Restoring age-dependent vaccine unresponsiveness by a novel ASP-1 adjuvant combination

通过新型 ASP-1 佐剂组合恢复年龄依赖性疫苗无反应

基本信息

  • 批准号:
    10220588
  • 负责人:
  • 金额:
    $ 73.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT ABSTRACT Infectious diseases are a major cause of morbidity and mortality in the expanding older population. While vaccines are efficient measures to prevent infections, a critical problem is that aging-associated changes in the immune system lead to decreased immunogenicity and clinical efficacy of most currently used vaccines. Novel strategies that increase vaccination efficacy and specifically target the aged immune system are imperative. An essential facet of these efforts is the use of combinatory adjuvants that synergistically potentiate more effective vaccine-induced immune responses against various pathogens. In this project we will define the mechanism of action (MOA) of a combination of a unique parasite protein adjuvant, rASP-1 with each of three well- characterized innate adjuvants: STING, TLR7/8 and RIG-I agonists, known to activate cytoplasmic pattern recognition receptors and Type I IFN signaling, which are specifically dampened in the aged population. We have shown that rASP-1 is a powerful adjuvant as it activates human and mouse dendritic cells to potentiate the differentiation of naïve CD4+ T cells into Th1, Th17 and Tfh-like cells. Transcriptomic analyses of rASP-1- activated hMoDCs revealed upregulation of the MyD88-independent activation pathway and interferon related genes. In mice, rASP-1 elicits a balanced Th1/Th2 antibody response, Th1-biased cellular immunity, and enhanced responses when co-administered with vaccines leading to increased survival following microbial challenge. Importantly, our preliminary data indicate that rASP-1 in combination with 2’3’-cGAMP (STING), R848 (TLR7/8) or 5’3p-hpRNA (RIG-I) in activated adult and aged mouse BMDCs can dramatically synergize beyond merely additive effects; it enhanced secretion of IL-12p40, IP-10 and/or IL-10. The synergy is exceptionally evident when it activates aged mouse BMDCs with the STING ligand. Therefore, we hypothesize that combining rASP-1 with STING, TLR7/8 or RIG-I agonists will synergistically activate early innate immune signaling that critically contributes to the establishment and nature of immune responses, and the duration and intensity of immune activation. We posit that this will help restore the aging-associated deficits in the critical regulatory pathways of the antiviral responses. Through comprehensive immunologic and transcriptomic analyses, the MOA through which rASP-1 in combination with these three PRR agonists leads to optimal activation of helper T cells driving humoral and cellular antiviral responses will be established in both mouse (Aim 1) and human (Aim 2) DCs (adult and aged), to establish that they are conserved, and then test their efficacy in vivo in adult and aged mice using the trivalent inactivated influenza vaccine (IIV3) as a model antigen (Aim 3). This project brings together a dynamic team with a history of collaboration and complementary expertise in vaccinology, immunology, biochemistry, innate cell receptor biology, adjuvants, and bioinformatics. We will deliver a novel, efficacious combination of innate cytoplasmic PRR adjuvants with rASP-1 that promotes protective long-lived adaptive responses and boosts efficacy of vaccines in aged populations.
项目摘要

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)

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Sara Lustigman其他文献

Sara Lustigman的其他文献

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{{ truncateString('Sara Lustigman', 18)}}的其他基金

Restoring age-dependent vaccine unresponsiveness by a novel ASP-1 adjuvant combination
通过新型 ASP-1 佐剂组合恢复年龄依赖性疫苗无反应
  • 批准号:
    10458553
  • 财政年份:
    2021
  • 资助金额:
    $ 73.71万
  • 项目类别:
Restoring age-dependent vaccine unresponsiveness by a novel ASP-1 adjuvant combination
通过新型 ASP-1 佐剂组合恢复年龄依赖性疫苗无反应
  • 批准号:
    10620718
  • 财政年份:
    2021
  • 资助金额:
    $ 73.71万
  • 项目类别:
Activating autophagy in filarial worms to identify novel macrofilaricides
激活丝虫中的自噬以鉴定新型大丝虫杀剂
  • 批准号:
    10198729
  • 财政年份:
    2020
  • 资助金额:
    $ 73.71万
  • 项目类别:
Activating autophagy in filarial worms to identify novel macrofilaricides
激活丝虫中的自噬以鉴定新型大丝虫杀剂
  • 批准号:
    10040523
  • 财政年份:
    2020
  • 资助金额:
    $ 73.71万
  • 项目类别:
The development of a recombinant vaccine against human onchocerciasis
人盘尾丝虫病重组疫苗的研制
  • 批准号:
    7919994
  • 财政年份:
    2009
  • 资助金额:
    $ 73.71万
  • 项目类别:
The development of a recombinant vaccine against human onchocerciasis
人盘尾丝虫病重组疫苗的研制
  • 批准号:
    9444432
  • 财政年份:
    2009
  • 资助金额:
    $ 73.71万
  • 项目类别:
The development of a recombinant vaccine against human onchocerciasis
人盘尾丝虫病重组疫苗的研制
  • 批准号:
    8512650
  • 财政年份:
    2009
  • 资助金额:
    $ 73.71万
  • 项目类别:
Malaria in Brazil: RBC variants & parasite invasion
巴西的疟疾:红细胞变异
  • 批准号:
    7913592
  • 财政年份:
    2009
  • 资助金额:
    $ 73.71万
  • 项目类别:
The development of a recombinant vaccine against human onchocerciasis
人盘尾丝虫病重组疫苗的研制
  • 批准号:
    7738645
  • 财政年份:
    2009
  • 资助金额:
    $ 73.71万
  • 项目类别:
The development of a recombinant vaccine against human onchocerciasis
人盘尾丝虫病重组疫苗的研制
  • 批准号:
    8099714
  • 财政年份:
    2009
  • 资助金额:
    $ 73.71万
  • 项目类别:

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