7HP349, an oral integrin activator to augment effectiveness of pre-exposure influenza vaccination

项目概要/摘要 年龄≥65岁的美国人占所有流感相关住院和死亡的57%和75%， 在2019-20赛季，尽管疫苗接种率为68%。流感疫苗的有效性较低， 老年人比年轻人更容易接种流感疫苗，需要高剂量（Fluzone® HD）或含佐剂（FluAd®）疫苗。 疫苗与循环毒株中的抗原错配导致保护不足，以及免疫应答差。 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免疫更相关。 疫苗对老年人的保护作用。用于增强疫苗效力的佐剂，如MPLA、CpG 和明矾，引发先天或抗体反应，但不是T细胞反应。虽然现有的佐剂或 增加的抗原负荷可部分改善血清转化、总体疫苗有效性和T细胞应答 在高危人群中可能是次优的。需要新的佐剂来诱导强大的T细胞应答， 病原体清除在老年人中，疫苗效果欠佳的一个关键因素是免疫衰老， 与年龄相关的免疫力逐渐下降。整合素α4β1和αLβ2介导的细胞粘附延长及其机制 同源配体，VCAM-1和ICAM-1，是有效的抗原呈递和T细胞引发所必需的。 抗原呈递细胞（APC）和幼稚T细胞之间的免疫突触，以及T细胞记忆和 效应器功能。APC-T细胞粘附缺陷减弱T细胞活化和记忆。与故障相关的缺陷 ICAM-1对活化树突状细胞的诱导作用可能会降低T细胞的启动，导致疫苗的不理想。 对老年人的有效性。7 HP 349是一种概念上的首次口服小分子变构α4β1/αLβ2激活剂， 可促进APC-T细胞粘附，提高辅助性T细胞功能及对老年流感的疗效 预防针在小鼠中，7 HP 349显著提高了流感、恰加斯病、SARS-CoV、 2和结核病疫苗，不仅通过体液应答，而且通过细胞介导的免疫， 从当前或新兴的竞争。一项首次人体I期临床研究，旨在评价 并于2021年第4季度完成了健康男性受试者中7 HP 349的PK。7 HP 349被证明是安全的， 生物利用度，无治疗相关严重不良事件。此外，最佳药代动力学剂量 被确认了在本申请中，我们建议评估7 HP 349作为流感疫苗接种的口服佐剂 在具有预先存在的免疫力的老龄小鼠中，这将是老年人接种疫苗的代表。此外，本发明还 为了激活老年流感的补充IND，我们计划完成额外要求的化学， 生产和控制活动，包括开发100 mg规格，以实现每日一次， 一粒药丸给药以提高患者依从性，并生产cGMP 7 HP 349制剂以支持 IND并为未来在老年受试者中进行的I/IIa期临床研究建立库存，以评估7 HP 349的安全性 并评估其与Fluzone® HD联合使用的免疫原性，这也将为其在临床上的应用奠定基础。 在增强其他传染病疫苗在脆弱亚群中的有效性方面的潜在用途。

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.