The purpose of this application is the development of a broad-spectrum pediatric vaccine against Category B Biodefense food and water borne pathogens: Shigella, Salmonella and Yersinia enterocolitica. Newborns, infants and young children are among the most vulnerable groups of the population who may not tolerate, neither respond adequately to vaccines that work in human adults. We will explore a novel platform technology consisting of nonliving, non-genetically modified, Lactococcus lactis particles, designated Gram-positive Enhancer Matrix (GEM) that will be engineered to display Type III secretion antigens from each of these pathogens on the particle surface. These antigen-displaying particles will be combined to produce a broad spectrum vaccine. The L. lactis GEM particles (probiotic derivatives) have an outstanding safety profile, can be administered mucosally, have strong adjuvant properties (the peptidoglycan envelope stimulates innate immunity), are highly stable (eliminating the need for cold chain), easy to manufacture and inexpensive. Preliminary studies evaluating GEM particles displaying Yersinia pestis LcrV showed that they are highly immunogenic and confer full protection against lethal bacterial infection in mice immunized as newborns. The antigen-carrying particles induced robust mucosal as well as systemic Th1 type immunity. A pediatric GEM-based vaccine that can protect against food and water borne diseases would be an important public health tool for purposes of biodefense but also to prevent enteric infection in school and day care settings, as well as for travelers. The work will be conducted in 4 Aims.
In Aim 1 we will construct the L. lactis GEM particles displaying Shigella IpaD and IpaB, Salmonella SipB and SipD and Yersinia LcrV and YopB protective antigens. Each particle will display two antigens from each of the target pathogens and the particles can be used alone or combined (in a multivalent format) as needed.
In Aim 2 we will perform studies in different animal models to demonstrate immunogenicity of the vaccine candidates.
In Aim 3 we will examine their protective efficacy using optimized immunization schedules and different challenge models.
In Aim 4 we will characterize the final product in terms of stability and overall safety to satisfy requirements for an Investigational New Drug (IND) application. At this stage we will start developing a clinical development plan and will seek funding sources to test these vaccines in humans. The work proposed is highly significant, as it addresses the need for a safe and effective pediatric vaccine for devastating food and water borne diseases for which no vaccines are available. We are the only group investigating the use of L. lactis GEM particles as pediatric enteric vaccines. If successful, this work will unravel a new vaccine paradigm to prevent infectious diseases in infants. The purpose of this project is to develop a novel non-living, non-genetically modified L. lactis-based multivalent vaccine to protect infants and young children against disease caused by Salmonella, Shigella and Yersinia enterocolitica (Category B pathogens). Conserved protective type III secretion proteins from these pathogens will be displayed on the particle surface. Immunogenicity and protective efficacy will be tested in mice immunized as newborns. Advantages of this vaccine technology include: an outstanding safety profile, broad protection against multiple pathogens, ease of delivery (mucosal vaccination) and simple and inexpensive production. Relevance: The purpose of this project is to develop a novel non-living, non-genetically modified L. lactis-based multivalent vaccine to protect infants and young children against disease caused by Salmonella, Shigella and Yersinia enterocolitica (Category B pathogens). Conserved protective type III secretion proteins from these pathogens will be displayed on the particle surface. Immunogenicity and protective efficacy will be tested in mice immunized as newborns. Advantages of this vaccine technology include: an outstanding safety profile, broad protection against multiple pathogens, ease of delivery (mucosal vaccination) and simple and inexpensive production.

Public Health Relevance

The purpose of this project is to develop a novel non-living, non-genetically modified L. lactis-based multivalent vaccine to protect infants and young children against disease caused by Salmonella, Shigella and Yersinia enterocolitica (Category B pathogens). Conserved protective type III secretion proteins from these pathogens will be displayed on the particle surface. Immunogenicity and protective efficacy will be tested in mice immunized as newborns. Advantages of this vaccine technology include: an outstanding safety profile, broad protection against multiple pathogens, ease of delivery (mucosal vaccination) and simple and inexpensive production.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI089519-05
Application #
8662687
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Alexander, William A
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Heine, Shannon J; Diaz-McNair, Jovita; Andar, Abhay U et al. (2014) Intradermal delivery of Shigella IpaB and IpaD type III secretion proteins: kinetics of cell recruitment and antigen uptake, mucosal and systemic immunity, and protection across serotypes. J Immunol 192:1630-40
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