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: 8410925
• 负责人: PAUL W. SPEARMAN
• 金额: $ 24.8万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410925
• 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 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. PUBLIC HEALTH RELEVANCE: This study will provide new information about how antibody responses that inhibit or neutralize HIV are generated in people who receive an HIV vaccine, as compared with HIV-infected individuals. Knowledge gained from this study will help in the design of new HIV vaccines, and will tell us whether a delayed booster vaccination with a different subtype or clade can produce antibodies to a number of different subtypes of HIV.

描述（由申请人提供）：开发能够引起广泛中和 HIV 疫苗株的疫苗方案仍然是一个重要但难以捉摸的目标。 HIV特异性抗体可以通过使用活载体疫苗、亚单位蛋白疫苗和其他方法来产生，但针对HIV初级分离株的显着中和作用尚未在人类疫苗试验中得到证实。 HIV 疫苗试验网络 (HVTN 049) 最近进行的一项试验是一个很好的例子，该试验对同源且易于中和的 SF162 菌株产生了高水平的中和作用，但对第 2 层菌株产生了非常小的广度，其中志愿者接受了诺华公司的 DNA 引发剂和重组、三聚体、V2 缺失、进化枝 B 包膜蛋白产品作为加强剂。 隔离。这将有助于设计未来的试验和免疫原，以了解疫苗接种者的 B 细胞反应与确实产生显着中和广度的 HIV 感染者亚群中的 B 细胞反应的比较。本申请的主要目标是将最先进的 B 细胞库和单克隆抗体技术应用于 HVTN 088 中登记的人类志愿者的反应分析，其中 HVTN 049 参与者正在接受进化枝 C 三聚体蛋白的加强免疫接种。这项研究将定义参与疫苗反应的 B 细胞亚群、抗体可变基因片段中存在的亲和力成熟程度、生成的 CDR3 环的长度，以及几年前已用进化枝 B 蛋白引发的疫苗接受者与未引发的疫苗接受者相比的中和表位。将从选定的受体中产生单克隆抗体，以进一步确定存在广度的性质，并测试可以通过疫苗接种引发交叉中和单克隆反应的假设。这些数据将提供重要的新信息，为设计旨在引发广泛中和抗体的艾滋病毒疫苗方案提供信息。 公共卫生相关性：这项研究将提供有关与艾滋病毒感染者相比，接受艾滋病毒疫苗的人如何产生抑制或中和艾滋病毒的抗体反应的新信息。从这项研究中获得的知识将有助于设计新的艾滋病毒疫苗，并将告诉我们不同亚型或进化枝的延迟加强疫苗接种是否可以产生针对许多不同艾滋病毒亚型的抗体。