Treatment-resistant UTI vaccine moves closer to reality

Chicago-A vaccine against urinary tract infections is a step closer to reality in the United States.

That may potentially help solve more than one major public health problem: the tremendous economic burden of UTIs, the antibiotic resistance that can make UTIs dire health emergencies, and the frustrating challenge of recurrent UTIs.

The potential new vaccine is a live attenuated mutant strain of Escherichia coli, a different approach from the vaccines available in Europe that are either bacterial extracts or heat-killed bacteria. Through genetic screening, researchers at Northwestern University Feinberg School of Medicine in Chicago generated the mutant E. coli strain, NU14ΔwaaL, from the normal uropathogenic NU14 strain, David Klumpp, PhD, associate professor of urology, told Urology Times at the AUA annual meeting here. The mutant defect is in the lipopolysaccharide (LPS) component of the bacterial cell wall.

"Moreover, this protection is effective against phylogenetically diverse E. coli."

Murine experiments with this new E. coli strain used intravesical administration of saline, wild-type NU14, or NU14ΔwaaL via catheter, followed 2 weeks later with a challenge of NU14 or a panel of uropathogenic E. coli (UPEC). One day later, investigators assessed the level of bacterial colonization in the mouse bladders.

Challenges ahead

Dr. Klumpp pointed out one of the hurdles for UTI vaccines: "If it's going to be useful clinically, a vaccine candidate would have to be broadly protective against phylogenetically diverse E. coli, and NU14ΔwaaL passes that test."

To test that ability, he and his colleagues selected a number of strains from the E. coli Reference Collection panel, including bacteria with both pyelonephritis and cystitis origins from the major phylogenetic groups most commonly associated with UTI, strains in the B2 and D groups, and strains from the less-commonly associated A phylogenetic group.

Unlike those mice inoculated with saline, immunization with the mutant strain significantly reduced colonization of the mouse bladders not only with NU14, but also with CFT073, a pyelonephritis strain of B2 origin, a group A strain, two group D strains, and another B2 strain. Thus, Dr. Klumpp said, the vaccine "is protective against phylogenetically diverse E. coli."

Further, the attenuated NU14ΔwaaL strain did not persist in the bladders of mice that were immunized with it, and reduced the prevalence of wild-type UPEC reservoirs. Recent work by Scott Hultgren, PhD, suggests that such intracellular UPEC reservoirs are protective niches that may underly recurrent UTI in some patients. So any UTI vaccine candidate should also demonstrate efficacy in eradicating such reservoirs.

Session chair Robert Moldwin, MD, told Urology Times that this is the first work he's seen in many years on a new UTI vaccine.

"In an era of increasing antibiotic resistance to our conventional agents, we are in desperate need of new strategies to deal with this terribly common problem. Unfortunately, it will probably need lots of refinement before it's ready for prime time," Dr. Moldwin said.

"These data were all obtained by immunization via intravesical administration, which, arguably, is not the ideal route for vaccinating patients, so our next efforts will be focused on finding the optimal route of administration: oral, rectal, vaginal, or intramuscular," Dr. Klumpp told Urology Times. "In addition, we plan to test whether this approach can be generalized by making similarly attenuated mutants in other uropathogens, including Proteus and Klebsiella, and in pathogens of other mucosal sites."