Dr. Barry's research in the Center for Vaccine Development focuses on the development of vaccines against enteric pathogens, including Shigella and enterotoxigenic E. coli (ETEC), that are responsible for significant morbidity and mortality throughout the world. Target populations include children in less developed counties who suffer the largest burden as well as travelers to endemic regions and deployed military personnel. These pathogens cause infection following ingestion and our strategy is to develop live attenuated strains that are delivered via the oral route. She has constructed live attenuated vaccine candidates of Shigella which have advanced to Phase I clinical trials where they have been demonstrated to be safe and immunogenic. The attenuated bacteria are also used as live vectors for the expression and delivery of antigens from heterologous pathogens. She has constructed a vaccine composed of attenuated Shigella expressing critical ETEC antigens. This multivalent vaccine is currently in Phase I clinical studies.
An additional area of research is the development of vaccines against Francisella tularensis, a pathogen of interest for bioterror countermeasure development. Vaccine candidates have been engineered with specific mutations and attenuation as well as immunogenicity are currently being evaluated.
Laboratory projects include the study of basic mechanisms of pathogenesis of Shigella, ETEC and Francisella, antigen identification, host responses, and model development. Techniques include molecular engineering, electron microscopy, zero gravity organoid models, and in vitro organ culture (IVOC). As illustrated in the figure below, IVOC has been used to identify ETEC fimbrial epitopes critical for binding to pediatric intestinal tissue. Panel A shows wild type ETEC binding to pediatric intestinal biopsy tissue and panel B shows lack of binding of a fimbrial mutant.
Barry, E.M., M.F. Pasetti, M.B. Sztein, K.L. Kotloff, A. Fasano, and M.M. Levine. Progress and pitfalls in Shigella vaccine research. Nature Reviews Gastroenterology & Hepatology. 2013, 10(4):245.
Faherty, C.S., J.M. Harper, T. Shea-Donahue, E. M. Barry, J.B. Kaper, A. Fasano, and J.P. Nataro. Chromosomal and plasmid-encoded factors of Shigella flexneri induce secretogenic activity ex vivo. PLoS One, 2012, 7(11):e49980. PMC3500342.
Faherty, C.S., J.C. Redman, D.A. Rasko, E.M. Barry*, and J.P. Nataro*. Shigella flexneri effectors OspE1 and OspE2 mediate induced adherence to the colonic epithelium following bile salts exposure. Molec. Microbiol., 2012, 85(1):107-121. *authors contributed equally to work. PMC3399131
Marohn, M.E., A.E. Santiago, K.A. Shirey, M. Lipsky, S.N. Vogel, and E.M. Barry. Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters are Critical for Pathogenesis. Infection & Immun., 2012, 80(7):2390-2401. PMC3416476
Wu, T., C. Grassel, M.M. Levine and E. M. Barry. Live attenuated Shigella dysenteriae 1 vaccine strains over-expressing Shiga toxin B subunit. Infection & Immun., 2011, 79(12):4912-4922. PMC3232646.
Reed, D. S., L. Smith, T. Dunsmore, A. Trichel, L.A. Ortiz, K. S. Cole, and E. M. Barry. Pneumonic tularemia in rabbits resembles the human disease as illustrated by radiographic and hematological changes after infection. PLoS One, 2011, 6(9):e24654. PMC3172242
Cole, L. E., M. H. W. Laird, A. Seekatz, A. Santiago, Z. Jiang, E. M. Barry, K. A. Shirey, K. A. Fitzgerald, and S. N. Vogel. Phagosomal retention of Francisella tularensis results in TIRAP/Mal-independent TLR2 signaling. J. Leukocyte Biology. 2009, 87:275-81. PMC2812562
Gaston, J.S., Inman, R.D., Ryan, E.T., Venkatesan, M.M., Barry, E.M., Hale, T.L., Bourgeois, A.L., and Walker, R.I. Vaccination of children in low-resource countries against Shigella is unlikely to present an undue risk of reactive arthritis. Vaccine, 2009, 27:5432-5434.
Baker, K., M.M. Levine, J. Morison, A. Phillips, and E.M. Barry. CfaE tip mutations in ETEC CFA/I fimbriae define critical human intestinal binding sites. Cellular Microbiology, 2009,11:742-754. PMC2921025
Cole, L.E., A. Santiago, E. Barry, T. J. Kang, K. A. Shirey, Z. J. Roberts, K. L. Elkins, A. S. Cross, and S. N. Vogel. The macrophage proinflammatory response to Francisella tularensis LVS requires coordination of multiple signaling pathways. J. Immunol., 2008, 180:6885-6891. PMC2637793
Kotloff, KL., J.K. Simon, M.F. Pasetti, M.B. Sztein, S. Wooden, S. Livio, W.C. Blackwelder, E.M. Barry, J.P. Nataro, W.D. Picking, and M.M. Levine. Safety and immunogenicity of CVD 1208S, a live, oral Shigella flexneri 2a vaccine grown on animal free media. Human Vaccines, 2007, 3:268-275.
Levine, M.M., K.L. Kotloff, E. M. Barry, M.F. Pasetti, and M.B. Sztein. Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard, road. Nature Reviews Microbiogy, 2007, 5(7):540-553.
Links of Interest:Center for Vaccine Development
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