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.

项目概要/摘要 年龄≥65 岁的美国人分别占所有流感相关住院和死亡人数的 57% 和 75%， 2019-20 赛季，尽管流感疫苗的接种率约为 68%，但流感疫苗的有效性较低。 老年人比年轻人更需要高剂量 (Fluzone® HD) 或佐剂 (FluAd®) 疫苗。 疫苗与流行毒株的抗原不匹配会导致保护不足，并且反应不佳 老年人仍然是主要的公共卫生问题，细胞介导的免疫可能比体液的相关性更好。 用于增强疫苗功效的佐剂，如 MPLA、CpG。 和明矾，会触发先天反应或抗体反应，但不会触发 T 细胞反应。 增加抗原载量可能会部分改善血清转化、整体疫苗有效性和 T 细胞反应 在高危人群中可能效果不佳，需要新的佐剂来诱导强效 T 细胞反应。 老年人疫苗效果不佳的一个关键因素是免疫衰老。 由整合素α4β1和αLβ2及其介导的逐渐与年龄相关的免疫衰退。 同源配体 VCAM-1 和 ICAM-1 对于有效的抗原呈递和 T 细胞启动至关重要 抗原呈递细胞 (APC) 和初始 T 细胞之间的免疫突触，以及 T 细胞记忆和免疫突触 APC-T 细胞粘附缺陷会减弱 T 细胞的激活和记忆功能。 活化树突状细胞上的 ICAM-1 诱导可能会减少 T 细胞启动，导致疫苗效果不佳 7HP349 是一种首创的口服小分子变构 α4β1/αLβ2 激活剂，对老年人有效。 可促进 APC-T 细胞粘附，改善 T 辅助功能和老年流感的有效性 在小鼠中，7HP349 显着提高了流感、恰加斯病、SARS-CoV-的有效性。 2 和结核疫苗，不仅通过体液反应，还通过细胞介导的免疫，这区分 来自当前或新兴竞争的首次人体 I 期临床研究，以评估安全性、耐受性。 7HP349在健康男性受试者中的PK已于2021年第4季度完成。7HP349被证明是安全的口服药物 此外，最佳药代动力学剂量具有生物利用度，没有与治疗相关的严重不良事件。 在本申请中，我们建议评估 7HP349 作为流感疫苗口服佐剂的作用。 在具有预先存在免疫力的老年小鼠中，这将代表老年人的疫苗接种。 为了激活老年流感的补充 IND，我们计划完成额外所需的化学， 制造和控制活动将包括开发 100 毫克剂量，以便每天一次， 一粒药剂量可提高患者依从性，并生产 cGMP 7HP349 药品以支持 IND 并为未来老年受试者的 I/IIa 期临床研究建立库存，以评估 7HP349 的安全性 并与Fluzone® HD联合评估其免疫原性，这也为其后续的推广奠定了基础 潜在用途是增强其他传染病疫苗对弱势群体的有效性。