Kinetics, evolution, and effector function of Fc repertoires during vaccination with native-like Env trimers

使用类似天然的 Env 三聚体进行疫苗接种期间 Fc 库的动力学、进化和效应子功能

• 批准号: 10328497
• 负责人: D. Noah Sather
• 金额: $ 87.74万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-20 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328497
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Antibodies; Antibody Response; Antigens; B-Cell Antigen Receptor; Binding; Biological Models; Cessation of life; Clinic; Development; Epitopes; Evolution; Goals; Growth; HIV-1; HIV-1 vaccine; IgG3; Immune response; Immunity; Immunization; Immunoglobulin G; Immunologics; Infection; Kinetics; Knowledge; Mediating; Mediator of activation protein; Methods; Modality; Molecular Conformation; Monoclonal Antibodies; Persons; Prevention strategy; Process; Regimen; Research; Research Personnel; Resolution; Risk; Role; Route; Scheme; Serology; Technology; Time; Vaccination; Vaccine Antigen; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Virus; antigen binding; env Gene Products; experience; high throughput technology; infection risk; insight; interest; neutralizing antibody; next generation sequencing; nonhuman primate; novel; novel vaccines; protective efficacy; response; treatment strategy; vaccine development; vaccine efficacy; vaccine evaluation

ABSTRACT A safe, effective vaccine remains the best hope for eradicating HIV-1, which now infects 37 million people worldwide and results in more than 1.2 million deaths and 1.8 million new infections each year. The only HIV-1 vaccine clinical trial to show vaccine efficacy was RV144, which achieved 31% protection from infection. Follow-on analyses identified immunological correlates of reduced risk of infection, finding that vaccine protection was not associated with neutralizing antibodies. Rather, protection was associated with non- neutralizing antibody activity, i.e., antibody effector function that is mediated through the constant Fc region. As such, there is intense interest in developing vaccines that can recapitulate and enhance the types of functional antibodies that were found in RV144. However, a gap exists in our knowledge of how such responses can best be elicited by vaccination, and how Fc-mediated activity is induced, evolves and endures. It is not clear what effect vaccine modalities have on this process, nor how it can be optimized. In this proposal, we aim to discover the most optimal methods by which Fc-mediated activity can be elicited by vaccines. We will assess several vaccine parameters, including antigen, adjuvant, route of inoculation, and prime/boost strategies. Importantly, we will use novel cutting edge, high throughput technologies to define the ontogeny, kinetics, evolution and duration of Fc antibody responses in unprecedented detail and breadth. Further, we will define the relationship between vaccine-elicited Fc-mediated function and the antigenic landscape of Env. Our goal is to gain fundamental immunological insights into how vaccines drive Fc-related antibody responses, and how vaccination modalities can be optimized to elicit highly functional, durable antibody responses against HIV-1. If successful, these findings would guide the development of the next generation of vaccines moving into the clinic, and would represent a significant step forward for HIV-1 vaccine development, and.

抽象的 安全有效的疫苗仍然是消除HIV-1的最佳希望，HIV-1现在感染了3700万人 全球，每年导致超过120万人的死亡和180万新感染。唯一的HIV-1 疫苗临床试验显示疫苗功效为RV144，可获得31％的感染保护。 后续分析确定了降低感染风险的免疫学相关性，发现疫苗 保护与中和抗体无关。相反，保护与非 - 中和抗体活性，即通过恒定FC区域介导的抗体效应功能。 因此，人们对开发可以概括和增强类型的疫苗有浓厚的兴趣 在RV144中发现的功能抗体。但是，我们对如何这样的知识存在差距 可以通过疫苗接种以及如何诱导FC介导的活性，发展和持久来引起反应。 尚不清楚疫苗方式对此过程有什么影响，或者如何优化疫苗。在此提案中， 我们旨在发现FC介导的活动可以通过疫苗引起的最佳方法。我们 将评估几个疫苗参数，包括抗原，辅助，接种途径和Prime/Boost 策略。重要的是，我们将使用新型的尖端，高吞吐量技术来定义个体发育， FC抗体反应的动力学，进化和持续时间是前所未有的细节和广度。此外，我们会的 定义疫苗吸引的FC介导的功能与Env的抗原景观之间的关系。我们的 目标是获得有关疫苗如何驱动FC相关抗体反应以及 如何优化疫苗接种方式以引起高功能耐用的抗体反应 HIV-1。如果成功，这些发现将指导下一代疫苗移动的开发 进入诊所，这将代表HIV-1疫苗开发的重要一步。