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: 10078258
• 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/10078258
• 关键词: Address; Animals; Antibodies; Antibody-mediated protection; Applications Grants; Biological; Biological Assay; Chiroptera; Communicable Diseases; Competitive Binding; Complement; Data; Disease; Disease Outbreaks; Enzyme-Linked Immunosorbent Assay; Epitopes; Escape Mutant; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Funding; Generations; Glycoproteins; Goals; Harvest; Human; Hybridomas; Immune response; Immunity; Immunize; Infection; Intervention; Knowledge; Lyssavirus; Maps; Mediating; Modeling; Mokola virus; Monoclonal Antibodies; Mus; Mutation; Natural Killer Cells; Pathway interactions; Phagocytosis; Property; Rabies; Rabies virus; Recombinants; Serum; Spleen; Structure; Suggestion; Testing; Therapeutic; Transgenic Mice; Vaccinated; Vaccines; Viral; Virus; antibody-dependent cell cytotoxicity; base; cross reactivity; design; immunogenicity; in vivo; neutralizing antibody; neutralizing monoclonal antibodies; novel; rabies virus glycoprotein G; receptor binding; response; seroconversion; vaccine-induced antibodies

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 在没有治疗的情况下，狂犬病几乎是100％致死的，估计每年有59,000人死亡。 当疫苗适当地施用后，它们会高效，使其成为经济上最大的一种 传染病之间的高影响干预措施。约有30,000人接受暴露后治疗 美国每年表示需要针对RABV的治疗选择。值得注意的是，十五个与狂犬病有关的病毒 （lyssavirues）同样是致命的，但足以避免避免当前的疫苗和生物制剂的保护， 基于经典狂犬病病毒（RABV）。 我们以前设计了结构知识的嵌合糖蛋白（G）以掺入大型外域 两种不同的乳胶病毒，RABV和Mokola病毒（MOKV）的区域。在体内，这种疫苗引起中和 针对RABV和MOKV的抗体，并保护含有MOK G或的病毒挑战 Rabv G.基于对RABV G的知识，这些初步数据表明i）嵌合G包括 来自RABV和MOKV的重要抗原区域以及II）引起的抗体应预防 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。 提议三个独立但互补的目标将R21的发现提升到一个新的水平。 第一个目的将研究嵌合G lyssavirus疫苗的免疫原性和保护质量 一组不同的裂解病毒。 AIM 2检查非RABV lyssavirus的抗原区域 糖蛋白（G）并通过隔离和表征Lyssavirus GS上的抗原区域来描述抗原区域 中和单克隆抗体（mAb）。防止RABV的教条是中和 抗体是必要且足够的。这不是研究非RABV溶解病毒的研究，也不是 我们先前研究的初步数据完全支持。因此，AIM 3将重新审视机制 防止在暴露前和暴露后申请中的裂解病毒的保护，并重新定义 中和和非中和抗体免受狂犬病的保护。