Urinary tract infections (UTIs) are common in women and the standard treatment is to use antibiotics, but for many women this approach only helps temporarily. UTIs can insidiously recur over and over again to ultimately dominate these patients' lives often leading to chronic pain and bladder dysfunction.
Accordingly, researchers have been exploring vaccines as an alternative approach to halting UTIs for over 20 years, but efficacy was always lacking.
Researchers working at the Duke University Medical Center report on a breakthrough in UTI vaccine development in the March 1, 2021, issue of the Proceedings of the National Academy of Sciences. For the first time the investigators saw the complete elimination of bacteria in the bladder of infected mice, where previously they would typically observe significant residual bacteria.
Success was made possible in large part by two new developments. The researchers directly administered the vaccine into the bladder to locally stimulate the site of infection instead of the traditional vaccination by intra-muscular systemic injection.
Secondly, their previous study determined activation the Th1 lymphocytes was needed, so they included a Th1-polarizing adjuvant CpG into the vaccine formulation. Together, this approach effectively conferred strong resistance to recurring bacterial infections in mouse models of UTI.
Principal investigator, Soman Abraham, Grace Kerby Distinguished Professor of Pathology, Immunology and Molecular Genetics & Microbiology in the School of Medicine, told BioWorld Science that he was very impressed with the results.
"We have been studying vaccines and vaccine strategies against UTIs for the past 20 years and no matter what the vaccine we tried, we could never completely eliminate bacteria from the bladder. At best, we could reduce the numbers by 90%, but there was always a residual population left behind that would persist months on end in the bladder of mice, even though when we looked at the urine, it was bacteria free. There remained a population that was refractive to elimination, but with this approach, we were able to completely clear all of the bacteria which is a striking finding."
When UTIs occur, much of the bladder lining is lost and if that lining is not quickly replaced, toxic compounds in urine can cause significant damage to the underlying tissue. In the absence of this bladder lining when urine contacts the underlying bladder tissue, patients feel acute pain, which is usually the point when they seek medical attention.
One year ago, Abraham's laboratory discovered that during UTIs, the bladder repairs damaged tissue primarily by recruiting Th2 lymphocytes that are specialized in tissue repair. But the recruitment of Th2 cells was done at the expense of the Th1 immune cells that normally serve to clear bacteria.
With this recognition, they designed their vaccine to specifically stimulate recruitment of Th1 cells by using CpG as an adjuvant. This is a well established and safe approach to boosting Th1 cells at sites of vaccination that proved to be very successful in the new study.
Administration of this vaccine was done via the urethra employing a catheter. The researchers showed that when the vaccine was administered into the bladder, it could recruit Th1 lymphocytes to come in and clear residual bacteria. Most significantly, this vaccine strategy also prevented any future bacterial infections. The investigators found that the direct administration of the vaccine formulation to the site of infection was efficacious, while the same vaccine administered via the intramuscular site was not as effective.
Abraham explained that by applying the vaccine directly to the bladder they could re-train the immune system of the bladder to evoke a more balanced immune response to future infection so that they are not only able to repair the damaged tissue but also clear all infecting bacteria.
Abraham has been studying urinary tract infections for about 40 years, looking at different aspects of this very common infection. In addition to studying the immune responses evoked by the bladder to infection, his team is trying to define how recurrent UTIs lead to loss of bladder function and chronic bladder pain to determine better rationale-based ways to treat urinary tract infections. Currently, most physicians treat UTI patients with antibiotics for prolonged periods, but this approach has the potential to exert negative effects on the microbiome in the gut and other body sites. Applying an effective vaccine could avoid antibiotic use altogether as suggested in this report.
Next the investigators plan to perform phase I trials with the help of clinicians to evaluate potential safety issues and one day hopefully provide therapeutic efficacy in patients with recurring UTIs.