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

摘要 一种安全有效的疫苗仍然是根除HIV-1的最大希望，HIV-1目前感染了3700万人 在全世界范围内，每年造成120多万人死亡和180万新感染。唯一的HIV-1 显示疫苗效力的疫苗临床试验是RV 144，其实现了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 保护作用与中和抗体无关。相反，保护与非- 中和抗体活性，即，通过恒定Fc区介导的抗体效应子功能。 因此，人们对开发能够概括和增强免疫缺陷病毒类型的疫苗有着浓厚的兴趣。 在RV 144中发现的功能性抗体。然而，在我们的知识中存在着一个缺口， 免疫应答最好通过疫苗接种引发，以及Fc介导的活性如何被诱导、进化和持续。 目前尚不清楚疫苗模式对这一过程有什么影响，也不清楚如何优化这一过程。在这一提议中， 我们的目标是发现疫苗可以引发Fc介导的活性的最佳方法。我们 将评估几个疫苗参数，包括抗原、佐剂、接种途径和初免/加强 战略布局重要的是，我们将使用新的尖端，高通量技术来定义个体发育， 以前所未有的细节和广度研究Fc抗体应答的动力学、演变和持续时间。此外，我们将 定义疫苗引起的Fc介导的功能和Env的抗原性景观之间的关系。我们 目标是获得疫苗如何驱动Fc相关抗体应答的基本免疫学见解， 如何优化疫苗接种方式，以引发高功能，持久的抗体反应， HIV-1如果成功，这些发现将指导下一代疫苗的开发， 进入临床，这将是HIV-1疫苗开发的重要一步。

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.