Enhancing Bladder Permeability to Enable a Single-Dose Vaccine Against Urinary Tract Infection

Abstract

Urinary tract infection (UTI) is one of the most prevalent bacterial infections worldwide, affecting approximately 150 million people each year. Remarkably, 20–30% of patients experience recurrent UTIs within 3-4 months. While antibiotics remain the primary treatment, they often fail to eliminate intracellular or antibiotic-resistant bacteria, causing recurrent UTIs.Several UTI vaccines have been developed to prevent recurrence, but most primarily elicit humoral responses, which are inefficient at clearing intracellular bacteria in the bladder. Intravesical vaccine delivery demonstrated local adaptive immune responses that target these hidden bacterial reservoirs, but requires multiple doses to overcome the tightly regulated epithelial barrier to induce an immune response in the bladder. Because the low permeability of the urothelium has been identified as a major obstacle to effective intravesical vaccination, we hypothesized that transient disruption of the superficial urothelium would enhance vaccine penetration and efficacy. Previous work from our lab demonstrated that mast cell–mediated exfoliation of the superficial bladder epithelium serves as a host defense mechanism during acute infection. Based on this observation, we tested mastoparan-7 (M7), a wasp venom–derived mast cell activator, as a tool to induce controlled exfoliation of the superficial epithelium. Notably, we observed that intravesical M7 treatment induced exfoliation of the superficial epithelium and a transient increase in bladder permeability, thereby improving penetration of vaccine antigens into the tissue. We then evaluated vaccine efficacy in a mouse model by administering M7 prior to an intravesical UTI vaccine (Vax) composed of CpG adjuvant and heat shocked uropathogenic Escherichia coli (UPEC), comparing M7+Vax, Vax only, and PBS groups. Two weeks after vaccination, M7+Vax mice exhibited significantly improved bacterial clearance following uropathogenic E.coli (UPEC) challenge compared with Vax only and PBS controls. Notably, a single M7+Vax dose conferred robust protection against UPEC challenge. We further investigated M7+Vax in a recurrent UTI model in which mice underwent three consecutive UPEC infections before vaccination. In recurrent UTI mice, M7+Vax again markedly enhanced bacterial clearance, and upon UPEC re challenge, bacterial clearance was superior in the M7+Vax group. In summary, M7 enhances the efficacy of UTI vaccines by transiently disrupting the urothelial barrier and promoting antigen delivery to the bladder mucosa. This strategy may reduce the need for multiple intravesical doses and represents a cost effective and potent approach for both prevention and treatment of recurrent UTIs.