Abstract
Abstract MF59 (AddaVax-like) is a clinically approved nanoemulsion adjuvant with an unclear mechanism of action. Here we introduce a novel approach to investigating the role of muscle regeneration in adjuvanted vaccine response. We found that AddaVax adjuvanted quadrivalent inactivated flu vaccine (QIV) induced a Th2 immune response with IL-4, -5, and -13 expression in the lungs 5 days after H1N1 lethal challenge. In contrast, IMDQ-PC (TLR7/8 agonist) induced a Th1 lung response and higher IgG2a titers. In BMDM cultures, we found AddaVax unlike IMDQ-PC to require IFNγ co-incubation for the induction of iNOS+ proinflammatory M1 phenotype. Since IFNγ is crucial for muscle regeneration, we hypothesized that AddaVax triggers macrophage-dependent muscle regeneration which leads to an enhanced Th2 vaccine response. We found that AddaVax adjuvanted QIV led to an increase of Arg-I+ M2 macrophages in the muscle 4 days post-injection, similar to late-stage Th2 response in regeneration. Using IgG titers, Our hypothesis was further supported by finding AddaVax response to be diminished in aged mice where regeneration is impaired, but rescuable by depletion of circulating monocytes and reconstitution with young BMDMs. Using in-depth characterization and selective depletion, we will investigate the crosstalk between muscle regeneration and AddaVax response allowing a better understanding of the potential muscle role in inhibiting the Th1 response necessary in viral infections, and cancer vaccines.
Published Version
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