A novel vaccination strategy to curb recUTIs

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ABSTRACT Urinary tract infections (UTIs) are the second most common bacterial infections in humankind. Women account for most infections with over 10% of infected subjects experiencing recurrent (rec)UTIs. Because of the high recurrence rates of UTIs many UTI vaccines are being tested and some are now in clinical trials. However, after almost three decades of effort, no effective UTI vaccine has yet emerged. Recently, we found that while antibodies raised against bacterial vaccine antigens are partially effective in clearing bladder bacteria, it is necessary to recruit pathogen-specific Th1 immune cells into the bladder before bacteria are eradicated. We found that we could recruit robust numbers of pathogen-clearing CD4 T cells into mouse bladders by transurethral instillation of a uropathogenic vaccine antigen (FimH) along with a Th1 polarizing adjuvant, CpG oligodeoxynucleotides. This vaccination strategy was highly protective because in addition to evoking FimH specific antibodies systemically, they were effective in recruiting pathogen eradicating Th1 cells into the bladder, potentially preventing future recurrence. Importantly, this vaccine was efficacious in naïve mice but also, in mice that have already experienced multiple UTIs, representing the population of patients most likely to receive a UTI vaccine. Before we advance to clinical studies, we seek to undertake additional mouse studies to optimize the bladder vaccine delivery and to identify appropriate surrogates of protection and vaccine efficacy obtained from sampling urine and blood that can be deployed even in a limited phase 1 clinical trial. Therefore, the following specific aims are proposed: (i), examine if bladder vaccination employing vaccine antigen containing nanoparticles is effective in evoking local protective immunity against UPEC infections in both naïve and thrice infected mice and (ii), identify surrogates and correlates of protection in mice that can potentially be used to evaluate bladder vaccination efficacy.