Defining clinically relevant viral epitopes with cow antibodies

用牛抗体定义临床相关的病毒表位

基本信息

批准号：
10014637
负责人：
Vaughn Vasil Smider
金额：
$ 35.86万
依托单位：
APPLIED BIOMEDICAL SCIENCE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10014637
关键词：
Amino Acids Animal Model Animals Antibodies Antibody Repertoire Antibody Response Antigens Binding Biochemical Cattle Common Epitope Communicable Diseases Cysteine Data Development Electron Microscopy Engineering Epitopes Flavivirus Future Genetic Engineering HIV HIV Antibodies HIV Envelope Protein gp120 Health Human Immune response Immunization Immunize Immunoglobulins Immunology Lead Length Maps Medical Molecular Monoclonal Antibodies Mus Mutagenesis Mutation Outcome Outcome Study Polysaccharides Positioning Attribute Property Protein Engineering Proteins Retroviridae Structure Structure-Activity Relationship Surface System Techniques Texas Trastuzumab Vaccination Vaccine Design Vaccines Viral Virus Virus Diseases X-Ray Crystallography antigen antibody binding antigen binding clinically relevant deep sequencing disulfide bond experimental study humanized antibody insight knob protein neutralizing antibody neutralizing monoclonal antibodies next generation novel novel vaccines prevent structural biology success tool vaccine development virology ward

项目摘要

Vaccines are the primary means by which to prevent, control, or eradicate infectious diseases. While many vaccines have been successfully developed and have resulted in enormous medical and veterinary benefit, there are certain viruses that have eluded effective vaccine development. Generally, viruses with multiple strains or that have high mutation rates can evade neutralizing antibodies, as their surface determinants are variable and result in the inability of neutralizing antibodies raised against one strain to bind and neutralize alternative strains. Certain rare epitopes, however, are required for viral infection and are conserved across strains. Interestingly, neutralizing antibodies against these rare epitopes tend to have long CDR H3 regions. In the case of HIV, long CDR H3s can pierce the viral glycan shield and reach into the conserved epitope on the gp120 spike protein. While long CDR H3 regions in human antibodies are infrequent in the repertoire, cattle routinely produce long (20-40 amino acids) and ultralong (40-70 amino acids) CDR H3 regions that have unique “stalk” and “knob” structural features that protrude far from the antibody surface. Therefore, cattle may be an excellent model organism to identify and define new and conserved neutralizing epitopes in these challenging viruses. Indeed, in preliminary experiments we have found that cattle make a robust and broadly neutralizing antibody response to the HIV gp120 antigen. Here we propose to use the unique cow antibody repertoire to define new conserved neutralizing epitopes on two viruses of great importance to human and animal health, HIV and BVDV. Effective vaccines against both of these viruses have been a major challenge to develop. We will immunize animals against these viruses, generate monoclonal antibodies that neutralize the virus as well as related strains, and molecularly map the antigen-antibody interaction using mutagenesis and structural biology techniques. Definition of new conserved epitopes could lead to engineered epitope-specific vaccines. Thus, the outcomes of this proposal could enable generation of next-generation vaccines for these two viruses, but could also have broad utility in vaccine development against other challenging viruses in the future.

疫苗是预防、控制或根除传染病的主要手段虽然许多疫苗已成功开发并已导致疾病。巨大的医疗和兽医效益，某些病毒已经逃脱有效的疫苗开发通常是具有多种毒株或具有高毒株的病毒。突变率可以逃避中和抗体，因为它们的表面决定因素是可变并导致针对一种菌株产生的中和抗体无法然而，结合并中和替代菌株是必需的。病毒感染并且在菌株之间保守。针对这些罕见的表位往往具有较长的 CDR H3 区域，就 HIV 而言，较长。 CDR H3 可以刺穿病毒聚糖屏蔽并到达病毒聚糖上的保守表位 gp120 刺突蛋白在人类抗体中很少见。根据库，牛通常产生长氨基酸（20-40 个氨基酸）和超长氨基酸（40-70 个氨基酸）氨基酸）CDR H3 区域具有独特的“茎”和“旋钮”结构特征，远离抗体表面因此，牛可能是一个很好的模型。生物体来识别和定义这些中新的和保守的中和表位事实上，在初步实验中我们发现牛会产生具有挑战性的病毒。针对 HIV gp120 抗原的强大且广泛中和的抗体反应。提议使用独特的牛抗体库来定义新的保守中和对人类和动物健康非常重要的两种病毒——艾滋病毒和针对这两种病毒的有效疫苗一直是人类面临的重大挑战。我们将针对这些病毒对动物进行免疫，产生单克隆抗体。中和病毒及相关毒株的抗体，并对病毒进行分子图谱分析使用诱变和结构生物学技术的抗原-抗体相互作用。新保守表位的定义可能会导致工程化表位特异性疫苗的产生。因此，该提案的结果可以使下一代的产生这两种病毒的疫苗，但也可能在疫苗开发中具有广泛的用途未来对抗其他具有挑战性的病毒。