The current anthrax vaccine imparts protective immunity by generating a humoral immune response against a single antigen, the PA exotoxin subunit. While this response neutralizes the two anthrax exotoxins and protects the recipient from toxin-related mortality, the recipient is not protected from spore germination, infection, and/or bacteremia. Moreover, protective immunity against PA must be generated via a lengthy injection schedule and maintained by a yearly booster. In an effort to improve upon the current vaccine formulation, we screened six of seven known virulence factors encoded by Bacillus anthracis epigenetic elements pXO1 and pXO2 as well as the major surface proteins EA1 and SAP. Screening was carried out in conjunction with a plasmid-based technology known for its ability to generate type 1 and type 2 T-helper responses. Long-term high level antibody titers were generated against the products of eag (EA1), sap (SAP), and the capA capsule synthesis subunit in vivo. Further analysis of PA- and EA1-vaccinated mice demonstrated antigen-specific type 1 helper responses including IFN-gamma secretion and lysis of EA1- or PA-loaded macrophages; further, an EA1 T-cell epitope was identified. The results demonstrate that anthrax antigens other than PA might be suitable for the generation of durable immune responses against anthrax.