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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：
10202672
负责人：
Vaughn Vasil Smider
金额：
$ 35.29万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202672
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