Priming mucosal pathogen-agnostic innate immunity with an intranasal TLR2/6 agonist in an aged population.

Background: Immunosenescence increases the susceptibility to viral respiratory infections, but its effects on nasopharyngeal innate immunity, a critical determinant of response to viral infection, are not well understood. INNA-051 is a Toll-like receptor (TLR)2/6 agonist that activates innate immune pathways associated with antiviral host defence in younger individuals (aged 19-53 years), and in pre-clinical models protects against diverse viruses. Here we assessed INNA-051 in older adults, measuring host defence indicators, and tested its ability to protect aged mice from influenza. Methods: Clinical safety, tolerability and elicitation of host defence biomarkers by 300 μg of intranasal INNA-051 were assessed in a cohort of 12 healthy older volunteers (aged 66-80 years) included in a recently reported randomised placebo-controlled, dose escalation phase 1 study. Aged mice (64 weeks) received repeated intranasal doses of INNA-051 on days -4 and -1 prior to infection with influenza (H3N2 Udorn, 500 PFU) and response was assessed on day 4 post-infection. Results: In humans INNA-051 was well tolerated and significantly increased innate immunity host defence pathways within 8 h after each dose. In aged mice, nose-only dosing of INNA-051 stimulated innate nasopharyngeal innate immunity, primed adaptive immunity and effectively reduced lung influenza viral load. Conclusions: INNA-051 induced innate immune priming in older individuals and attenuated influenza infection in aged mice. TLR2/6 agonist-mediated responses remain functional in older individuals and this study supports further clinical investigation in aged populations known to be susceptible to viral respiratory infections.