HIV-Specific B Cell Repertoire in Humans Following Cross-Clade Immunization

跨进化枝免疫后人类 HIV 特异性 B 细胞库

• 批准号: 8500181
• 负责人: PAUL W. SPEARMAN
• 金额: $ 18.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500181
• 关键词: Affinity; Antibodies; Antibody Formation; Antigens; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Binding Sites; Biological Assay; Clinical Trials Design; Cloning; Combined Vaccines; Complex; DNA; Data; Enrollment; Epitopes; Flow Cytometry; Future; Gene Family; Generations; Genes; Goals; HIV; HIV Vaccine Trials Network; HIV vaccine; Human; Human Herpesvirus 4; Human Volunteers; Hybridomas; Immunization; Immunoglobulin Somatic Hypermutation; Individual; Knowledge; Length; Life; Maps; Measures; Membrane; Memory B-Lymphocyte; Monoclonal Antibodies; Multiple Myeloma; Nature; Participant; Performance; Phylogeny; Population; Protein Subunits; Proteins; Recombinant Antibody; Recombinants; Regimen; Rest; Reverse Transcriptase Polymerase Chain Reaction; Secondary Immunization; Sequence Analysis; Specificity; Structure; Techniques; Technology; Testing; United States National Institutes of Health; V3 Loop; Vaccination; Vaccines; Viral; Virion; antigen binding; base; design; env Gene Products; insight; neutralizing antibody; neutralizing monoclonal antibodies; novel; protein B; response; vaccine development; vector vaccine; volunteer

DESCRIPTION (provided by applicant): The development of a vaccine regimen capable of eliciting broad neutralization of HIV vaccine strains remains an important but elusive goal. HIV-specific antibodies can be raised through the use of live vector vaccines, subunit protein vaccines, and other approaches, but the generation of significant breadth of neutralization against primary isolates of HIV has not yet been demonstrated in a human vaccine trial. A recent trial performed by the HIV Vaccine Trials Network (HVTN 049), in which volunteers received a DNA prime and a recombinant, trimeric, V2-deleted, clade B envelope protein product from Novartis as a boost, is a good example of a trial that generated high levels of neutralization against the homologous and easily-neutralized SF162 strain but yielded very little breadth against Tier 2 isolates. It will be helpful in designing future trials and immunogens to understand how the B cell response in vaccinees compares to that seen in the subpopulation of HIV-infected individuals who do develop significant neutralization breadth. The major goal of the present application is to apply state-of-the-art B cell repertoire and monoclonal antibody technologies to the analysis of responses of human volunteers enrolled in HVTN 088, in which HVTN 049 participants are receiving booster immunizations with a clade C trimeric protein. This study will define the B cell subsets involved in the vaccine response, the degree of affinity maturation present in antibody variable gene segments, the length of the CDR3 loops generated, and the neutralization epitopes targeted in vaccine recipients who have been primed with the clade B protein years before in comparison with those who are unprimed. Monoclonal antibodies will be generated from selected recipients to further define the nature of breadth present and to test the hypothesis that cross-neutralizing monoclonal responses can be elicited through vaccination. These data will provide important new information that will inform the design of HIV vaccine regimens designed to elicit broadly- neutralizing antibodies.

描述（由申请人提供）：开发能够引起HIV疫苗菌株广泛中和的疫苗方案仍然是一个重要但难以捉摸的目标。可以通过使用活载体疫苗，亚基蛋白疫苗和其他方法来提高HIV特异性抗体，但是在人类疫苗试验中尚未证明针对HIV的原发性分离株的显着中和广度的产生。 HIV疫苗试验网络（HVTN 049）进行的一项试验，其中志愿者获得了DNA素数和重组，三聚体，V2删除的，v2，副本B的信封蛋白产品作为Boost，是一个很好的示例，是一个很好的示例，它的一个很好的示例是一个很好的试验，它具有很少的过滤量，较高的中性差异很少，但易于易于同源且易于脱离themologial and tragier and tragier and tragier sf-162226222622622262226226226222622622622626226226262262622。分离物。这将有助于设计未来的试验和免疫原子，以了解疫苗中的B细胞反应与确实会产生显着中和广度的HIV感染个体的亚群相比。本应用的主要目的是将最先进的B细胞库和单克隆抗体技术应用于HVTN 088参加的人类志愿者的反应分析，其中HVTN 049参与者正在接受分支C递送蛋白的助推器免疫。这项研究将定义涉及疫苗反应的B细胞子集，抗体可变基因片段中存在的亲和力成熟程度，产生的CDR3环的长度以及针对疫苗接收者的中和表位，与进化枝B蛋白相比，与进化枝B蛋白相比，与那些未熟悉的人相比。单克隆抗体将从选定的接受者产生，以进一步定义宽度的性质，并检验以下假设：可以通过疫苗接种来引发跨中和单克隆反应。这些数据将提供重要的新信息，这些信息将为艾滋病毒疫苗方案的设计提供信息，旨在引起广泛中和抗体。