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