Epitope optimization for heterologous prime-boost HIV vaccines

异源初免-加强 HIV 疫苗的表位优化

基本信息

批准号：
9138212
负责人：
TIMOTHY J CARDOZO
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9138212
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Affect Antibodies Antibody Formation Antigens B-Lymphocyte Epitopes Binding CD8B1 gene Characteristics Codon Nucleotides Communities Complex DNA DNA Sequence Epitopes Foundations Genetic Glycoproteins Goals HIV HIV Envelope Protein gp120 HIV Infections HIV vaccine Human Immune response Immunization Individual Link Molecular Molecular Conformation Monoclonal Antibodies Neutralization Tests Oryctolagus cuniculus Outcome Physiological Plasma Proteins Protocols documentation Quantitative Structure-Activity Relationship Reagent Research Research Project Grants Serum Source Structure-Activity Relationship Surface System Technology Testing United States National Institutes of Health Ursidae Family V3 Loop Vaccine Clinical Trial Vaccine Design Vaccines base design env Genes high reward high risk human subject immunogenic improved innovation interest novel polyclonal antibody programs public health relevance research study resistant strain response three dimensional structure vaccine trial vector

项目摘要

DESCRIPTION (provided by applicant): As a result of the RV144 trial and numerous recent studies, heterologous prime-boost HIV vaccine strategies have emerged as the leading approach to elicit immune responses that could protect against HIV infection. The molecular basis of the heterologous approach over homologous approaches is not well understood, however. In particular, immune responses to vector or DNA priming immunizations that are then amplified by protein boost immunization are complex and obscure. In this proposal, we will perform experiments that may clarify unsuspected, fundamental aspects of the immune responses to the prime that are amplified by the protein boost. To test this, we will control for many factors in a heterologous prime-boost experiment, varying only the conformational B-cell epitopes between prime and boost. Our innovative hypothesis is that the conformation of B-cell epitopes in the prime influences those self-same epitopes in the boost. Rabbits will be immunized with an array of DNA primes constructed to express or exclude specific immunogenic HIV variable loop epitopes and then boosted with an immunofocused protein immunogen that exclusively bears those epitopes. We expect to observe whether the expression of a conformational epitope in the prime amplifies or retards elicitation of neutralizin antibodies from that self-same epitope provided on the protein boost. The results will clearly provide the first consistent rationale for selecting or designing HIV env genes for use in priming immunizations. This exploratory R21 project will thus form the foundation for a unique long-term research program into the molecular details of the interaction between priming and boosting immunizations in a heterologous prime-boost strategy. These details may be crucial for designing an efficacious HIV vaccine.

描述（由申请人提供）：根据 RV144 试验和近期的大量研究，异源初免-加强 HIV 疫苗策略已成为引发可预防 HIV 感染的免疫反应的主要方法。异源方法的分子基础。然而，对同源方法的免疫应答尚不清楚，然后通过蛋白质加强免疫来放大对载体或 DNA 引发免疫的免疫反应是复杂且模糊的。可能会澄清对初免免疫反应的未预料到的基本方面，这些免疫反应是由蛋白质加强增强放大的。为了测试这一点，我们将在异源初免加强实验中控制许多因素，仅改变初免和初免之间的构象B细胞表位。我们的创新假设是，初免中 B 细胞表位的构象会影响初免中的相同表位，而兔子将用一系列 DNA 初免进行免疫，以表达或排除特定的免疫原性 HIV。可变环表位，然后用专门带有这些表位的免疫聚焦蛋白质免疫原进行加强，我们期望观察初等蛋白中构象表位的表达是否会放大或延迟来自蛋白质加强提供的相同表位的中和素抗体的引发。结果将为选择或设计用于启动免疫的 HIV 包膜基因提供第一个一致的基本原理，因此，该探索性 R21 项目将为独特的基础奠定基础。一项针对异源初免-加强策略中初免和加强免疫之间相互作用的分子细节的长期研究计划，这些细节对于设计有效的艾滋病毒疫苗可能至关重要。