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
• 负责人: Siddhartha De
• 金额: $ 99.93万
• 依托单位: 7 HILLS PHARMA, LLC
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10544403
• 关键词: Acute; Adjuvant; Adult; Adverse reactions; Alleles; Animal Model; Antibody Response; Antigen Presentation; Antigen-Presenting Cells; Antigens; Applications Grants; Biodistribution; Bioinformatics; Biological; Biological Assay; Biological Availability; Biological Testing; Blood specimen; Canis familiaris; Cell Adhesion; Cell Adhesion Molecules; Cessation of life; Chagas Disease; Chronic; Clinical; Clinical Research; Clinical Trials; Codon Nucleotides; Collaborations; Country; Cytotoxic T-Lymphocytes; DNA; DNA Vaccines; Development; Dose; Drug Kinetics; Economic Burden; Effectiveness; Epitopes; Female; Formulation; Future; Health Care Costs; Heart failure; Human; Hypersensitivity; Immune; Immune response; Immunity; Immunization; Immunoglobulin G; Immunotherapy; In Vitro; Infection; Innate Immune Response; Integrins; Intercellular adhesion molecule 1; Interruption; Intramuscular Injections; Investigation; Investments; Latin America; Lead; Ligands; Lipids; Mediating; Memory; Modeling; Monitor; Mus; Mycobacterium tuberculosis; Oral; Parasites; Pathogenesis; Pathogenicity; Phase; Phenotype; Plasma; Play; Preparation; Production; Productivity; Regimen; Research; Risk; Role; Safety; Small Business Innovation Research Grant; Study Subject; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Travel; Treatment Efficacy; Trypanosoma cruzi; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccine Production; Vaccines; Vascular Cell Adhesion Molecule-1; Work; adaptive immunity; aluminum sulfate; base; capsule; cell motility; chagasic cardiomyopathy; commercialization; cytokine; design; efficacy evaluation; efficacy study; expression vector; global health; immunogenicity; improved; male; migration; mouse model; novel; pathogen; pre-clinical; preclinical efficacy; preclinical safety; preclinical study; premature; product development; prophylactic; prototype; receptor; response; small molecule; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine safety; vector

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.

项目摘要/摘要 克鲁齐锥虫（TC）是Chagas病（CD）的病因。 > 700万案件，〜81 拉丁美洲有TC暴露的百万风险，以及从内在到其他国家的大规模迁移 包括美国自发传播TC的美国，CD仍然是全球健康问题。 目前尚无预防治疗前往内在国家或可能的人的治疗的疗法 已经被TC感染了。 Chagas心肌病和心力衰竭的经济燃烧，估计 〜100亿美元由于医疗保健费用和过早死亡而失去生产率，为 投资针对CD的免疫疗法的开发。我们已经开发了两个组件 DNA疫苗（TCG2/TCG4）用于CD，并在控制中证明了该原型疫苗的临床前效率 小鼠模型中的TC发病机理。疫苗效率在很大程度上取决于稳健TH1响应的诱导 为了清除TC等细胞内病原体。整联蛋白细胞粘附分子α4β1和αLβ2及其 配体VCAM-1和ICAM-1分别在适应性免疫史的激活中起着至关重要的作用。 T细胞与抗原呈递细胞（APC）之间的长时间整联蛋白介导的相互作用，特别是通过 αLβ2/ICAM-1轴是有效的T细胞启动和长期T细胞介导的记忆所必需的。 增强细胞粘合剂可能会促进T细胞启动和随后的免疫复杂。 7HP349是临床 - 阶段，概念，口服，小分子，阳性变构激活剂的α4β1和αLβ2整合素，可以 促进内源性整联蛋白配体 - 受体接合，促进细胞粘合剂并改善T辅助功能 以及CD疫苗接种的有效性。我们已经证明7HP349增强了 CD小鼠模型中的原型TCG2/TCG4 DNA疫苗。此外，7HP349具有有利的临床前 安全性和药代动力学特征，发现在1期临床研究中是安全且耐受性的 健康的男性受试者。在此SBIR赠款应用程序中，我们建议开发CD的疫苗接种方案 由双科斯通DNA疫苗（BCV） - 辅助组合组成，与7HP349或其他整合素激活剂， 7HP577，展示了BCV-Adjuvant组合和制造临床的临床前效率和安全性 CGMP BCV级并进行调整以支持I/IIA期临床研究，以评估 疫苗 - 辅助组合，此后评估其在人类中的免疫原性。提出的研究 将允许开发一种新型的疫苗接种方案，以预防治疗TC感染和CD。