Urinary tract infections (UTIs) caused by extraintestinal pathogenic E. coli (ExPEC) account for nearly 1.3 million emergency room visits and 245,000 hospitalizations per year for women in the U.S. alone. Approximately half of all women will experience a symptomatic UTI in their lifetime, and 25% will experience a recurrence within 6 to 12 months. While several attempts have been made to design a vaccine to address this important medical need, no vaccines are currently available. The goal of this proposal is to develop a broad- spectrum, multivalent subunit vaccine based on bacterial iron receptor proteins (IRPs). Iron is an essential nutrient for bacteria, and IRPs make excellent vaccine targets because they are highly conserved and are induced during infection in response to the low availability of iron in the host. Our innovative vaccine production strategy for bacteri mimics iron restriction through use of an iron chelator to enrich the content of these proteins on the surface of the cell, whereupon they can be purified through a proprietary platform process to create a subunit vaccine. Protective immunity to a pathogen such as ExPEC likely requires an optimal immune response at mucosal surfaces. Bacterial IRPs are attractive targets but present a significant challenge for vaccine development due to their insolubility and the low efficiency with which these antigens can be delivered across the mucosal epithelium to the underlying lymphoid tissue. The current proposal will address these issues by combining a novel IRP antigen composition with several innovative CpG delivery systems in order to maximize mucosal immune responses to ExPEC and provide protection against UTI. In Aim 1, IRPs will be purified from a selected, broadly-expressing ExPEC strain and incorporated into nanolipoprotein particles or derivatives of chitosan nanoparticles. Mice will be immunized with these nanoparticle formulations to screen for production of antigen-specific secretory IgA, thereby determining which types of nanoparticles stimulate a robust mucosal immune response to IRPs. Aim 2 will proceed to evaluate the protective efficacy of promising vaccine candidates in a clinically relevant mouse model of UTI. Successful completion of the work outlined in this proposal will provide proof of concept for a novel UTI vaccine based on iron receptors packaged in a nanoparticle delivery vehicle, advance our understanding of mucosal immunity, and provide an evidence- based rationale for the development of outer membrane protein subunit vaccines against bacterial pathogens that invade through a mucosal port of entry.
Public Health Relevance Statement: Public Health Relevance: Urinary tract infections are the most common bacterial infection in the United States, disproportionately affecting women and exerting a negative impact on health care costs that is estimated at $2.4 billion annually. Although E. coli is known to be the primary cause of disease, no vaccine is currently available. The project described in this proposal will develop an E. coli vaccine that combines two innovative technologies: isolation of a unique class of bacterial iron receptor proteins and a nanoparticle delivery system designed to produce a protective immune response in the urinary tract.
NIH Spending Category: Biodefense; Bioengineering; Biotechnology; Emerging Infectious Diseases; Immunization; Infectious Diseases; Nanotechnology; Prevention; Urologic Diseases; Vaccine Related
Project Terms: Accounting; Address; Adjuvant; Affect; Animal Testing; Animals; Antibiotics; Antigen-Presenting Cells; Antigens; Bacteria; Bacterial Infections; base; Biochemical; Bladder; Cell surface; Chelating Agents; Chitosan; Clinical; clinically relevant; cost; Data; design; Development; Disease; Drug Formulations; economic impact; Emergency department visit; Engineering; Ensure; Environment; Epithelium; Escherichia coli; Escherichia coli Vaccines; evidence base; experience; Feces; Female; Future; Goals; Growth; Health; Health Care Costs; Hospitalization; Human; Immune response; Immunity; Immunization; immunogenic; Immunoglobulin A; Immunoglobulin G; improved; Industry; Infection; Infectious Disease Immunology; innovation; innovative technologies; Invaded; Iron; Kidney; Licensing; Lipid Bilayers; Lipoproteins; Lymphoid Tissue; manufacturing process; manufacturing scale-up; Measures; Mediating; Medical; Membrane; Membrane Proteins; Microbiology; Monitor; Morbidity - disease rate; mouse model; Mucosal Immune Responses; Mucosal Immunity; Multi-Drug Resistance; Mus; Mutation; nano; nanoparticle; Nanotechnology; novel; novel vaccines; Nutrient; Organ; particle; pathogen; Pathogenesis; pathogenic Escherichia coli; Patients; Phase; phase 1 study; Population; prevent; Probability; Process; Production; protective efficacy; protein expression; Protein Subunits; Proteins; receptor; Recurrence; Research; Resistance; resistant strain; response; Scientific Advances and Accomplishments; Secretory Immunoglobulin A; Serum; standard of care; Subunit Vaccines; success; Surface; System; Technology; Tissues; United States; Urinary tract; Urinary tract infection; Urine; Vaccine Antigen; vaccine candidate; vaccine delivery; Vaccine Design; vaccine development; vaccine efficacy; Vaccine Production; Vaccines; vaccinology; Variant; Visit; Woman; Work
