SEP 13, 2018 12:00 PM PDT

Outer Membrane Remodeling of Attenuated Salmonella to Create a Mucosal Vaccine Against Acinetobacter Baumannii

Speaker
  • Professor, Center for Vaccine Development, University of Maryland Baltimore
    Biography
      For over 15 years, Dr. Galen has focused on the construction of attenuated bacterial vaccines and their use as live vectors to deliver foreign antigens to the immune system. His work has had broad applications to the development and pre-clinical testing of a variety of live vaccines against both eukaryotic and prokaryotic pathogens, including the etiological agents for malaria, SARS, plague, anthrax, tetanus, enteric fever, and most recently infections caused by Clostridium difficile.

      Dr. Galen has been involved in instrumental research on the development of plasmid-based expression systems for delivery of foreign antigens from both prokaryotic and eukaryotic organisms.

      He has invented two novel systems:

      - Antigen transport system for export of antigens out to the surface of attenuated S. Typhi.
      - Plasmid stabilization and selection system that removes the need for plasmid selection using antibiotics and guarantees plasmid retention in vivo after introduction into live vector strains.
      Dr. Galen's work has resulted in multiple patents issued in both the United States and abroad.

      Recent efforts have focused on the design and development of novel vaccines and therapeutic treatments against enteric disease caused by Clostridium difficile. On the vaccine side, Dr. Galen has worked on the development of a live oral vaccine designed to elicit toxin neutralizing antibodies against the three known toxins of C. difficile: Toxin A (TcdA), toxin B (TcdB), and binary toxin (CDT). On the therapeutic treatment side, he is collaborating on a unique project to engineer a probiotic strain of yeast called Saccharomyces boulardii to efficiently and stably deliver in situ therapeutically relevant levels of a novel tetravalent neutralizing antibody against CDI enterotoxins TcdA and TcdB, to interrupt recurrent disease.

    Abstract

    While rapid identification of pathogens, novel therapeutic interventions, and passive immunization have critical roles in disease control, none can substitute for pre-existing protective immunity. Mucosally delivered bacterial live vector vaccines represent a practical and effective strategy for immunization.  In live vector vaccines, genes that encode protective antigens of unrelated pathogens are expressed in an attenuated vaccine strain and delivered mucosally to generate relevant local and systemic immune responses. We hypothesize that by appropriate manipulation of novel Salmonella enterica serovar Typhi live vector platform technologies, we can construct a mucosally administered bivalent vaccine against potentially lethal infections caused by Acinetobacter baumannii.  Our unique research strategy is designed to remodel the outer membrane of an attenuated S. Typhi-based live vector vaccine into an antigen presentation platform in which protective outer membrane antigens from A. baumannii are mucosally delivered to immune inductive sites via a novel inducible outer membrane vesicle delivery system. Mucosal delivery of recombinant outer membrane vesicles (rOMVs) via live vector vaccines offers significant advantages over conventional acellular OMV-based vaccination strategies including: 1] sustained in vivo delivery to mucosal inductive sites, and 2] delivery of rOMVs enriched in properly folded protective antigens. To enhance delivery of these protective antigens to immune effector cells, thereby improving the protective efficacy of this mucosal vaccine, we enhance delivery of rOMVs through inducible over-expression of the hypervesiculating protein PagL. If successful, our novel and highly innovative approach could result in a mucosal live carrier vaccine, effective against potentially lethal systemic and pulmonary infections with A. baumannii, which could prove highly valuable in both civilian and military settings.

    Learning Objectives: 

    1. What is a carrier vaccine?    
    2. How can carrier vaccines be used to combat the antibiotic resistance crisis in public health?


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