Project 1: The impact of innate immune responses on the development of broadly neutralizing antibodies by vaccination

项目 1：先天免疫反应对通过疫苗接种产生广泛中和抗体的影响

基本信息

批准号：
10731281
负责人：
Kristina De Paris
金额：
$ 25.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731281
关键词：
Adjuvant Adult Affinity Age Agonist Animals Antibodies Antibody Response Antigen-Presenting Cells Autologous B-Cell Activation B-Cell Antigen Receptor B-Cell Development B-Lymphocytes Binding Sites Biological Response Modifiers Cell Lineage Cell Separation Cells Childhood Coculture Techniques Collaborations Complex Computer Models Cytometry Data Data Analyses Dendritic Cells Dendritic cell activation Development Emulsions Frequencies Future Glycoproteins Goals HIV HIV Antibodies HIV envelope protein HIV vaccine Heart Human Immune Immunization Immunoglobulin Somatic Hypermutation Infant Innate Immune Response Knock-in Mouse Leadership Licensing Macaca mulatta Mediating Memory B-Lymphocyte Molecular Profiling Mus Newborn Infant Pathway interactions Pattern recognition receptor Peripheral Blood Mononuclear Cell Phase Phenotype Plasma Plasma Cells Population Process Property Proteome Regimen Regulation Reporting Research Design Research Project Grants Saponins Signal Pathway Specificity Structure of germinal center of lymph node T-Lymphocyte TLR3 gene TLR4 gene TLR7 gene Testing Toll-like receptors Vaccinated Vaccination Vaccine Adjuvant Vaccine Design Vaccines aluminum sulfate cell type commensal bacteria cytokine immune activation immunoregulation improved lymph nodes microbiome microbiota monocyte mouse model nanoparticle neutralizing antibody peripheral blood power analysis programs reconstitution response single-cell RNA sequencing transcriptome sequencing transcriptomics vaccine development vaccine evaluation vaccine strategy vaccine trial vaccine-induced antibodies

项目摘要

ABSTRACT - PROJECT 1 The induction of broadly neutralizing antibodies (bNAb) by HIV vaccination remains a major challenge. Rational B-cell-lineage vaccine design with native HIV envelope trimers has emerged as the most promising vaccine strategy. Yet, while HIV Env glycoprotein trimers targeting the respective germline B cell receptor have been successful in inducing autologous tier 2 neutralizing antibodies by vaccination, the induction of antibodies able to neutralize heterologous strains remains limited. Numerous studies have reported that vaccine-induced antibody responses can be enhanced by the inclusion of adjuvants in the vaccine regimen. The potential of adjuvants to impact the induction of bNAb, however, is largely unexplored. The long-term goal of Project 1 is to identify mechanisms by which adjuvants can enhance the induction and maturation of bNAbs. We present preliminary data that immunization of infant rhesus macaques (RM) with the germline targeting BG505 GT1.1 SOSIP mixed with the TLR7,8-based adjuvant 3M-052 in stable emulsion (SE) resulted in the induction of bNAb precursors against the CD4 binding site (CD4bs), indicative of VRC01-like bNAbs, in 3 of 5 animals by 1.5 years. Studies in adult RM have reported that the inclusion of 3M-052 in HIV vaccine regimens promotes the induction of long-lived plasma cells, and HIV vaccines with TLR3- or TLR4-based adjuvants in germline BCR knock-in mice have been associated with increased somatic hypermutation (SHM) and the induction of VRC01-like bNAb precursors. However, the mechanisms by which 3M-052 or other TLR-based adjuvants support germinal center activity, SHM, the induction of HIV bNAb precursors, and/or the development of long-lived plasma cells remain unknown. The objective of Project 1 is to identify the determinants of the initial steps in the induction of bNAb precursors. We hypothesize that adjuvants given in combination with BG505 GT1.1 SOSIP trimers alter the developmental pathway of Env-specific B cells through the induction of specific innate responses that will impact affinity maturation of bNAb precursors. Understanding the complex process of B cell development towards bNAb- producing B cells in response to HIV vaccination and its regulation will require broad omics-based approaches that this Program will apply. Project 1 will thoroughly assess innate immune responses via transcriptomics, single cell (sc) RNA-sequencing, immunome analysis by CyTOF, and proteome analysis of soluble immune mediators in plasma. To determine whether bNAb development can be impacted by the choice of adjuvant, we will ask whether the yield of bNAb precursors after BG505 GT1.1 SOSIP immunization differs dependent on innate responses induced by 3M-052-SE versus a saponin-based adjuvant (Aim 1), and dependent on adjuvant- specific immune cell activation and function in lymph nodes (Aim 2). In collaboration with Project 2, we will define how these innate responses are modulated by commensal bacteria (Aim 3). The results are expected to inform the development of new targeted immunomodulatory approaches of the vaccine prime to optimize the induction of bNAb precursors and provide a framework for bNAb-targeting HIV vaccine evaluation and down-selection.

摘要 - 项目 1 通过 HIV 疫苗接种诱导广泛中和抗体 (bNAb) 仍然是一个重大挑战。合理的采用天然 HIV 包膜三聚体的 B 细胞谱系疫苗设计已成为最有前途的疫苗战略。然而，虽然针对各自种系 B 细胞受体的 HIV Env 糖蛋白三聚体已被通过疫苗接种成功诱导自体 2 级中和抗体，该抗体的诱导能够中和异源菌株的能力仍然有限。大量研究表明，疫苗诱导的通过在疫苗方案中加入佐剂可以增强抗体反应。的潜力然而，佐剂影响 bNAb 诱导的作用很大程度上尚未被探索。项目1的长期目标是确定佐剂增强 bNAb 诱导和成熟的机制。我们呈现使用针对 BG505 GT1.1 的种系对幼年恒河猴 (RM) 进行免疫的初步数据 SOSIP 与基于 TLR7,8 的佐剂 3M-052 在稳定乳液 (SE) 中混合，导致 bNAb 的诱导 1.5 岁时，5 只动物中的 3 只出现了针对 CD4 结合位点 (CD4bs) 的前体，表明存在 VRC01 样 bNAb。针对成人 RM 的研究报告称，将 3M-052 纳入 HIV 疫苗方案可促进诱导种系 BCR 敲入中使用基于 TLR3 或 TLR4 的佐剂的长寿命浆细胞和 HIV 疫苗小鼠体细胞超突变 (SHM) 增加和 VRC01 样 bNAb 的诱导相关前体。然而，3M-052 或其他基于 TLR 的佐剂支持生发中心的机制活性、SHM、HIV bNAb 前体的诱导和/或长寿命浆细胞的发育仍然存在未知。项目 1 的目标是确定 bNAb 诱导初始步骤的决定因素前体。我们假设佐剂与 BG505 GT1.1 SOSIP 三聚体联合使用会改变 Env 特异性 B 细胞的发育途径通过诱导特定的先天反应来影响 bNAb 前体的亲和力成熟。了解 B 细胞向 bNAb 发展的复杂过程产生 B 细胞以响应 HIV 疫苗接种及其调控需要广泛的基于组学的方法该计划将适用。项目 1 将通过转录组学、单一方法彻底评估先天免疫反应细胞 (sc) RNA 测序、CyTOF 免疫组分析以及可溶性免疫介质的蛋白质组分析在血浆中。为了确定 bNAb 的开发是否会受到佐剂选择的影响，我们将询问 BG505 GT1.1 SOSIP 免疫后 bNAb 前体的产量是否因先天性而异 3M-052-SE 与基于皂苷的佐剂（目标 1）诱导的反应，并且依赖于佐剂- 淋巴结中的特异性免疫细胞激活和功能（目标 2）。与项目 2 合作，我们将定义共生细菌如何调节这些先天反应（目标 3）。预计结果将告知开发疫苗的新靶向免疫调节方法以优化诱导 bNAb 前体，并为 bNAb 靶向 HIV 疫苗评估和向下选择提供框架。