The overall goal of this proposal is to construct a vaccine that is broadly protective against multiple enteropathogens of public health importance to the U.S. population. These enteropathogens include Shigella (including S. dysenteriae 1, a bioterror threat agent), enterotoxigenic E. coli (ETEC) (the major cause of traveler's diarrhea) and the emerging pathogens shiga toxin producing E. coli (STEC) (main cause of hemolytic uremic syndrome, HUS) and enteroaggregative E. coli (EAEC) (recently recognized as an important agent of pediatric diarrheal disease in the U.S.A). These enteropathogens are all Category B risk agents of biodefense concern. A vaccine with broad coverage against this group would be beneficial to multiple segments of the US population, including: 1) adult and child travelers who visit less developed countries where these infections are hyperendemic;2) children in certain areas high risk areas of the US;3) and for mass immunization in the face of deliberate bioterror spread most of these pathogens. Immunization by the mucosal route is an effective method for induction of mucosal and systemic immune responses, believed to be important in protection against these enteropathogens. Studies during the first MARGE funding cycle revealed the ability of our live attenuated S. dysenteriae 1 vaccine strain expressing Stx1 B to induce high titer Stx1 neutralizing antibodies in an animal model, in addition to S. dysenteriae 1 LPS specific antibodies that are critical for protection against S dysenteriae 1 disease. The elicitation of antitoxin that neutralizes Stx1 suggests the potential to confer protection against other Shiga toxin expressing pathogens such as STEC. In this application we propose to extend the spectrum of coverage of our multivalent live vector enteric vaccine by expressing protective antigens from STEC and EAEC. In a rational step-wise manner, Shiga toxin B subunits from Stx1 and Stx2, a chimeric toxoid Stx2A1B, and the protective AAF/II fimbrial antigen from EAEC will be engineered in attenuated derivatives of S. dysenteriae 1, and S. flexneri serotypes 3a and 6 using a novel ssb-stabilized plasmid system, Optimal live vector-antigen configurations will be evaluated for protection against STEC infection in a rabbit model or inhibition of cell binding and biofilm formation by EAEC. Combined with ongoing Shigella-ETEC vaccine constructions, a tetravalent enteropathogen vaccine will be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057168-10
Application #
8442356
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$236,466
Indirect Cost
$28,709
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Li, Huiguang; Hwang, Young; Perry, Kay et al. (2016) Structure and Metal Binding Properties of a Poxvirus Resolvase. J Biol Chem 291:11094-104
Ramachandran, Girish; Tennant, Sharon M; Boyd, Mary A et al. (2016) Functional Activity of Antibodies Directed towards Flagellin Proteins of Non-Typhoidal Salmonella. PLoS One 11:e0151875
Ray, Greeshma; Schmitt, Phuong Tieu; Schmitt, Anthony P (2016) C-Terminal DxD-Containing Sequences within Paramyxovirus Nucleocapsid Proteins Determine Matrix Protein Compatibility and Can Direct Foreign Proteins into Budding Particles. J Virol 90:3650-60
Chou, Yi-ying; Cuevas, Christian; Carocci, Margot et al. (2016) Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor. J Virol 90:4494-510
Fraley, Stephanie I; Athamanolap, Pornpat; Masek, Billie J et al. (2016) Nested Machine Learning Facilitates Increased Sequence Content for Large-Scale Automated High Resolution Melt Genotyping. Sci Rep 6:19218
Levy, Revital; Rotfogel, Ziv; Hillman, Dalia et al. (2016) Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction. Proc Natl Acad Sci U S A 113:E6437-E6446
Molleston, Jerome M; Sabin, Leah R; Moy, Ryan H et al. (2016) A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev 30:1658-70
Riblett, Amber M; Blomen, Vincent A; Jae, Lucas T et al. (2016) A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection. J Virol 90:1414-23
Ramachandran, Girish; Boyd, Mary Adetinuke; MacSwords, Jennifer et al. (2016) Opsonophagocytic Assay To Evaluate Immunogenicity of Nontyphoidal Salmonella Vaccines. Clin Vaccine Immunol 23:520-3
Plaut, Roger D; Stibitz, Scott (2015) Improvements to a Markerless Allelic Exchange System for Bacillus anthracis. PLoS One 10:e0142758

Showing the most recent 10 out of 360 publications