Sublingual Vaccine Shows Efficacy in Preventing Recurrent UTIs, Helping to Eliminate Need for Antibiotics

Pharmacy Times® interviewed J. Curtis Nickel, MD, Health Canada research chair in urologic pain and inflammation and a professor of urology at Queen's University in Kingston, Ontario, on his research recently presented at the American Urological Association 2023 Annual Meeting in Chicago, Illinois in a presentation titled "MV140 sublingual vaccine reduces risk of recurrent urinary tract infection (rUTI) in North American women: Results from the first North American clinical experience study."

Pharmacy Times: How can treatment of recurrent UTIs contribute to antibiotic resistance?

J. Curtis Nickel, MD: Antibiotic resistance is a major health care concern worldwide. It is becoming more important as our antibiotic pipeline dries up. And recurrent urinary tract infections are a large part of the problem.

Since the guideline recommendation for women with recurrent urinary tract infections, as 3 or more a year, and many patients suffer up to 6 per year, is antibiotics. Now, for prevention, we treat patients with 3 to 6 months of low dose antibiotics—sometimes even longer. Many of these patients have been on and off antibiotics for years, and even decades. So almost truckloads of antibiotics are being used in this patient population to treat and prevent recurrent urinary tract infections. And it’s this massive amounts of antibiotics in these patient populations that will results in individual patients microbiome becoming resistant to antibiotics, so new antibiotics have to continually be introduced to that particular patient. But it also, likely, although it's hard to prove, but likely, contributes to the overall international perspective, that antibiotic resistance is caused by the overuse of antibiotics in our patient populations, including for recurrent urinary tract infections.

Image Credit: Adobe Stock - ake1150

Pharmacy Times: Are there other treatments available besides antibiotics for recurrent UTIs?

Nickel: Antibiotics are essentially a poison that kills living microorganisms. So many patients elect or try to avoid antibiotics, if at all possible. Not only are they perceived to be toxic to life by killing off organisms that might be beneficial to our general health, they also cause significant side effects in many patients, [such as] not only allergies, which potentially can be lethal in rare instances, [but also] they cause side effects, gastrointestinal side effects, skin side effects, a feeling of unwellness that patients tell us about. But also, we know the long-term antibiotics, [including] particular classes such as the fluoroquinolones can have long term impact on the muscular skeletal system, the cardiovascular system, and the psychological wellbeing of patients. So patients want to avoid antibiotics, and we do have options for those patients.

The proven therapy, which is very simple, is to increase fluid intake to at least or more than one and a half liters per day. This has been proven in a number of studies to reduce the risk of recurrent urinary tract infections in postmenopausal women who are estrogen deficient. The use of intra vaginal estrogen preparations have also proven efficacious.

We know that, in many patients, cranberry extract can help reduce UTIs. But the cranberry extract has to contain the active ingredient of PAC's or PACs. If they do not, and 90% of cranberry preparations on the shelf at health food stores and even pharmacies, do not indicate that they have a validated concentration of PACs—those products won't work. So it has to be a validated and accredited product.

For patients with recurrent E. coli UTI, which is the most common organism, for some patients, the use of D-mannose, which is a sugar isomer that blocks the E. Coli from attaching to the bladder wall, may prove efficacious, although the evidence isn't as strong as the other methods that I told about. And many of my patients, even though the evidence is not as strong as some of the other interventions that I've described, use probiotics, and particularly those patients who have been on chronic or long-term antibiotics feel, in their case, that probiotics help them on their way to health, and perhaps they do we reduce recurrent urinary tract infections. And then of course, there's new immunomodulatory or vaccine approaches that we're working on, and we'll discuss in this story that we're telling today.

Pharmacy Times: Could you discuss the vaccine in development and its delivery method?

Nickel: I have been personally involved in the clinical evaluation of a sublingual vaccine sprayed under the tongue to prevent urinary tract infection. MV140, or as it's known as a trade name Uromune, has been around for about a decade. When first approached by the company in Spain, who developed and manufactures this product, I was a bit reluctant and hesitant to take part because I'd had other experience with vaccines that were not as favorable as I would like. And I was not under the impression that there was enough data for me to really become involved.

But as there was more and more use in Europe, and data was accumulating, I became very interested. And I became interested in 2 aspects: One is in a randomized placebo controlled trial, which provides real evidence of whether or not a vaccine will prevent recurrent UTIs compared to placebo. I became involved in the design, analysis, publication, and presentation of that particular study, which we published last year in New England Journal of Medicine, and it showed that this vaccine sprayed under the tongue for 3 months improve the bladder immunity, such that we had a significant decrease in recurrent urinary tract infections compared to placebo.

In fact, almost 55% to 60% of the patients who were having 6 UTIs per year had 9 months, which was the efficacy period in the trial, of no UTIs, with a reduction of over 75% of UTIs in the overall population. Well, that study stirred me to start a Health Canada approved study in my institution to look at the only North American clinical research experience with this particular vaccine. And I was able to use this vaccine and 64 of my patients with an average of 6 UTIs per year, who had been on lots of antibiotics previously with variable success. And in this real-life clinical experience study, over 40% of patients became completely UTI free. Well, there was an 80% reduction in the total number of UTIs in the population. And in patients who did have a UTI, many of them explained to me that the UTI was less severe than the ones they were having before the vaccine to the extent that many patients didn't even require antibiotics to treat a recurrent UTI after vaccination.

This vaccine is sprayed under the tongue at 2 sprays a day for 3 months through sort of a nonspecific innate immune process, which includes trained immunity, and a more specific adaptive immune response that travels rather than systemically like injectable vaccines, travels through the lymph system to the various mucosal surfaces, and changes the immune milieu or composition of the mucosa, including the urethra and bladder, where it balances the immune system to a pre-recurrent UTI or chronic UTI status. And this is what I believe, or we believe, is contributing to the benefits we see with this vaccine.

Pharmacy Times: Is there a potential application for other disorders that can cause or mimic recurrent UTIs, such as interstitial cystitis or cystitis cystica?

Nickel: The particular vaccine Uromune or MV140 has been extensively studied in recurrent uncomplicated UTIs in women. And as it becomes available in markets in various parts of the world, that will be the major indication.

However, studies have been ongoing in more elderly patients in nursing homes, in men, and it's even planned in children and adolescents with recurrent UTIs as well as more complicated UTIs, [such as] those patients with neurogenic bladder, who may even require intermittent catheterization. Those are indications that may turn out to come true in the future, and I certainly hope so, because those are all problematic cases. There are other medical conditions we deal with, that looked like an infection, such as interstitial cystitis, bladder pain syndrome, which patients have bladder pain, urgency, and frequency. Those patients, many of them are believed to have some sort of immunological etiology, and we wonder whether or not balancing the mucosal immune system will have any benefit?

Well, in fact this year at the AUA, I did present a small sub study that we did in Kingston, Ontario, Canada, in which we had 16 patients—not very many, but it's a start—16 patients that had been diagnosed with interstitial cystitis bladder pain syndrome [ICBPS], who also had recurrent urinary tract infections causing flares. So I could incorporate those patients into our clinical trial based on Health Canada approval of recurrent urinary tract infections.

What was so remarkable in these patients who were refractory to our standard treatments for interstitial cystitis, is that 8 out of the 16 did extremely well to the point that they could almost be called cured, or they're not suffering any major symptoms of ICBPS and get along with their life. While 14 out of the 18 had a significant reduction in UTIs, and believed that they had had significant improvement in their symptoms. So this is a specific type of ICBPS who have a phenotype associated with recurrent UTIs.

I guess in the future, we'll be looking at that and larger randomized placebo-controlled trial in that patient population. And we may initiate a clinical evaluation of this vaccine in the overall population of ICBPS, particularly those with an inflammatory or potentially immunologic etiology.

Pharmacy Times: What are next steps following these study results?

Nickel: Uromune or MV140 is available in many countries in Europe and the EU, in UK, Australia, New Zealand, in a Special Access Programs are named patient programs, in which the physicians have to fill out forms because antibiotics aren't working or the patients are having difficulty.

In those studies, we recently looked at over 20,000 patients who received this treatment in these Special Access Programs. And although we don't have efficacy data, the safety data looked very, very good. The vaccine has been approved in I believe, the Dominican Republic, but also recently in Mexico. In Canada, Health Canada is looking at the file because of the huge unmet need, and it is hoped that they will give conditional approval to the vaccine for using prescription in Canada for women with recurrent UTIs based on the 5 or 6 studies have done in Europe. The randomized placebo-controlled study published in the New England Journal of Medicine evidence and the Canadian early experience real world study that we did in Kingston. That's hopeful.

It will be slower to be approved in the United States as the FDA has very rigid rules on approving vaccines, and I expect another large, randomized placebo-controlled study done in North America may be required before it's available in the US. And like I said, in the future, studies may show that it could be used in nursing homes for the elderly infirm patients where recurrent UTIs are a major problem. It may prove to be efficacious in neurogenic bladders and in preventing complicated UTIs in men, perhaps even in children and adolescents. So this is an exciting time for immunomodulator therapy in the prevention and treatment of recurrent UTIs rather than the sort of burn and destroy approach we use with antibiotics.

Pharmacy Times: How might the development of more vaccines addressing chronic infections, such asrecurrent UTIs, impact the burden of antibiotic resistance on health systems?

Nickel: Well, I personally believe that vaccines are going to be a part of the answer, not only for treatment of recurrent UTIs but complicated UTIs. There are other vaccines not available in North America, one that I'm particularly aware of Uro-Vaxom that has proven efficacy and is a well-tolerated. Uromine which I described today I think is going to be a game changer.

There's another study that is looking right now at an injectable vaccine for the prevention of complicated UTI and urosepsis. And this may be a huge game changer in patients with the more lethal type of UTIs.

I also believe that all the work that has been done in the field of vaccines in preventing COVID-19 will spill out into other infectious diseases such as recurrent or complicated UTI. And this also will be a great boon to our field.

By reducing the large amount of antibiotics that we presently use for the treatment and management of UTIs, recurrent UTIs, and complicated UTIs, there's no doubt in my mind that we will see a reduction in the risk of the further development of antibiotic resistance in these patient populations, which will probably be reflected in the overall population and health of a country, or even internationally. So like I said, the future of immunomodulatory therapy for UTIs is going to be a breakthrough and a game changer.