In search for antigens which may form the basis for improved subunit or live attenuated B. anthracis vaccines, extensive genomic, proteomic and serologic analyses coupled with functional screens for surface exposed and/or secreted proteins, were carried out. The screens resulted in selection of over 50 promising novel in-vivo expressed immunogens, classified as S-Layer Homology (SLH) proteins, repeat proteins, hydrolytic enzymes and ABC transporters. DNA vaccination experiments established that most of these novel antigens are indeed able to elicit a strong humoral response. Yet, unlike the major B. anthracis immunogen Protective Antigen (PA), none of the selected immunogens could provide protection against a subsequent virulent B. anthracis strain challenge. When over-expressed in an attenuated non-toxinogenic and non-encapsulated B. anthracis platform strain, at least three of the novel antigens did confer partial protection against a lethal B. anthracis challenge.