Integrin activator-adjuvanted DNA vaccine against Trypanosoma cruzi infection

项目总结/摘要 克氏锥虫（Trypanosoma cruzi，Tc）是南美锥虫病（Chagas disease，CD）的病原体。记录在案的病例超过700万例，约81 拉丁美洲有100万人面临接触Tc的风险，以及从地方病流行国家向其他国家的大规模迁移 包括美国在内，也发生Tc的本土传播，CD仍然是全球健康问题。 目前还没有治疗方法来治疗前往流行国家的成年人或可能 已经感染了Tc。查加斯病心肌病和心力衰竭的经济负担，估计为 约100亿美元的医疗费用和过早死亡造成的生产力损失，为以下方面提供了强有力的理由： 投资开发针对CD的免疫疗法。我们已经开发了一种双组分 CD的DNA疫苗（TcG 2/TcG 4），并证明了该原型疫苗在控制CD中的临床前有效性。 小鼠模型中的Tc发病机制。疫苗的有效性在很大程度上取决于对强有力的TH 1应答的诱导 用于清除细胞内病原体如Tc。整合素细胞粘附分子α4β1和αLβ2及其相互作用 配体VCAM-1和ICAM-1分别在获得性免疫的激活中起重要作用。 T细胞和抗原呈递细胞（APC）之间的延长的整合素介导的相互作用，特别是通过 αLβ2/ICAM-1轴是有效T细胞启动和长期T细胞介导记忆所必需的。 增强细胞粘附可以促进T细胞引发和随后的免疫应答。7 HP 349是一种临床- 阶段，首次概念，口服，小分子，α4β1和αLβ2整联蛋白的正变构激活剂，可 促进内源性整合素配体-受体结合，促进细胞粘附，改善T辅助细胞功能 以及CD疫苗的有效性。我们已经证明，7 HP 349增强了 原型TcG 2/TcG 4 DNA疫苗在CD小鼠模型中的作用。此外，7 HP 349具有良好的临床前 安全性和药代动力学特征，并在一项1期临床研究中发现安全性和耐受性良好， 健康男性受试者。在这项SBIR拨款申请中，我们建议开发一种CD疫苗接种方案， 由双顺反子DNA疫苗（BCV）-佐剂与7 HP 349或另一种整联蛋白激活剂的组合组成， 7 HP 577，证明了BV-佐剂组合的临床前有效性和安全性，并生产临床 cGMP级BCV和佐剂，以支持I/IIa期临床研究，评估 疫苗-佐剂组合，然后评价其在人体中的免疫原性。拟议的研究 将允许开发一种新的疫苗接种方案来治疗Tc感染和CD。

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.