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

项目摘要/摘要 在所有与流感相关的住院和死亡病例中，65岁的美国人分别占57%和75%，≥ 分别在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感染，需要大剂量(福来登®HD)或佐剂(福来得®)疫苗。 疫苗与流行毒株的抗原不匹配导致保护不足，对 老年人仍然是主要的公共卫生问题。细胞免疫可能比体液免疫相关性更好 老年人的疫苗免疫保护。用于增强疫苗效力的佐剂，如MPLA、CpG 和明矾，会引发先天或抗体反应，但不会引发T细胞反应。而现有的佐剂或 增加抗原载量可能会部分改善血清转化率、整体疫苗效力和T细胞反应 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细胞反应 病原体清除。老年人疫苗效果不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α-4-β-1和α-L-β-2延长细胞黏附的研究 同源配体VCAM-1和ICAM-1对于有效的抗原递呈和T细胞启动是必不可少的。 抗原提呈细胞(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细胞黏附缺陷会削弱T细胞的激活和记忆。年龄相关缺陷 ICAM-1对激活的树突状细胞的诱导可能会减少T细胞的预置，导致次优疫苗 在老年人中的有效性。7HP349是一种概念第一的口服小分子变构α4β1/αLβ2激活剂， 可促进APC-T细胞黏附，改善T辅助功能和老年流感的疗效 接种疫苗。在小鼠中，7HP349显著提高了对流感、恰加斯病、SARS-CoV-2的疗效。 2和结核病疫苗，不仅通过体液反应，而且还通过细胞免疫，这区分了 它来自当前或新兴的竞争对手。一项评价其安全性、耐受性的首例人类I期临床研究 健康男性受试者7HP349的PK于2021年4月完成。7HP349被证明是安全的和口服的 生物利用度，没有与治疗相关的严重不良反应。此外，最佳药动学剂量 已被确认。在此应用中，我们建议评估7HP349作为流感疫苗口服佐剂的作用。 在具有预先存在的免疫力的老化小鼠中，这将代表老年人接种疫苗。另外， 为了激活老年流感的补充IND，我们计划完成额外的必需化学， 制造和控制活动，包括开发100毫克的强度，以实现每天一次， 一次给药改善患者依从性，并生产cGMP 7HP349药物产品以支持 为未来老年受试者的I/IIa期临床研究评估7HP349的安全性而进行IND和建立清单 并结合Fluzone®HD评价其免疫原性，这也将为其 在增强其他传染病疫苗在脆弱亚人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.