Structure-based Vaccine Design for CCHFV

基于结构的 CCHFV 疫苗设计

基本信息

批准号：
10624297
负责人：
Kartik Chandran
金额：
$ 42.85万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-25 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624297
关键词：
Acute Africa Animal Model Antibodies Antibody Response Antibody Therapy Antigens Case Fatality Rates Categories Category A pathogen Cells Central Asia Chimeric Proteins Classification Complex Coronavirus Crimean Hemorrhagic Fever Crimean-Congo Hemorrhagic Fever Virus Data Data Protection Disease Disease Outbreaks Dyes Engineering Epitope Mapping Epitopes Evaluation Family Filovirus Funding Genome Geographic Locations Glycoproteins Goals Human IFNAR1 gene Immune response Immunocompromised Host Immunologics Incidence International Laboratories Licensing Life Livestock Membrane Fusion Middle East Molecular Monoclonal Antibodies Morbidity - disease rate Mucins Mus Nairovirus National Institute of Allergy and Infectious Disease Pathogenesis Patients Process Proteins Public Health RNA Viruses Reagent Respiratory syncytial virus Sampling Site Southern Europe Structure Subunit Vaccines Technology Therapeutic antibodies Tick-Borne Diseases Ticks Vaccine Antigen Vaccine Design Vaccines Viral Viral Envelope Proteins Viral Genome Viral Hemorrhagic Fevers Virus Virus Diseases Western Asia Work clinical development cross reactivity design disorder prevention experience global temperature immunogenicity improved in vivo insight interest lead candidate medical countermeasure migratory bird mortality mouse model nanoparticle neutralizing antibody novel novel vaccines prevent self assembly structural glycoprotein synergism tick-borne tick-borne pathogen tool type I interferon receptor vaccine candidate vaccine development vector

项目摘要

Project Summary/Abstract Crimean-Congo hemorrhagic fever virus (CCHFV) causes a life-threatening tick-borne disease in humans. The disease presents as a severe form of hemorrhagic fever with a case fatality rate of 10–40%. CCHFV outbreaks have spanned a wide geographic area ranging from Western and Central Asia, the Middle East, Africa and Southern Europe. Increasing global temperatures, migratory birds, and the international livestock trade have all potentially contributed toward the spread of Hyalomma ticks—the primary vector for CCHFV. Expanding endemic zones, widespread morbidity and significant mortality make CCHFV an acute threat to public health and thus is listed as a NIAID Category A priority pathogen. The viral genome encodes a glycoprotein precursor that is processed into two structural glycoproteins—Gn and Gc—and two secreted glycoproteins—a mucin-like domain and GP38. Protective antibodies have been isolated that target Gc or GP38, suggesting that these two proteins should be given priority for vaccine development. Here we propose to engineer Gc- and GP38-based immunogens that focus the immune response onto broadly conserved epitopes that are capable of eliciting protective antibody responses. To accomplish our goal, we will structurally characterize CCHFV glycoproteins and their interactions with human-derived antibodies, rationally engineer vaccine antigens based in part on the structural information, and characterize the immune responses elicited by these antigens in animal models. These results will be used to guide further improvements of the immunogens, including display on self-assembling multi-valent nanoparticles, and the most promising candidates will be evaluated in a lethal murine model of CCHFV challenge. Given our expertise, unique reagents, and preliminary data, we are confident that we can deliver a state-of-the-art subunit vaccine candidate with the potential to induce cross-reactive protective antibodies, thereby satisfying an unmet need against this NIAID Category A tick-borne pathogen.

项目摘要/摘要 Crimean-Congo出血热病毒（CCHFV）在人类中引起威胁生命的tick传播疾病。该疾病是一种严重的出血热形式，病例死亡率为10-40％。 CCHFV 爆发已经跨越了一个广泛的地理区域，从西亚和中亚，中东，非洲和南欧。升高全球温度，候鸟和国际牲畜贸易都可能有助于透明壁虱的传播，这是CCHFV的主要向量。扩大内在区域，宽度发病率和重大死亡率使CCHFV成为急性威胁因此，公共卫生被列为NIAID类别的优先病原体。病毒基因组编码A 糖蛋白前体被加工成两个结构性糖蛋白（GN和GC）和两个分泌糖蛋白 - 粘蛋白样域和GP38。保护性抗体已被隔离为靶向GC或 GP38，表明应将这两种蛋白质用于疫苗开发。我们在这里提出针对基于GC和GP38的免疫原子的提议，该免疫原子将免疫响应聚焦于广泛能够引起受保护抗体反应的保守表位。为了实现我们的目标，我们将在结构上表征CCHFV糖蛋白及其与人类衍生抗体的相互作用，理性工程师疫苗抗原部分基于结构信息，并表征这些抗原在动物模型中引起的免疫反应。这些结果将用于进一步指导免疫原子的改进，包括在自组装多纳米颗粒上显示，以及最有希望的候选人将在CCHFV挑战的致命鼠模型中评估。鉴于我们专业知识，独特的试剂和初步数据，我们有信心我们可以提供最先进的亚基疫苗候选者具有诱导交叉反应性保护抗体的潜力满足对这一NIAID类别的未满足的需求。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineering, structure, and immunogenicity of a Crimean-Congo hemorrhagic fever virus pre-fusion heterotrimeric glycoprotein complex.

克里米亚-刚果出血热病毒融合前异三聚体糖蛋白复合物的工程、结构和免疫原性。

DOI：
10.1101/2024.04.20.590419
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
McFadden,Elizabeth;Monticelli,StephanieR;Wang,Albert;Ramamohan,AjitR;Batchelor,ThomasG;Kuehne,AnaI;Bakken,RussellR;Tse,AlexandraL;Chandran,Kartik;Herbert,AndrewS;McLellan,JasonS
通讯作者：
McLellan,JasonS