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Title: Subdominant antigens in bacterial vaccines: Am779 is subdominant in the anaplasma marginale outer membrane vaccine but does not associate with protective immunity

item ALBARRAK, SALEH - Washington State University
item BROWN, WENDY - Washington State University
item Noh, Susan
item REIF, KATHRYN - Washington State University
item Scoles, Glen
item TURSE, JOSHUA - Washington State University
item NORIMINE, JUNZO - Washington State University
item Ueti, Massaro
item PALMER, GUY - Washington State University

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/29/2012
Publication Date: 9/28/2012
Citation: Albarrak, S.M., Brown, W.C., Noh, S.M., Reif, K.E., Scoles, G.A., Turse, J.E., Norimine, J., Ueti, M.W., Palmer, G.H. 2012. Subdominant antigens in bacterial vaccines: Am779 is subdominant in the anaplasma marginale outer membrane vaccine but does not associate with protective immunity. PloSONE 7(9):e46372.

Interpretive Summary: Components of the outer membrane of Anaplasma marginale induce protection against challenge. However, these known protective immunogens are expensive and difficult to make in large quantities. Consequently, the current focus of vaccine development is in the identification of specific outer membrane proteins that are both conserved and induce protective immunity and could be produced efficiently in large quantities. AM779 is a highly conserved outer membrane protein that is present in the known protective immunogens. However, the immune response directed toward AM779 in animals immunized with these protective immunogens is poor. In this study, it was determined that the weak immune response could be partially overcome (T cell response, but not the antibody response) by immunization with only AM779. Despite this boost in the specific AM779 T cell response, immunization with this protein failed to induce protection against challenge.

Technical Abstract: Identification of specific antigens responsible for the ability of complex immunogens to induce protection is a major goal in development of bacterial vaccines. Much of the investigation has focused on highly abundant and highly immunodominant outer membrane proteins. Recently however, genomic and proteomic approaches have facilitated identification of minor components of the bacterial outer membrane that have previously been missed or ignored in immunological analyses. Immunization with Anaplasma marginale outer membranes or a cross-linked surface complex induces protection against bacteremia upon challenge; however the components responsible for protection within these complex immunogens are unknown. Using outer membrane protein AM779 as a model, we demonstrated that this highly conserved but minor component of the A. marginale surface was immunologically sub-dominant in the context of the outer membrane or surface complex vaccines. Immunologic sub-dominance could be overcome by targeted vaccination with AM779 for T lymphocyte responses but not for antibody responses, suggesting that both abundance and intrinsic immunogenicity determine relative dominance. Importantly, immunization with AM779 supports that once priming is achieved by specific targeting, recall upon infectious challenge is achieved. While immunization with AM779 alone was not sufficient to induce protection, the ability of targeted immunization to prime the immune response to highly conserved but low abundance proteins supports continued investigation into the role of sub-dominant antigens, individually and collectively, in vaccine development for A. marginale and related bacterial pathogens.