Vaccination may be the greatest public health achievement of our time. With an explosion of antibiotic resistance, developing vaccines against multi-drug resistant (MDR) bacterial pathogens is more important than ever, but most current vaccine strategies fail to target conserved structures that would allow them to protect across serotype, strain and species boundaries. We have developed a protective antigen strategy that targets the type III secretion system (T3SS) of important Gram-negative bacteria and which should be efficacious regardless of serotype, thereby working across genus (e.g. Shigella) or species (e.g. Salmonella enterica) boundaries. With this antigen strategy, we have elicited broad serotype-independent protection against infections by bacteria that are becoming increasingly antibiotic resistant. This strategy employs an adjuvant and provides 70-90% protection in mice against lethal challenge by multiple Shigella species and it protected five of six monkeys from developing severe dysentery after challenge with Shigella sonnei. This same platform has elicits serotype-independent protection against Salmonella enterica challenge (70% protection) as well as other Gram-negative bacteria. To reach complete (100%) protection, we have developed a novel adjuvant carrier platform to create next generation vaccine candidates. With the adjuvant carrier platform, the protective antigen simultaneously enters into antigen presenting cells. This protective antigen will be combined with a carrier to form a multi-protein antigen delivery vehicle to drive uptake by dendritic cells and transport to regional lymph nodes for extended antigen presentation. We hypothesize that the antigen-carrier platform will provide broad serotype-independent protection against all strains of the pathogen including MDR species/strains.
The specific aims being proposed are to: 1) Validate cross-strain protection for clinical MDR strains; 2) Optimize the three candidate vaccines using the new particle; 3) Complete the proof-of-concept efficacy studies, including immune response assessment, in appropriate animal models; 4) Assess vaccine efficacy following subclinical pre-exposure to the pathogen as often occurs; 5) Complete biophysical characterization of the top vaccine candidates for subsequent formulation. By the completion of this project, we will have demonstrated that our antigen-carrier platform will prevent infections by MDR Gram negative pathogens.

Public Health Relevance

Vaccination may be the greatest public health achievement of our time. As antibiotic resistance becomes more prevalent among pathogenic bacteria, vaccines will become even more important, however, many vaccines being developed only work against a narrow range of bacteria, even within a single genus or species, due to being ?serotype-specific.? To overcome this limitation, we have developed a new vaccine strategy that provides protection across serotype, strain and species boundaries. This nanoparticle-antigen platform will provide broad protection against pathogenic Shigella, Salmonella and Pseudomonas. Furthermore, it will provide preventative measure that overcomes the increasing development of antibiotic resistance in these important pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1)
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Mills, Melody
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University of Kansas Lawrence
Schools of Pharmacy
United States
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