A Novel Vaccine to Prevent Urinary Tract Infections

DESCRIPTION provided by applicant Urinary tract infections UTIs caused by extraintestinal pathogenic E coli ExPEC account for nearly million emergency room visits and hospitalizations per year for women in the U S alone Approximately half of all women will experience a symptomatic UTI in their lifetime and will experience a recurrence within to 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 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 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 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 $ 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