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，控制或放射性传染性的主要手段疾病。尽管许多疫苗已经成功开发并导致巨大的医疗和兽医利益，有些病毒已经避开有效的疫苗开发。通常，具有多种菌株或高的病毒突变速率可以逃避中和抗体，因为它们的表面决定剂是可变并导致无法中和抗体针对一种菌株的抗体结合并中和替代菌株。但是，某些罕见的表位需要病毒感染并在跨菌株中保守。有趣的是，中和抗体在这些罕见的表位上，CDR H3区域往往具有很长的CDR区域。在艾滋病毒的情况下，很长 CDR H3S可以刺穿病毒性聚糖屏蔽层，并伸入配置的episodeTope GP120尖峰蛋白。虽然人类抗体中长的CDR H3区域很少见曲目，牛通常产生长（20-40个氨基酸）和Ultralong（40-70）氨基酸）CDR H3区具有独特的“茎”和“旋钮”结构特征的CDR H3区域远离抗体表面。因此，牛可能是一个很好的模型识别和定义新的并构成中和表位的有机体具有挑战性的病毒。确实，在初步实验中，我们发现牛会做对HIV GP120抗原的强大而广泛的抗体反应。我们在这里建议使用独特的牛抗体库来定义新的保守中和关于对人类和动物健康，艾滋病毒和 BVDV。针对这两种病毒的有效疫苗一直是发展。我们将对这些病毒进行免疫动物免疫，产生单克隆中和病毒以及相关菌株并分子绘制的抗体使用诱变和结构生物学技术的抗原抗体相互作用。新的保守表位的定义可能导致设计的表位特异性疫苗。这是该提案的结果可以使下一代产生这两种病毒的疫苗，但在疫苗开发中也可能具有广泛的效用反对将来其他挑战病毒。