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
• 负责人: Siddhartha De
• 金额: $ 92.82万
• 依托单位: 7 HILLS PHARMA, LLC
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10693536
• 关键词: 2019-nCoV; Adjuvant; Aging; Agreement; American; Animal Model; Antibody Response; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated; B-Lymphocytes; Biological Assay; Biological Availability; Cell Adhesion; Cellular Immunity; Cessation of life; Chagas Disease; Chemistry; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Control Groups; Cross Reactions; Cyclic GMP; Data; Defect; Dendritic Cells; Development; Disease; Dosage Forms; Dose; Drug Kinetics; Effectiveness; Elderly; Enzyme-Linked Immunosorbent Assay; Equipment and supply inventories; Exposure to; Flow Cytometry; Fluzone; Formulation; Foundations; Future; Guidelines; Hemagglutinin; Hospitalization; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza vaccination; Integrin alpha4beta1; Integrin-mediated Cell Adhesion Pathway; Integrins; Intercellular adhesion molecule 1; Life; Ligands; MF59; Measures; Memory; Morbidity - disease rate; Mucous Membrane; Mus; Neuraminidase; New Caledonia; Oral; Pharmaceutical Preparations; Phase; Play; Populations at Risk; Public Health; Recommendation; Risk; Role; Safety; Schedule; Seasons; Serious Adverse Event; Serum; Shapes; Speed; Surrogate Markers; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccines; Vascular Cell Adhesion Molecule-1; Viral; Viral Antigens; Virus; Work; adaptive immunity; age related; aged; aluminum sulfate; cell motility; compliance behavior; cross reactivity; enzyme linked immunospot assay; first-in-human; human old age (65+); immunogenicity; immunological synapse; immunosenescence; improved; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; male; manufacture; mortality; mouse model; pandemic disease; pathogen; pill; pre-Investigational New Drug meeting; pre-clinical; preclinical study; programs; residence; response; safety assessment; safety testing; seroconversion; small molecule; vaccine access; vaccine effectiveness; vaccine efficacy; vaccine response; vaccine trial; young adult

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.

项目摘要/摘要 ≥65岁的美国人占所有与影响力相关的住院和死亡的57％和75％ 在2019-20季节，多皮的疫苗发生率约为68％。流感疫苗有效性较低 比年轻人年龄大，需要高剂量（Fluzone®HD）或调整后的（Fluad®）疫苗。 疫苗与循环菌株中的抗原不匹配导致保护不足，并且反应不佳 老年人仍然是主要的公共卫生问题。细胞介导的免疫力可能比体液更好地相关 较早的疫苗保护免疫力。用于提高疫苗效率的调节器，例如MPLA，CPG 和明矾，触发先天或抗体反应，而不是T细胞反应。在现有的调节器或 抗原负荷增加可能会部分改善血清转化，整体疫苗有效性和T细胞反应 处于危险人群中可能是次优的。需要新的调节器，以诱导强大的T细胞反应 病原体清除。老年人中次优疫苗有效性的关键因素是免疫衰老， 逐渐与年龄相关的免疫下降。整联蛋白α4β1和αLβ2介导的延长细胞粘附及其 同源配体VCAM-1和ICAM-1对于有效的抗原表现和T细胞启动至关重要 抗原出现细胞（APC）和幼稚的T细胞之间的免疫突触，以及T细胞的记忆和 效应器功能。缺陷APC-T细胞粘合剂可减弱T细胞激活和记忆。与年龄有关的缺陷 在激活的树突状细胞上的ICAM-1诱导中，可能会降低T细胞启动，从而导致次优疫苗 古老的有效性。 7HP349是一种概念，口服，小分子，变构α4β1/αlβ2活化剂， 可以促进APC-T细胞粘附，并提高T辅助功能和老年影响的有效性 疫苗接种。在小鼠中，7HP349显着提高了影响力，chagas病，sars-cov-的有效性 2和结核病疫苗，不仅是通过体液反应，还通过细胞介导的免疫来区分的 它来自当前或新兴的竞争。第一阶段的第一阶段临床研究，以评估安全性，耐受性 健康男性受试者的7HP349的PK在4Q 2021完成。7HP349被证明是安全的和口服的 可生物利用，没有与治疗有关的严重不良事件。另外，最佳药代动力学剂量 在此应用程序中，我们建议评估7HP349作为对影响力疫苗的口服调整 在具有先前免疫力的老化小鼠中，这将代表老年人的疫苗接种。此外， 为了激活老年影响的补充IND，我们计划完成其他必需的化学， 制造和控制活动将包括开发100毫克的强度以每天启用一次， 一种药丸来提高患者依从性，并生产CGMP 7HP349药物以支持 IND并为未来的IIA阶段IIA临床研究建立库存，以评估7HP349的安全性 并评估其与Fluzone®HD结合使用的免疫原性，这也将为其奠定基础 在脆弱的亚人群中增强其他传染病疫苗的有效性的潜在用途。