Enteric Bacterial Pathogens - Improving Vaccine Safety and Efficacy of Combination Vaccines for Diarrheal Diseases and Select Agents

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

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Overview

Public Health Issue: Enteric bacterial diseases cause approximately 5 million episodes of diarrhea/yr in the U.S. and kill more than 2 million children worldwide annually. A paucity of data regarding specific human-bacterial interactions and human immune responses has limited the development of enteric vaccine products, e.g., the limited availability both of predictable models for pre-clinical testing of vaccine safety and surrogate immune markers of vaccine efficacy. However, it is encouraging that recent research has led to novel oral live attenuated vaccine candidates that have improved safety profiles, and these vaccine candidates have also been proposed for use as multivalent vaccines against diarrheal or other diseases, including vaccines for biodefense. Since these live attenuated enteric bacterial vaccines are delivered orally they have tremendous utility for rapid and widespread immunization to provoke multivalent protection against many disease agents.

Regulatory Contribution: A large number of attenuated enteric bacterial vaccines are being evaluated for use as live oral vaccines for protection against various diarrheal diseases(e.g. cholera, typhoid fever, shigellosis, and enterotoxigenic E. coli disease). Research into these vaccines permits the FDA to develop and evaluate approaches to determine the safety of these novel vaccines. In addition, this research is aimed at optimizing preclinical disease models to assess safety, toxicity, efficacy (e.g., immunogenicity and establishment of surrogate markers of protection) and manufacturing issues (e.g., product characterization such as strain stability).

Research Approach: The laboratory conducts studies into host-enteric bacterial pathogen interactions to identify important topics that affect vaccine/live biotherapeutic safety, and develop and evaluate tests to determine the safety of new candidate vaccines/live biotherapeutics. In addition, animal model development and immunological studies are underway to assess the effectiveness (e.g., immunogenicity and surrogate markers that correlate with protection), stability, and safety for live, oral attenuated single purpose or multivalent vaccines and for live biotherapeutics.

Mission Relevance & Outcomes: This research will enhance our regulatory abilities by providing tools (e.g. defined technical approaches, new immunological or other surrogate marker assays and pre-clinical disease tests such as animal models, increased understanding of pathogenesis) for use in evaluation of the safety, toxicity and effectiveness of new single and combination live, oral enteric bacterial vaccines and live biotherapeutics.

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Publications

Infect Immun 2008 Nov;76(11):5294-304
Enhanced Microscopic Definition of Campylobacter jejuni 81-176 Adherence to, Invasion into, Translocation across, and Exocytosis from Polarized Human Intestinal Caco-2 Cells.
Hu L, Tall BD, Curtis SK, Kopecko DJ

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

Vaccine 2007 Aug 14;25(33):6167-75
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.
Hu L, Bray MD, Osorio M, Kopecko DJ

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