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

基本信息

  • 批准号:
    10544403
  • 负责人:
  • 金额:
    $ 99.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-14 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Trypanosoma cruzi (Tc) is the causative agent of Chagas disease (CD). With >7 million recorded cases, ~81 million at risk of Tc exposure in Latin America, and large-scale migration from endemic to other countries including the USA where autochthonous transmission of Tc also occurs, CD remains a global health concern. Currently no therapies exist to prophylactically treat adults traveling to endemic countries or those who may already be infected with Tc. The economic burden for chagas cardiomyopathy and heart failure, estimated at ~$10 billion due to healthcare costs and lost productivity by premature deaths, provides a strong rationale for investment in the development of immune therapies against CD. We have already developed a two-component DNA vaccine (TcG2/TcG4) for CD and demonstrated preclinical efficacy of this prototype vaccine in controlling Tc pathogenesis in a mouse model. Vaccine efficacy depends heavily on the induction of a robust TH1 response for the clearance of intracellular pathogens like Tc. Integrin cell adhesion molecules α4β1 and αLβ2 and their ligands, VCAM-1 and ICAM-1, respectively, play an essential role in the activation of adaptive immunity. Prolonged integrin-mediated interactions between T cells and antigen presenting cells (APCs), particularly via the αLβ2/ICAM-1 axis, are required for effective T cell priming and long-term T cell mediated memory. Augmenting cell adhesion may facilitate T cell priming and subsequent immune responses. 7HP349 is a clinical- stage, first-in-concept, oral, small-molecule, positive allosteric activator of α4β1 and αLβ2 integrins, which could facilitate endogenous integrin ligand-receptor engagement, promote cell adhesion, and improve T helper function and the effectiveness of CD vaccination. We have demonstrated that 7HP349 augments the effectiveness of the prototype TcG2/TcG4 DNA vaccine in a mouse model of CD. Additionally, 7HP349 has a favorable preclinical safety and pharmacokinetic profile, and was found to be safe and well tolerated in a Phase 1 clinical study in healthy male subjects. In this SBIR grant application, we propose to develop a vaccination regimen for CD consisting of a bicistronic DNA vaccine (BCV)-adjuvant combination with 7HP349 or another integrin activator, 7HP577, demonstrate preclinical efficacy and safety of the BCV-adjuvant combination, and manufacture clinical grade cGMP BCV and adjuvant to support a Phase I/IIa clinical study to assess the safety and tolerability of the vaccine-adjuvant combination, and thereafter to evaluate its immunogenicity in humans. The proposed studies will allow the development of a novel vaccination regimen to prophylactically treat Tc infection and CD.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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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

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
  • 批准号:
    10693536
  • 财政年份:
    2023
  • 资助金额:
    $ 99.93万
  • 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:
    10665082
  • 财政年份:
    2022
  • 资助金额:
    $ 99.93万
  • 项目类别:

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