Muscle macrophage regenerative response after squalene-adjuvanted influenza vaccination drives Th2-skewed response and is reduced with age 2354

Abstract Description We found that the AddaVax (MF59-like)-adjuvanted quadrivalent inactivated flu vaccine (aQIV) increases protection against subsequent H1N1 infections in 6-8-week-old mice and induces a Th2-skewed immune response, marked by increased Th2 cytokines in the lungs after infection. MF59’s mechanism is unclear but appears to depend on muscle injury. We observed a muscle regenerative response, including an early proinflammatory phase (eosinophils, neutrophils, CD8+ T-cells, CX3CR1+Ly6C+iNOS+ macrophages; iNOS+ muMφ) and a later prorepair phase (Tregs, ArgI+ muMφ) after AddaVax and aQIV injections. Additionally, muMφ appeared in the draining lymph nodes (dLNs) of the aQIV group on day 4, coinciding with the onset of a B-cell response. In aged mice (18-24 months), muMφ were reduced in muscle and dLNs 4 days after aQIV injection, consistent with age-related impairment in muscle regeneration. This was accompanied by a loss of Th2 skewing in the immune response, suggesting a role for regenerative macrophages in AddaVax’s mechanism. We then injected aged mice with fluorescently labeled bone marrow-derived macrophages from young mice (yBMDMs) one day before aQIV vaccination. The yBMDMs infiltrated the muscle, internalized the vaccine, and drained to the lymph nodes, rescuing the Th2 response in the lungs. Our findings highlight the role of macrophages in vaccine response and underscore the importance of studying muscle regeneration and factors affecting it like age when developing vaccines. Funding Sources NIH/NIAID R21AI176069 Topic Categories Vaccines and Immunotherapy (VAC)