Where the Fuck Is Our UTI Vaccine?

The difficulty in coming up with a long-term solution is largely related to the delicate beauty of the female anatomy, and to antibiotics: They work pretty well against UTIs, and they are advantageous from a big pharma perspective because they get people to spend more money over time. But overuse of antibiotics is causing problems for individual, environmental, and public health; resistance could be the end of us all. (Taking antibiotics also usually gives you another persistent genital problem, a yeast infection.) Then, there are the valiant chronic UTI sufferers: Recurrent UTIs occur in about one in ten cases, and according to Dr. David J. Klumpp, a professor of urology at Northwestern University's Feinberg School of Medicine, they sometimes mean E. coli—the bacteria that causes about 80 percent of UTIs—has built up latent "reservoirs" along the walls of the bladder, waiting to re-infect you just when you thought your days of crying on the toilet were finally over.

Is there hope? Because of my ongoing interest in this subject, I have also heard tell of a mythical UTI vaccine, available in Germany and other European countries, but further research revealed it to be probably not that great. Yesterday, a group of Swiss researchers published a study that suggests we could be on the road to an oral, non-antibiotic medicine that would be able to target the protein (FimH) that helps E. coli stick to the inside of your bladder, which is what causes a UTI. But we stinging, burning sufferers should not make the mistake I made when I got excited about the German "UTI vaccine": This research has been going on for years, plagued by a subject-inappropriate lack of urgency. Desperate for more answers, I spoke with Klumpp about why, despite uproarious demand, American women do not have the UTI cure they deserve.

BROADLY: What have been the difficulties in developing a vaccine or other treatment for UTIs? It seems like a widespread enough problem that there would be a market for treatments and an incentive to fund research—is that a misconception on my part?
Dr. David J. Klumpp: The epidemiology is indeed compelling: Approximately half of all women will suffer a UTI, and about 25 percent of those will suffer recurrent UTI. The unmet clinical need is obvious, as UTIs are the second-most common infection [in humans]. Furthermore, antibiotic resistance is increasing among all bacterial pathogens, including those causing UTI (most commonly uropathogenic E. coli, or UPEC). [Uropathogenic just means it's a pathogen of or related to the urinary tract. Who knew! Anyway, it will be helpful for to remember that throughout this article he refers to this bad E. coli as UPEC.]

Efforts to develop a UTI vaccine and other approaches have been ongoing among at least several labs, but these have met with variable levels of success in animal models. We and others have also received NIH funding to pursue strategies for a UTI vaccine and alternatives approaches.

Unfortunately, the obstacles to a UTI vaccine are not strictly technical or limited by federal research funding. Our own efforts, albeit modest, to commercialize an E. coli–based live vaccine were frustrating and surprising to us. While we anticipated a UTI vaccine would be a "no-brainer," our efforts to pitch a UTI vaccine to the industry were met with skepticism that the return wouldn't be worth the considerable investment in safety trials. Big pharma seeks to invest in pills taken daily to treat chronic conditions. We learned that antibiotics against UPEC were still considered "good enough," compared with the marginal gains of a vaccine and the potential risks of targeting immune responses anywhere near the female reproductive tract. So our estimation of the market differed from that of VC and pharma representatives we encountered.

Do you know much about the vaccines and treatments available in countries like Germany? I've heard anecdotally (and from friends translating German articles for me) that those treatments aren't considered particularly effective, and that some doctors doubt they work at all—do you know why?
In Europe, an extract of UPEC is used, Uro-Vaxom. My understanding is that Uro-Vaxom lacks efficacy. I speculate that Uro-Vaxom might be more effective if they developed a vaginal suppository, or maybe they already tried that and it failed or induced unwanted side effects.

When you say an "extract" of UPEC is used, do you mean that they just do what I, a person who has no understanding of medicine, know as a traditional vaccine, i.e., they inject you with a small amount of the problem-causing thing so you become immune to it?
An "extract" is a preparation derived from the whole. In it's crudest sense, you can think of the difference between whole fruit pieces and the same fruit blended into a smoothie. Or in the case of living bacteria, maybe the difference between a cow and hamburger. On top of this, there may be a chemical extraction process with a solvent used to remove or concentrate specific components thought relevant or harmful (think: decaffeination of coffee). You are correct to use the vaccine concept here—treatment with this bacterial gimmick would be intended to generate an immune response. However, as I see now from [manufacturer] terra-lab.com, [Uro-Vaxom] is taken orally.

While some vaccines are administered orally, oral administration is also know to induce "tolerance"—the opposite of stimulating a protective immunity—usually a desirable response because immunity (allergy) to foods is not good. I'm listening to All Things Considered right now, and they're discussing how early introduction of peanuts to young children may reduce peanut allergy [or increase tolerance]. Similarly, Uro-Vaxom may fail because ingestion will induce tolerance.

Are there other treatments/technologies developing to treat recurrent UTIs?
Ultimately, effectively targeting recurrent UTI will require a therapy that addresses the potential routes of infection. Excluding "complicated" and catheter-associated UTI, a female patient acquires a UTI when UPEC initially attach to the vaginal surface and then migrate into the urethra to infect the bladder (cytistis) or the kidney (pyelonephritis). An effective vaccine that generates robust immune responses in the form of antibodies can kill UPEC during the initial infection phase, thereby preventing recurrent UTI in patients afflicted by re-infection.

However, work primarily from Scott Hultgren's lab and the labs of his protégées has shown that UPEC can linger within cells that line the bladder. These UPEC reservoirs, much like reservoirs of the herpes virus, can be latent but then reemerge as another route to recurrent UTI. The data for UPEC reservoirs in mice are very strong, and supportive data in humans suggest that at least a subset of recurrent UTI patients may fall into this second route to recurrent UTI. I highlight this second route because any effective vaccine must also eradicate the UPEC reservoirs. Whereas antibodies are effective against pathogens that exist outside of host cells, antibodies are ineffective against "intracellular" pathogens, like these UPEC reservoirs.

So putting this together, for an effective recurrent UTI that benefits women afflicted by re-ascending infection OR re-emergent infection from UPEC reservoirs, we will need a vaccine that both induces antibodies and cell-mediated immunity. That is within the capabilities of us in the research community, but translation to the clinic will require commercial incentives that are beyond our control.

Just to clarify, you're not saying that a bunch of scientists somewhere have a perfectly good UTI vaccine sitting around and the pharmaceutical industry is uninterested—it's a dual problem that 1) you can't get a great vaccine, and 2) the pharmaceutical industry is making too much money off regular antibiotics?
Humans are obviously more complicated than mice, so the saying in medicine goes, "Cancer has been cured many times in mice." At least three of us [UTI researchers] (Hultgren, Mobley, Klumpp) have therapies that work in mice, but that's still a long distance from something effective and marketable for humans. For example, we also have a patent on a live E. coli–based therapy. But we've not yet garnered interest from the industry to develop it further, and thus it languishes, although we are currently testing an alternative approach in dogs.

So are we trapped? Are antibiotics the only way to really treat a UTI?
Cranberry is touted, but although it can't hurt, its efficacy has never been demonstrated, despite an NIH funding initiative. Antibiotic therapy is the gold standard treatment for acute, "uncomplicated" UTI (i.e., not recurrent or due to anatomic/physiologic abnormalities; by definition, for example, male UTI is "complicated"), although the efficacy of such therapy for resolving symptoms is now unclear. A clinical study [from 2010] revealed that antibiotic therapy (Cipro) was no more effective in resolving symptoms than ibuprofen. Similarly, our own studies in mice revealed that a three-day course of Cipro did not alter the duration of pain. An analogy here is when you stub your toe: It doesn't matter whether you rub it furiously or dance around your bedroom; the pain will last 30-60 seconds.