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

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.

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.

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.

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.