Urinary tract infections are painful and recur all too often with no apparent cause: Ask any woman who has missed days of work due to one, or had to find emergency treatment while on vacation.

University of Michigan scientists have made an important step toward what could become the first effective vaccine to prevent urinary tract infections, if the robust immunity achieved in mice can be reproduced in humans.

The research findings, which appear online Sept. 18 in PLoS Pathogens, could have broad effects, including reduced health care costs. Urinary tract infections (UTIs) affect 53 percent of all women and 14 percent of men at least once in their lives. They lead to lost work time and 6.8 million medical provider’s office visits, 1.3 million emergency room visits and 245,000 hospitalizations a year, with an annual cost of $2.4 billion in the United States.

U-M scientists screened thousands of bacterial proteins and identified three strong candidates to use in a vaccine to prime the body to fight Escherichia coli, the cause of most uncomplicated urinary tract infections. The vaccine prevented infection and produced key types of immunity when tested in mice.

“The results of our study are very encouraging. We would like to connect with interested clinicians and move on to a clinical trial,” says Harry L. T. Mobley, Ph.D., the study’s senior author and the Frederick G. Novy Professor and chair of the U-M Department of Microbiology and Immunology.

Other scientists have attempted to develop a vaccine for UTIs over the past two decades, but U-M’s potential vaccine has several strong points that may better its chances of success where other attempts have failed:
• It alerts the immune system to iron receptors on the surface of bacteria that perform a critical function allowing infection to spread.
• Administered in the nose, it induces an immune response in the body’s mucosa, a first line of defense against invading pathogens. The response, also produced in mucosal tissue in the urinary tract, should help the body fight infection where it starts.

Context
UTIs are of particular concern for people with repeated infections who may develop resistance to antibiotics commonly used as treatment. Factors that heighten the need for a vaccine, at least for people at greater-than-average risk, include increasing antibiotic resistance, allergic reactions and the unhealthy effects of antibiotics on beneficial microorganisms in the gut. Infections in the upper urinary tract are a particular concern in children, who may be left with permanent kidney damage.

Four out of five uncomplicated urinary tract infections, the type that sickens otherwise healthy people, are caused by certain strains of E.coli capable of infecting the urinary tract. Other types of E. coli not implicated in urinary tract infections include those that cause food poisoning outbreaks, as well as beneficial ones that live in the digestive tract.

Research details
Mobley’s team used a systematic approach to look for key parts of the bacterium that could be used in a vaccine to elicit an effective immune response. They used screening methods from bioinformatics, genomics and proteomics to look for these proteins expressed by a strain of E. coli obtained from an infected patient.

“To identify candidates for the vaccine, we have used a comprehensive, unbiased approach that hasn’t been used previously,” says Christopher Alteri, Ph.D., one of the study’s first authors and a U-M research fellow in microbiology and immunology. “Also, we identified an entire class of molecules, instead of single molecules from different classes.”

The U-M researchers identified six potential vaccine candidates after screening 5,379 possible proteins. Strikingly, all six were members of a class of receptors that the bacteria use to latch onto iron in the host’s body, which they need to grow and cause infection.

Of the six proteins, three were very effective at preventing infection in mice that were immunized nasally and were then exposed to the E. coli strain. The team also tested the vaccine against another well studied strain and found it equally effective.

What’s next
Mobley’s team is currently testing more strains of E. coli obtained from women treated at U-M. Most of the strains produce the same iron-related proteins the vaccine targets, an encouraging sign that the vaccine could work against most urinary tract infections. Mobley hopes to see the vaccine move forward into a phase 1 trial in humans. If successful, the vaccine would take several more years to reach the market.

Patents/Disclosures: The U-M Office of Technology Transfer has applied for patent protection for this technology. The University is presently looking for licensing partners to help bring the technology to market.

Additional U-M authors: Erin C. Hagan, co-first author; Kelsey E. Sivick, co-first author; and Sara N. Smith

Citation: PLoS Pathogens, Sept. 18, 2009; doi:10.1371/journal.ppat.1000586

Funding: National Institutes of Health
Source:  University of Michigan Health System