Pan-lyssavirus therapeutics and mechanisms of protection against lyssaviruses

泛狂犬病病毒疗法和抗狂犬病病毒的保护机制

• 批准号: 10311511
• 负责人: Matthias Johannes Schnell
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10311511
• 关键词: Address; Animals; Antibodies; Antibody-mediated protection; Applications Grants; Biological Assay; Biological Products; Chiroptera; Communicable Diseases; Competitive Binding; Complement; Data; Disease; Disease Outbreaks; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Escape Mutant; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Funding; Generations; Glycoproteins; Goals; Harvest; Human; Hybridomas; Immune response; Immunity; Immunize; Infection; Intervention; Knowledge; Lyssavirus; Mediating; Modeling; Mokola virus; Monoclonal Antibodies; Mus; Mutation; Natural Killer Cells; Pathway interactions; Persons; Phagocytosis; Property; Rabies; Rabies virus; Recombinants; Serum; Spleen; Suggestion; Testing; Therapeutic; Transgenic Mice; Vaccinated; Vaccines; Viral; Virus; Visit; antibody-dependent cell cytotoxicity; cross reactivity; design; immunogenicity; in vivo; neutralizing antibody; neutralizing monoclonal antibodies; novel; receptor binding; response; seroconversion

Abstract Rabies disease is nearly 100% lethal in the absence of treatment, killing an estimated 59,000 people annually. When vaccines are properly administered, they are highly efficacious, making them one of the most economically high-impact interventions among infectious diseases. About 30,000 people receive post-exposure treatment in the USA annually indicating the need for treatment options against RABV. Of note, fifteen rabies-related viruses (lyssaviruses) are similarly lethal, but divergent enough to evade protection from current vaccines and biologics, which are based on the classical rabies virus (RABV). We previously designed a structurally-informed chimeric glycoprotein (G) to incorporate large ectodomain regions of two divergent lyssaviruses, RABV and Mokola virus (MOKV). In vivo, this vaccine elicited neutralizing antibodies against both RABV and MOKV and protected against challenge with viruses containing MOK G or RABV G. Based on knowledge of the RABV G, these preliminary data suggest that i) the chimeric G includes important antigenic regions from both RABV and MOKV and that ii) the elicited antibodies should protect against challenge. Moreover, some data also raised the compelling suggestion that antibody mechanisms in addition to neutralization may contribute to protection. Three independent but complementary aims are proposed to take the discoveries of the R21 to the next level. The first Aim will investigate the immunogenicity and protective quality of a chimeric G lyssavirus vaccine against a panel of different lyssaviruses of importance. Aim 2 examines antigenic regions of non-RABV lyssavirus glycoproteins (G) and delineate the antigenic regions on the lyssavirus Gs by isolating and characterizing neutralizing monoclonal antibodies (mAbs). The dogma for protection against RABV is that neutralizing antibodies are necessary and sufficient. This has not been studies for non-RABV lyssaviruses and is not completely supported by preliminary data from our previous study. Therefore, Aim 3 will revisit the mechanism of protection against Lyssaviruses in pre- and post-exposure applications and redefine the function of neutralizing and non-neutralizing antibodies for protection from rabies.

抽象的 如果不接受治疗，狂犬病几乎 100% 致死，每年估计有 59,000 人死亡。 如果疫苗接种得当，它们会非常有效，使其成为最经济的疫苗之一 传染病的高影响力干预措施。大约 30,000 人接受暴露后治疗 美国每年都表明需要针对 RABV 的治疗方案。值得注意的是，十五种与狂犬病相关的病毒 （狂犬病毒）同样具有致命性，但差异足以逃避当前疫苗和生物制剂的保护， 它们基于经典狂犬病病毒（RABV）。 我们之前设计了一种结构知情的嵌合糖蛋白（G）来整合大的胞外域 两种不同的狂犬病病毒（RABV 和 Mokola 病毒（MOKV））的区域。在体内，这种疫苗引发了中和 针对 RABV 和 MOKV 的抗体，并防止含有 MOK G 或 MOK G 的病毒的攻击 RABV G。基于对 RABV G 的了解，这些初步数据表明 i) 嵌合 G 包括 RABV 和 MOKV 的重要抗原区域，并且 ii) 引发的抗体应防止 挑战。此外，一些数据还提出了令人信服的建议，即抗体机制除了 中和可能有助于保护。 提出了三个独立但互补的目标，将 R21 的发现提升到一个新的水平。 第一个目标将研究嵌合 G 狂犬病病毒疫苗的免疫原性和保护质量 一组不同的重要狂犬病病毒属病毒。目标 2 检查非 RABV 狂犬病病毒的抗原区域 糖蛋白 (G) 并通过分离和表征来描绘狂犬病病毒 G 上的抗原区域 中和单克隆抗体（mAb）。预防 RABV 的教条是中和 抗体是必要且充分的。这还没有针对非 RABV 狂犬病病毒进行过研究，也不是 我们之前研究的初步数据完全支持。因此，Aim 3将重新审视该机制 在暴露前和暴露后应用中对狂犬病病毒的保护，并重新定义其功能 用于预防狂犬病的中和和非中和抗体。