Urinary tract infections (UTIs) are now the most common cause of outpatient infections worldwide.

These painful infections can lead to life-threatening illnesses if left untreated, but doctors are usually limited to prescribing antibiotics for UTIs, which can negatively impact the immune system. In a breakthrough from Duke University, the researchers say they have developed a vaccine that successfully treated UTIs in mice and rabbits without depleting the animals’ immunity.

Widespread disease

A strange stinging sensation when you urinate, married with the constant need to ‘go,’ is an early sign that you may have a UTI. One of the most prevalent bacterial infections globally, this condition is capable of causing extreme pain during urination, affecting internal organs. It can even make you lose control of your bladder.

Uropathogenic E. coli (UPEC) bacteria cause the bug in 80% of all cases. A popular drug target, these microbes reside in the urinary tract as part of our microbiota: the collective name for the trillions of microorganisms that live inside and on us, contributing to our health.

But if UPEC (along with ‘friendly’ E. coli) is already present in our microbiome, why doesn’t it always infect us? The explanation lies in the term ‘homeostasis,’ a balanced state an organism reaches to optimize its survival. Using this facility, the menagerie of bacteria, fungi, and viruses living in our microbiota can co-exist in a symbiotic state with us, helping to regulate digestion and immunity while producing essential vitamins.

However, specific pathogens, drugs, or foods can disrupt this micro-ecosystem, causing various health conditions. Antibiotics are known to be among the worst offenders here, particularly with recurrent illnesses like UTIs, which denote multiple rounds of medicine. These repetitive drug regimes are currently being blamed for a sharp rise in drug-resistant bugs and raised health risks – meaning UTIs may be difficult, if not impossible, to treat in the future.

To avoid this eventuality, the scientists say they have developed a vaccine administered under the tongue that they showed to be as effective as high-dose oral antibiotics at protecting mice from the UPEC bacteria. They also showed that their vaccine caused no harm to the animal’s microbiota.

“In a mouse model of UTI, we demonstrate equivalent efficacy to high-dose oral antibiotics but with significantly less perturbation of the gut microbiome,” said the researchers in their study published in Science Advances. “We also formulate our vaccine as a rapid-dissolving sublingual tablet that raises response in mice and rabbits. Our approach represents a promising alternative to antibiotics for the treatment and prevention of UTIs.”

Why the wait?

Scientists have been attempting to create a vaccine for UTIs for decades. Still, they have failed, mainly due to problems with getting the medication to penetrate the cellular mucosa, the special layer of soft, moist tissue that coats the mouth, throat, and urinary tract. 

Through lit reviews, the team noted that placing a vaccine under the tongue elicited robust antibody responses in their target, the urinary tract, and the mucosal walls throughout the body. After discovering this possible solution, they constructed a dissolvable nanofiber tablet comprising many repeating peptides (short-chain amino acids) modified to include polymers imparting mucus adhesion.

The self-assembling tablet also integrated three proteins that normally reside on the surface of UPEC bacteria targeted in the study. As these proteins are isolated from the bacteria, they are called epitopes: molecules designed to produce a response from the patient’s immune system without causing infection.

 The team ensured that the epitopes used were exclusive to UPEC so there would be no danger of their vaccine targeting species of ‘friendly’ E. coli in the microbiome. Assured that by targeting all three receptors, they had designed a vaccine that would be effective against a human UTI – the researchers then challenged mice with CFT073, a UPEC strain isolated from human patients.

Promising data

When the team placed the nanofiber vaccines under the animal’s tongues, they dissolved rapidly, reducing the potential for oral delivery where it would have proved ineffective. Their investigation also found traces of the tablet 12 hours after the researchers had applied it, even with impromptu access to food and water.

In tests, the team gave the mice an initial ‘primer’ tablet and four boosters to promote the production of antibodies against all three UPEC epitopes. The scientists then compared this set of animals to a control group of unvaccinated mice. Results show that half of the unimmunized mice died due to the challenge, while all vaccinated mice survived with the tablet imparting a year’s worth of protection.

They add that the nanofiber-generated antibodies did not attack any other E. coli species in the microbiota. “Our vaccine raises responses in the urinary tract and blood without eliciting detectable IgA antibodies in the feces, suggesting that there is minimal response in the commensal microbe-rich gastrointestinal tract,” they expand.

Towards a vaccine

The team explains that although the results are promising, studies in larger animal models are still needed. They say this is because the premise of a vaccine for UTIs is so new that there is no way to glean the long-term effect of this medication in humans.

Of particular concern, they say, is the idea of developing a non-specific or universal vaccine to target other species of bacteria that cause these infections, as it may target commensal bacteria indiscriminately.

The researchers say, “The influence of antibiotics on the microbiome is reflected in the alarming rise of antibacterial resistance.” And shockingly, “Modeling has forecast that, by 2050, current practices would result in 10 million additional deaths per year by infection and a global economic cost of $100 trillion.” Consequently, this makes “it likely that safe, effective treatment and prevention of UTIs will become increasingly challenging.”

However, there is a ray of hope with their work representing “an early step toward a safe and broadly effective vaccine to prevent UPEC-mediated infection” that “leverages the unique advantages of a sublingual supramolecular nanofiber vaccine platform to address this challenge.”