Epitope-Based Design and Modified RNA Platform for Bivalent Marburgvirus Vaccine

基于表位的二价马尔堡病毒疫苗设计和修饰 RNA 平台

基本信息

批准号：
10512752
负责人：
Alexander Bukreyev
金额：
$ 76.7万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10512752
关键词：
Adverse effects Algorithm Design Animal Model Antibodies Antibody Repertoire Antigen-Antibody Complex Antigens Binding Case Fatality Rates Cells Central Africa Clinical Trials Complex Computational Biology Computer Models Computer software Data Dermal Dermatitis Development Disease Disease Outbreaks Dose Ebola Ebola Vaccines Ebola virus Elements Epidemic Epitope Mapping Epitopes Family Filovirus Formulation Future Generations Geography Glycoproteins Human Immune Immune response Immunology Infection Laboratories Licensing Marburgvirus Mediating Membrane Messenger RNA Mission Modeling Molecular Biology Monoclonal Antibodies Mucins Mutation Pathogenicity Polysaccharides Probability Protein Conformation Protein Engineering Proteins Pseudouridine RNA RNA vaccine Recombinants Research Design Resolution Reston Rodent Scaffolding Protein Structure Sudan Survivors Techniques Testing Therapeutic Toxic effect Transplantation United States National Institutes of Health Vaccine Antigen Vaccine Clinical Trial Vaccine Design Vaccines Validation Vasculitis Viral Viral Antibodies Virus Virus Diseases Western Africa Wing design forest glycosylation human monoclonal antibodies immunogenic immunogenicity improved in silico in vivo innovation interdisciplinary approach lipid nanoparticle neutralizing antibody nonhuman primate novel novel vaccines pathogen pathogenic virus protective efficacy rational design receptor binding response scaffold screening vaccine candidate vaccine delivery vaccine development vaccine evaluation vaccine platform vaccinology virology

项目摘要

PROJECT SUMMARY/ABSTRACT The Marburg virus (MARV) and Ravn virus (RAVV), which both belong to the genus Marburgvirus of the family Filoviridae, cause the severe disease in humans, with case fatality rates up to 90%. There are no licensed vaccines against marburgviruses. Clinical trials of vaccine candidates against Ebola virus (EBOV), which belongs to the genus Ebolavirus of the family Filoviridae, demonstrated that the high vaccine doses that are required to induce an immune response at the protective level result in toxic effects associated with their principal component EBOV glycoprotein (GP). We and others have recently isolated and characterized human monoclonal antibodies (mAbs) to MARV and EBOV and defined the principal antigenic determinants for neutralization and protection on filovirus GP. We have demonstrated the successful protection of non-human primates against MARV by passively transferred mAbs. The central hypothesis of this study is that the epitopes of naturally-occurring human protective antibodies from survivors of a MARV infection can be used as templates for optimal rationally-designed structure-based vaccines. This hypothesis is supported by our recent extensive progress in the isolation of protective mAbs from survivors in conjunction with the recent advances in computational immunology techniques. We propose the rational design of structure-based vaccine MARV candidates that present the immunogenic determinants on GP. As in the wild-type (wt) GP, antigenic elements on the protein are obscured by glycosylation, the glycan cap and the mucin-like domain. The designed antigens are expected to better present protective determinants than the wt GP. We also propose that a vaccine based on conserved GP epitopes will be protective against both MARV and RAVV. The vaccine will use a highly innovative vaccine delivery platform based on pseudouridin-modified RNA delivered in a lipid nanoparticle formulation. The proposal is based on an interdisciplinary approach with a diverse team of experts in computational modeling, antibody and antigen discovery, filovirus virology, immunology and vaccinology. The Meiler computational group will use the ROSETTA software platform techniques to design novel structure- based vaccine candidate antigens, using high-resolution structures of antigen-antibody complexes in the GP receptor-binding domain. The Crowe laboratory will generate recombinant antigens and antibodies, validate proper structure and function of the constructs, and determine the fine details of their biomolecular interaction. Moderna Therapeutics will provide the innovative mRNA vaccine platform. The Bukreyev and Geisbert laboratories will test the vaccine constructs expressing the designed antigens in rodent and non-human primate models of marburgviruses, and the Bukreyev laboratory will perform in-depth characterization of the immune response. The completion of this proposal will result in the development of a universal and safe next- generation vaccine, which will be protective against both MARV and RAVV. The generated antigen will be compatible with any existing advanced vaccine platform currently in clinical trials.

项目摘要/摘要 Marburg病毒（Marv）和Ravn病毒（RAVV）都属于家族的马尔伯格病毒属 fileviridae，导致人类严重疾病，病例死亡率高达90％。没有许可针对马堡病毒的疫苗。针对埃博拉病毒（EBOV）的疫苗候选者的临床试验，该试验属于家族filoviridae的埃博氏病毒属，证明高疫苗的剂量是在保护水平上诱导免疫反应需要导致与其相关的毒性作用主成分EBOV糖蛋白（GP）。我们和其他人最近孤立和表征了人类单克隆抗体（mAb）对MARV和EBOV，并定义了主要的抗原决定因素对丝状病毒GP的中和和保护。我们已经证明了对非人类的成功保护灵长类动物通过被动转移mab对抗MARV。这项研究的中心假设是表位 MARV感染幸存者的天然人类保护抗体可以用作最佳理性设计的基于结构的疫苗的模板。这个假设得到了我们最近的支持与最新的进步相结合的隔离保护单元格的广泛进展计算免疫学技术。我们提出了基于结构的疫苗MARV的合理设计在GP上呈现免疫决定因素的候选者。如野生型（WT）GP中的抗原元素蛋白质上的糖基化，糖基帽和粘蛋白样结构域遮盖了蛋白质。设计预计抗原比WT GP更好地存在保护性决定因素。我们还建议基于保守的GP表位的疫苗将对MARV和RAVV均具有保护作用。疫苗将使用基于脂质中交付的假素修饰的RNA的高度创新的疫苗输送平台纳米颗粒制剂。该提案基于与多样的专家团队的跨学科方法在计算建模，抗体和抗原发现，丝状病毒病毒学，免疫学和疫苗学。 Meiler计算小组将使用Rosetta软件平台技术设计新颖的结构 - 基于GP中抗原抗体复合物的高分辨率结构，基于疫苗的抗原受体结合域。 Crowe实验室将产生重组抗原和抗体，验证构造的正确结构和功能，并确定其生物分子相互作用的细节。 Moderna Therapeutics将提供创新的mRNA疫苗平台。 Bukreyev和Geisbert 实验室将测试在啮齿动物和非人类中表达设计抗原的疫苗构建体马堡病毒的灵长类动物模型和布克里耶夫实验室将进行深入的表征免疫反应。该提案的完成将导致下一步的普遍安全和安全的发展一代疫苗，将对MARV和RAVV具有保护作用。产生的抗原将是与目前在临床试验中的任何现有的高级疫苗平台兼容。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antibody responses to filovirus infections in humans: protective or not?

DOI：
10.1016/s1473-3099(21)00006-2
发表时间：
2021-10-28
期刊：
LANCET INFECTIOUS DISEASES
影响因子：
56.3
作者：
Ilinykh, Philipp A.;Bukreyev, Alexander
通讯作者：
Bukreyev, Alexander

RosettaCM for antibodies with very long HCDR3s and low template availability.

DOI：
10.1002/prot.26166
发表时间：
2021-11
期刊：
Proteins
影响因子：
2.9
作者：
Kodali P;Schoeder CT;Schmitz S;Crowe JE , Jr;Meiler J
通讯作者：
Meiler J

Computationally Designed Cyclic Peptides Derived from an Antibody Loop Increase Breadth of Binding for Influenza Variants.

DOI：
10.1016/j.str.2020.04.005
发表时间：
2020-10-06
期刊：
Structure (London, England : 1993)
影响因子：
0
作者：
Sevy AM;Gilchuk IM;Brown BP;Bozhanova NG;Nargi R;Jensen M;Meiler J;Crowe JE Jr
通讯作者：
Crowe JE Jr

Human-likeness of antibody biologics determined by back-translation and comparison with large antibody variable gene repertoires.