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:
  • 金额:
    $ 25.61万
  • 依托单位:
  • 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

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 HIV疫苗接种诱导广泛中和抗体(BNAB)仍然是一个主要挑战。合理的 带有本机HIV信封三聚体的B细胞赛疫苗设计已成为最有前途的疫苗 战略。然而,尽管针对各自种系B细胞受体的HIV ENV糖蛋白三聚体已是 成功通过疫苗接种诱导自体层2中和抗体,抗体能够诱导 中和异源菌株仍然有限。大量研究报道了疫苗诱导的 通过在疫苗方案中添加佐剂可以增强抗体反应。潜力 然而,佐剂会影响BNAB的诱导效果。项目1的长期目标是 确定佐剂可以增强BNAB的诱导和成熟的机制。我们在场 婴儿恒河猕猴(RM)免疫的初步数据,其靶向BG505 GT1.1的种系 SOSIP与TLR7,8基于稳定乳液(SE)中的基于TLR7,8的佐剂3M-052导致BNAB诱导 针对CD4结合位点(CD4B)的前体,指示了VRC01样BNAB,在5只动物中有3只动物中有1。5年。 成人RM的研究报告说,在HIV疫苗方案中纳入3M-052促进了诱导 长寿命的浆细胞和具有TLR3-或TLR4基的HIV疫苗在种系BCR敲入中 小鼠与体细胞超突变(SHM)和VRC01样BNAB的诱导有关 前体。但是,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/或长期浆细胞的发展保持 未知。项目1的目的是确定BNAB诱导的初始步骤的决定因素 前体。我们假设与BG505 GT1.1 SOSIP三聚体结合使用的佐剂改变了 通过诱导特定的先天反应,ENV特异性B细胞的发展途径将影响 BNAB前体的亲和力成熟。了解B细胞开发对BNAB的复杂过程 响应HIV疫苗接种及其调节将需要广泛的基于OMIC的方法来产生B细胞 该程序将适用。项目1将通过转录组学彻底评估先天免疫反应 细胞(SC)RNA测序,通过细胞进行免疫组分析和可溶性免疫介质的蛋白质组分析 在血浆中。为了确定BNAB开发是否会受到佐剂的选择影响,我们将询问 BG505 GT1.1 SOSIP免疫后BNAB前体的产量是否取决于先天 由3M-052-SE诱导的反应与基于皂苷的佐剂(AIM 1),并取决于辅助 - 特异性免疫细胞激活和淋巴结的功能(AIM 2)。与项目2合作,我们将定义 这些先天反应如何通过共生细菌调节(AIM 3)。结果应告知 疫苗素数的新靶向免疫调节方法的开发以优化诱导 BNAB前体的含量,并为靶向BNAB的HIV疫苗评估和下调提供了框架。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据

数据更新时间:2024-06-01

Kristina De Paris的其他基金

Core C: B Cell Core
核心C:B细胞核心
  • 批准号:
    10731279
    10731279
  • 财政年份:
    2023
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10731277
    10731277
  • 财政年份:
    2023
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
Project 2: Microbial determinants of HIV broadly-neutralizing antibody precursor induction in infants
项目2:婴儿中HIV广泛中和抗体前体诱导的微生物决定因素
  • 批准号:
    10731282
    10731282
  • 财政年份:
    2023
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
Core B: Non-human Primate Core
核心B:非人类灵长类核心
  • 批准号:
    10731278
    10731278
  • 财政年份:
    2023
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
Determinants of HIV broadly-neutralizing antibody precursor induction in infants
婴儿中 HIV 广泛中和抗体前体诱导的决定因素
  • 批准号:
    10731276
    10731276
  • 财政年份:
    2023
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
Vaccine-induced SARS-CoV-2-specific T cell responses in patients with X-linked Agammaglobulinemia
X 连锁无丙种球蛋白血症患者中疫苗诱导的 SARS-CoV-2 特异性 T 细胞反应
  • 批准号:
    10593523
    10593523
  • 财政年份:
    2023
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
Immunogenicity and Efficacy of SARS-CoV-2 stabilized prefusion Spike protein vaccines in infant rhesus macaques
SARS-CoV-2 稳定预灌注 Spike 蛋白疫苗在幼年恒河猴中的免疫原性和功效
  • 批准号:
    10223634
    10223634
  • 财政年份:
    2020
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
Subingual-parenteral Vaccination to Prevent Oral HIV Transmission in Infants
舌下注射疫苗预防婴儿经口艾滋病毒传播
  • 批准号:
    10172886
    10172886
  • 财政年份:
    2018
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
Subingual-parenteral Vaccination to Prevent Oral HIV Transmission in Infants
舌下注射疫苗预防婴儿经口艾滋病毒传播
  • 批准号:
    10425465
    10425465
  • 财政年份:
    2018
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:
The Pros and Cons of Trained Immunity Induced by Vaccines for Tuberculosis Prevention
结核病预防疫苗诱导的训练免疫的利与弊
  • 批准号:
    9207318
    9207318
  • 财政年份:
    2016
  • 资助金额:
    $ 25.61万
    $ 25.61万
  • 项目类别:

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