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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Disease-causing Gut Bacteria: Improving Vaccine Safety and Efficacy of Combination Vaccines to Protect Against Diarrheal Diseases and Select Agents

Principal Investigator: Dennis J. Kopecko, PhD
Office / Division / Lab: OVRR / DBPAP / LESTD

General Overview

Intestinal bacteria cause about 5 million cases of diarrhea each year in the United States and annually kill more than 2 million children worldwide. The development of vaccines to protect against these diseases is impeded by the lack of detailed understanding of how specific bacteria interact with the human body during infections and how the immune system responds to these infections.

Therefore, we are analyzing the bacterial genes responsible for the changes in human cells and organs that are part of the development of disease. We are also developing animal models of disease and studying the animal and human immune responses that protect against illness. This information helps us to evaluate new vaccine products to determine their safety and ability to trigger protective immune responses and to analyze data on vaccine manufacture and the stability of manufactured products.

Scientific Overview

Enteric bacterial diseases cause approximately 5 million episodes of diarrhea per year in the U.S. and kill more than 2 million children worldwide annually. Additionally, the threat of the use of highly infectious microbial pathogens as offensive bioterrorist (BT) weapons poses an international threat.

A lack of understanding of specific host-bacterial interactions and immune responses has limited the development of enteric vaccines. However, the safety of certain mutant attenuated strains has led to proposals to use them as carriers of foreign antigens in multivalent vaccines against diarrheal or other diseases. Therefore, we are evaluating a large number of attenuated enteric bacterial mutants for use as live oral vaccines for protection against various diarrheal diseases (e.g. cholera, typhoid fever, shigellosis, and ETEC disease) and bioterrorist threats ( e.g., anthrax). Improved understanding of host-pathogen interactions continues to help us to develop and assess increased safety of attenuated mutants. In addition, new combination live, oral vaccines are being studied to optimize animal models to assess immunogenicity, strain stability, and establish potential correlates of protection.

Our laboratory conducts studies into host-enteric bacterial pathogen interactions to define new components that affect vaccine safety and evaluate procedures to assess the safety of new candidate vaccines. In addition, animal model development and immunological studies are employed to assess the immunogenicity, effectiveness, stability/safety, and potential immune correlates of protection for live, oral attenuated single purpose or multivalent vaccines. We have also participated in collaborative projects aimed at increasing the stability of dried, live vaccines (i.e. to remove the requirement for storage in refrigerator and to extend useful shelf life).

This research will enhance our regulatory abilities by providing tools (e.g. defined antigens, new immunological or other assays and modified animal models) for evaluating the safety and effectiveness of new, live, combination oral enteric bacterial carrier vaccines. Identification of host-pathogen interactions may also lead to new diagnostic tools for enhanced detection of these disease agents that will be useful in evaluating vaccines.


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Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma.
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Room temperature stabilization of oral, live attenuated Salmonella enterica serovar Typhi-vectored vaccines.
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Enhanced tumor suppression in vitro and in vivo by co-expression of survivin-specific siRNA and wild-type p53 protein.
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Genetic stability of vaccine strain Salmonella Typhi Ty21a over 25 years.
Kopecko DJ, Sieber H, Ures JA, Fürer A, Schlup J, Knof U, Collioud A, Xu D, Colburn K, Dietrich G

Infect Immun 2009 Apr;77(4):1475-82
Anthrax protective antigen delivered by Salmonella enterica serovar Typhi Ty21a protects mice from a lethal anthrax spore challenge.
Osorio M, Wu Y, Singh S, Merkel TJ, Bhattacharyya S, Blake MS, Kopecko DJ

Methods Mol Biol 2009;487:161-87
Bacterial delivery of siRNAs: a new approach to solid tumor therapy.
Xu DQ, Zhang L, Kopecko DJ, Gao L, Shao Y, Guo B, Zhao L

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Enhanced Microscopic Definition of Campylobacter jejuni 81-176 Adherence to, Invasion into, Translocation across, and Exocytosis from Polarized Human Intestinal Caco-2 Cells.
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Curr Issues Mol Biol 2008;10(1-2):13-6
Considerations in the development of live biotherapeutic products for clinical use.
Ross JJ, Boucher PE, Bhattacharyya SP, Kopecko DJ, Sutkowski EM, Rohan PJ, Chandler DKF, Vaillancourt J

Clin Cancer Res 2008 Jan 15;14(2):559-68
Effects of Plasmid-Based Stat3-Specific Short Hairpin RNA and GRIM-19 on PC-3M Tumor Cell Growth.
Zhang L, Gao L, Li Y, Lin G, Shao Y, Ji K, Yu H, Hu J, Kalvakolanu DV, Kopecko DJ, Zhao X, Xu DQ

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Core-linked LPS expression of Shigella dysenteriae serotype 1 O-antigen in live Salmonella Typhi vaccine vector Ty21a: Preclinical evidence of immunogenicity and protection.
Xu de Q, Cisar JO, Osorio M, Wai TT, Kopecko DJ

Cancer Res 2007 Jun 15;67(12):5859-64
Intratumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs.
Zhang L, Gao L, Zhao L, Guo B, Ji K, Tian Y, Wang J, Yu H, Hu J, Kalvakolanu DV, Kopecko DJ, Zhao X, Xu DQ

Infect Immun 2006 May;74(5):2697-705
Campylobacter jejuni Induces Maturation and Cytokine Production in Human Dendritic Cells.
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Microb Pathog 2006 Mar;40(3):91-100
Signal transduction events involved in human epithelial cell invasion by Campylobacter jejuni 81-176.
Hu L, McDaniel JP, Kopecko DJ

Microbiology 2005 Sep;151(Pt 9):3097-105
Ca2+ release from host intracellular stores and related signal transduction during Campylobacter jejuni 81-176 internalization into human intestinal cells.
Hu L, Raybourne RB, Kopecko DJ

Clin Cancer Res 2005 Sep 1;11(17):6333-41
Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo.
Gao L, Zhang L, Hu J, Li F, Shao Y, Zhao D, Kalvakolanu DV, Kopecko DJ, Zhao X, Xu DQ

Infect Immun 2004 Nov;72(11):6382-9
Cytokine response to infection with Bacillus anthracis spores.
Pickering AK, Osorio M, Lee GM, Grippe VK, Bray M, Merkel TJ



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