7HP349, an oral integrin activator to augment effectiveness of pre-exposure influenza vaccination

7HP349,一种口服整合素激活剂,可增强暴露前流感疫苗接种的有效性

基本信息

  • 批准号:
    10693536
  • 负责人:
  • 金额:
    $ 92.82万
  • 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:
    2023-04-26 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Americans aged ≥65 years accounted for 57% and 75% of all influenza-related hospitalizations and deaths, respectively, in the 2019-20 season, despite a vaccination rate of ~68%. Flu vaccine effectiveness is lower in the elderly than in younger adults, requiring either a high-dose (Fluzone® HD) or an adjuvanted (FluAd®) vaccine. Antigen mismatch in vaccine vs. circulating strains results in insufficient protection, and poor responses in the elderly remain major public health concerns. Cell-mediated immunity may correlate better than humoral immunity for vaccine protection in the elderly. Adjuvants used to enhance vaccine efficacy, such as MPLA, CpG and alum, trigger either innate or antibody responses, but not a T cell response. While existing adjuvants or increased antigen load may partially improve seroconversion, overall vaccine effectiveness and T cell responses may be suboptimal in at-risk populations. New adjuvants are needed that induce robust T cell responses for pathogen clearance. A key factor for suboptimal vaccine effectiveness in the elderly is immunosenescence, a gradual age-related immune decline. Prolonged cell adhesion mediated by integrins α4β1 and αLβ2 and their cognate ligands, VCAM-1 and ICAM-1, is essential for effective antigen presentation and T cell priming at the immune synapse between antigen presenting cells (APCs) and naïve T cells, as well as for T cell memory and effector functions. Deficient APC-T cell adhesion attenuates T cell activation and memory. Age-related defects in ICAM-1 induction on activated dendritic cells may decrease T cell priming, resulting in suboptimal vaccine effectiveness in the elderly. 7HP349 is a first-in-concept, oral, small-molecule, allosteric α4β1/αLβ2 activator that may promote APC-T cell adhesion, and improve T helper function and the effectiveness of geriatric influenza vaccination. In mice, 7HP349 significantly improved the effectiveness of influenza, Chagas disease, SARS-CoV- 2 and tuberculosis vaccines, not only via humoral responses but also cell-mediated immunity, which differentiates it from current or emerging competition. A first-in-human Phase I clinical study to evaluate the safety, tolerability and PK of 7HP349 in healthy male subjects was completed in 4Q 2021. 7HP349 was shown to be safe and orally bioavailable, with no treatment-related serious adverse events. Additionally, the optimal pharmacokinetic dose was identified. In this application, we propose to evaluate 7HP349 as an oral adjuvant to influenza vaccination in aging mice with pre-existing immunity, that would be representative of vaccination in the elderly. Additionally, to activate a supplemental IND for geriatric influenza, we plan to complete additional required Chemistry, Manufacturing and Control activities that will include development of a 100 mg strength to enable once daily, one pill dosing to improve patient compliance, and manufacture of cGMP 7HP349 Drug Product to support the IND and build inventory for a future Phase I/IIa clinical study in elderly subjects to assess the safety of 7HP349 and to evaluate its immunogenicity in combination with Fluzone® HD, which will also lay the foundation for its potential use in enhancing the effectiveness of other infectious disease vaccines in vulnerable sub-populations.
项目总结/文摘

项目成果

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Siddhartha De其他文献

Siddhartha De的其他文献

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{{ truncateString('Siddhartha De', 18)}}的其他基金

Integrin activator-adjuvanted DNA vaccine against Trypanosoma cruzi infection
整合素激活剂佐剂 DNA 疫苗对抗克氏锥虫感染
  • 批准号:
    10665082
  • 财政年份:
    2022
  • 资助金额:
    $ 92.82万
  • 项目类别:
Integrin activator-adjuvanted DNA vaccine against Trypanosoma cruzi infection
整合素激活剂佐剂 DNA 疫苗对抗克氏锥虫感染
  • 批准号:
    10544403
  • 财政年份:
    2022
  • 资助金额:
    $ 92.82万
  • 项目类别:

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