）（AIL）（AIL（AIL）（AIL）（AIL）（AIL）（AIL）（AIL）（AIL）（AIL） LASV和LCMV的相关菌株。然后，我们将通过进行抗体结合竞争测定法和表征选定的病毒变异剂对所选BNHMAB抗神经抗性的选定病毒变异体，从而确定由选定的OWA BNHMAB识别的LASV GP的GP亚基和特异性氨基酸耐药性（AIM 3）。最后，我们将检查具有最佳体外神经化谱的选定OWA BNHMAB的体内中和活性和治疗价值（AIM 4）。 OWA BNHMAB的鉴定和表征构成了免疫治疗药物的潜在开发以治疗LF和其他OWA诱导的疾病的第一个和必要的步骤，而在该人类中，疫苗无法获得疫苗，现有抗病毒药的有限效率有限。此外，这些BNHMAB针对的表位的鉴定将为能够产生能够诱导类似的体育经瘤病毒BNHMAB反应的免疫原子提供有价值的信息，以开发针对引起HF的人OWA的通用疫苗，以及通过这些高度抗脑膜药物和活性鉴定的鉴定的范围，以识别较广泛的静态药物，并识别范围的鉴定。 BNHMABS。