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Many studies have demonstrated that encapsulation of protein antigens in polymeric microparticles (MPs) via emulsion techniques results in total IgG antibody titers comparable to alum formulations, however, the antibodies themselves are non\u2010neutralizing. To address this issue, a coaxial electrohydrodynamic spraying (electrospray) technique is used to formulate a microparticulate\u2010based subunit anthrax vaccine under conditions that minimize recombinant protective antigen (rPA) exposure to harsh solvents and high shear stress. rPA and the adjuvant resiquimod are encapsulated either in separate or the same acetalated dextran MPs. Using a murine model, the electrospray formulations lead to higher IgG2a subtype titers as well as comparable total IgG antibody titers and toxin neutralization relative to the FDA\u2010approved vaccine (BioThrax). BioThrax provides no protection against a lethal inhalational challenge of the highly virulent Ames <jats:italic>Bacillus anthracis<\/jats:italic> anthrax strain, whereas 50% of the mice vaccinated with separately encapsulated electrospray MPs survive. 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