Influenza places a significant health and economic burden on society. Efficacy of seasonal influenza vaccines can be suboptimal due to poor matching between vaccine and circulating viral strains. An influenza vaccine that is broadly protective against multiple virus strains would significantly improve vaccine efficacy. The highly conserved ectodomain of matrix protein 2 (M2e) and 3'3' cyclic GMP-AMP (cGAMP) were selected as the antigen and adjuvant, respectively, to develop the basis for a potential universal influenza vaccine. The magnitude and kinetics of adaptive immune responses can have great impact on vaccine efficacy. M2e and cGAMP were therefore formulated within acetalated dextran (Ace-DEX) microparticles (MPs) of varying degradation profiles to examine the effect of differential vaccine delivery on humoral, cellular, and protective immunity. All Ace-DEX MP vaccines containing M2e and cGAMP elicited potent humoral and cellular responses in vivo and offered substantial protection against a lethal influenza challenge, suggesting significant vaccine efficacy. Serum antibodies from Ace-DEX MP vaccinated mice also demonstrated cross reactivity against M2e sequences of various viral strains, which indicates the potential for broadly protective immunity. Of all the formulations tested, the slowest-degrading M2e or cGAMP MPs elicited the greatest antibody production, cellular response, and protection against a viral challenge. This indicated the importance of flexible control over antigen and adjuvant delivery. Overall, robust immune responses, cross reactivity against multiple viral strains, and tunable delivery profiles make the Ace-DEX MP platform a powerful subunit vaccine delivery system.,Copyright © 2018 Elsevier B.V. All rights reserved.