It’s Time to Embrace Vaccination as We Enter the Postantibiotic Era of Recurrent Urinary Tract Infection Management

You have accessJournal of UrologyJU Forum1 Jun 2024It's Time to Embrace Vaccination as We Enter the Postantibiotic Era of Recurrent Urinary Tract Infection Management R. Christopher Doiron, Tiziana Cotechini, and J. Curtis Nickel R. Christopher DoironR. Christopher Doiron Corresponding Author: R. Christopher Doiron, MD, MPH, FRCSC, Department of Urology, Queen's University, 76 Stuart St, Kingston General Hospital, Victory 4, Kingston, ON K7L 2V7, Canada ( ([email protected]) , Tiziana CotechiniTiziana Cotechini , and J. Curtis NickelJ. Curtis Nickel View All Author Informationhttps://doi.org/10.1097/JU.0000000000003969AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail It is difficult to dispute the public health relevance of recurrent UTI (rUTI). The astronomical cost and quality of life burden to society are sobering, and the contribution of rUTIs to the antimicrobial resistance crisis is undeniable. As practicing clinicians, we understand this as a lived experience—our clinics are overrun with rUTI patients, mostly women, who are desperate for treatment options. We have entered the postantibiotic era of rUTI management, and it is time to embrace vaccination as a legitimate, safe, and efficacious treatment for prevention of rUTI in women. In 2022, the updated AUA/Canadian Urological Association/Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction uncomplicated rUTI guideline was released.1 Built on the 2019 effort, it is an excellent clinical tool and addresses many of the important challenges of rUTI. The guideline references a single trial involving immunoactive agents, and the panel stops short of making a formal recommendation with respect to vaccination for UTI prevention. The most updated European Association of Urology UTI guideline in 2023 acknowledges immunoactive preparations, providing a "strong recommendation" for their use in preventing rUTI, supported with level 1a evidence. Many level 1 studies supporting various vaccination preparations over placebo in preventing UTI among rUTI patients are currently available in the literature. The evidence continues to mature, but vaccines are still difficult to access for patients, with regulatory approvals lagging in many jurisdictions—none of the vaccine preparations discussed currently have Food and Drug Administration approval for use in preventing rUTI. We hope this situation changes soon—our patients can no longer wait. The Landscape of UTI Vaccines OM-89 aka UroVaxom The immunoactive preparation with the longest history among UTI vaccines is OM-89. This immunostimulant, a 6-mg oral capsule of lyophilized bacterial lysates from 18 strains of Escherichia coli, is delivered daily for 3 months (± booster dose for the first 10 days of months 6-9). A meta-analysis of 7 placebo-controlled randomized controlled trials (RCTs) demonstrates an odds ratio (OR) of 0.36 (95% CI 0.14-0.92; P < .01; I2 = 91%)2 favoring the vaccine over placebo in preventing rUTI. MV140 aka Uromune MV140—a sublingual spray comprised of 4 strains of heat-inactivated uropathogens (E coli, Klebsiella pneumoniae, Enterococcus faecalis, and Proteus vulgaris) delivered daily for 3 months—has the most contemporary clinical evidence showing efficacy and safety in preventing rUTI in women. A systematic review3 evaluating clinical evidence for MV140 revealed 19 clinical trials evaluating the sublingual vaccine's ability to prevent rUTIs. An analysis of 2 comparative trials meeting strict rUTI and outcome criteria showed a UTI-free rate of 35% to 58% among 519 vaccinated subjects compared to 0% among 469 subjects in the prophylactic antibiotic control groups.3 A further 3 uncontrolled studies that met the same criteria showed a UTI-free rate ranging from 33% to 78% over 9 to 24 months of follow-up in 412 MV140-treated subjects. This efficacy was confirmed in a recent pivotal multicenter RCT4 that showed 56% (95% CI 44%-67%) and 58% (95% CI 44%-67%) of subjects UTI-free at 9 months of follow-up among women who received 3 and 6 months of MV140 treatment, respectively, compared to 25% (95% CI 15%-35%) of those receiving placebo. Several ongoing RCTs are in progress.5 A first-in-North America uncontrolled, prospective, cohort study of MV1406 reflects previously published level 1 studies confirming safety and efficacy. Solco-Urovac/StroVac Most successfully formulated as a vaginal suppository delivered weekly for 3 weeks (± monthly booster for 3 months), Solco-Urovac contains cell lysates from 10 uropathogenic bacterial strains: E coli × 6, K pneumoniae, Proteus mirabilis, Proteus morganii, and E faecalis. In a meta-analysis of 3 phase II trials that included booster dosing, the vaccine prevented UTI compared to placebo with an OR of 0.23 (95% CI 0.11-0.48; P < .001; I2 = 0%).2 At 6 months, 46% to 56% of patients vaccinated were UTI-free compared to 17% to 22% in the placebo arm.2 The nonbooster dosing trials did not show efficacy in preventing UTIs compared to placebo. Prospective clinical trials with a parenteral version of Solco-Urovac, StroVac, showed reasonable efficacy, though a recent multicenter RCT7 did not show improvement in UTI reduction compared to placebo. Additional RCTs are ongoing.8 ExPECV4/V10 Vaccines targeting the lipopolysaccharide O-antigens of extraintestinal pathogenic E coli (ExPEC) of various serotypes, delivered intramuscularly, have been developed. ExPEC4V targets O-antigen serotypes O1A, O2, O6A, and O25B, while the ExPEC10V formulation broadens its reach to include coverage of 10 serotypes. Although these vaccines have shown promising tolerability and immune responses among subjects, they have yet to be examined beyond phase II trials for the purposes of evaluating prevention of rUTI.9 The ExPEC vaccines are targeted toward preventing invasive extraintestinal pathogenic E coli diseases, including septicemia, and may ultimately be less relevant to the rUTI population. One such phase III trial is actively recruiting, evaluating ExPEC9V's efficacy in preventing E coli bacteremia (NCT04899336). Vaccine Safety All UTI vaccines described here have excellent safety profiles. Data from a meta-analysis revealed only 9 cases of vaccine discontinuation out of 604 subjects receiving OM-89. There were also 9 cases of discontinuation in the 582 placebo subjects2 while no serious adverse events (SAEs) were reported. MV140 has a robust safety profile with data from 22,000 subjects receiving the vaccine through compassionate or named patient programs worldwide (NCT04173013). In the pivotal RCT4 there was a similar number of adverse events (AEs) in the 2 treatment and placebo arms, with most being mild and self-limited. Only 9 of the total 205 AEs reported were judged to be a result of the vaccine—these 9 AEs occurred in 2 placebo subjects and 3 subjects from the 3-month intervention arm. Seven SAEs were reported among 5 subjects, none of which were judged to be secondary to the intervention. Among the 3 phase II trials of Solco-Urovac,2 there were no SAEs reported and only mild AEs, with the most common being vaginal irritation among 14 subjects. No subjects of the 148 in the studies discontinued treatment. The ExPEC4V vaccine was well tolerated and safe in its phase Ib trial,9 with no SAEs and no difference in reported AEs between the vaccine and placebo arms. The most common AE reported was transient injection site discomfort.9 Challenges Facing UTI Vaccination The nature of immunoactive preparations is that they often contain whole cell bacteria (in the case of UTI vaccine preparations, inactivated or attenuated) or components of bacterial pathogens. Their regulation appropriately requires a thorough evaluation and approval process, like most vaccinations, as they are considered a higher-risk intervention. Furthermore, from a regulatory perspective, UTIs are considered a disease with a low mortality rate that already has a well-established and effective treatment—antibiotics. UTI is therefore not perceived to be a priority disease, making vaccine approval problematic. This represents a major public health failure on the part of government and industry—another disappointment in our health care systems' handling of an important women's health issue. There are, of course, still unanswered questions in the UTI vaccination space that warrant investigation. Should we boost? If yes, when and how often? How effective is the vaccine at generating long-term immunological memory? Is the vaccine effective in the elderly? What about other special populations such as children or those with neurogenic bladders? Where does vaccination fit within a multimodal approach to rUTI prevention? Is it safe to use in the immunocompromised? Should this treatment be considered vaccination, or is immunotherapy/immunomodulation more appropriate terminology? The success of mucosal-based vaccination is attributed to activation of mucosal immune responses resulting in cross talk and homing of immune cells between mucosa of the oral cavity/gastrointestinal tract/vagina and urinary tract (both pathogen-specific humoral and cell-mediated responses) with the sublingual impact appearing superior in magnitude and duration compared to oral and vaginal routes. While this appears to neutralize the pathogen on the mucosal surface before it causes infection, more work on mechanism of action and route of administration is warranted. Despite these uncertainties, the efficacy and safety question for the uncomplicated, female rUTI patient appears to be answered for more than 1 immunoactive agent described here. Getting the Vaccine to Those Who Need It Level 1 evidence supports the use of vaccination for prevention of UTI among women with rUTIs. Many of these women suffer significantly lower quality of life and are desperate for effective treatment that will not cause them harm. Embracing a vaccine approach to rUTI management does not mean we should forget the rest of the players. Antibiotics will continue to have a pivotal role while nonantibiotic prophylactic measures, including proanthocyanidins (cranberry) and vaginal estrogen,1 can provide benefit. UTI vaccination should not compete with these strategies, but should be used in concert with them as part of a multimodal approach to treating this challenging, refractory condition. Our increasing understanding of urinary tract infection—eg, understanding the epigenetic changes that occur in urothelial stem cells in the setting of acute UTI that may lead to the recurrent phenotype10—dovetail with rapid advances in new approaches to vaccine development spurred by the COVID-19 pandemic. While the future offers hope for even more effective immunomodulatory strategies for women with rUTI, we should embrace the innovation that current UTI vaccination approaches offer today. REFERENCES 1. . Updates to recurrent uncomplicated urinary tract infections in women: AUA/CUA/SUFU guideline. J Urol. 2022; 208(3):536-541. Link, Google Scholar 2. . Role of vaccines for recurrent urinary tract infections: a systematic review. Eur Urol Focus. 2020; 6(3):593-604. Crossref, Medline, Google Scholar 3. . Could sublingual vaccination be a viable option for the prevention of recurrent urinary tract infection in Canada? A systematic review of the current literature and plans for the future. Can Urol Assoc J. 2020; 14(8):281-287. Crossref, Medline, Google Scholar 4. Sublingual MV140 for prevention of recurrent urinary tract infections. NEJM Evid. 2022; 1(4):EVIDoa2100018. Crossref, Medline, Google Scholar 5. Evaluation of MV140 in preventing recurrent urinary tract infections: a multicentre double-blind randomized controlled trial protocol. BJU Int. 2023. Google Scholar 6. . MV140 sublingual vaccine reduces recurrent urinary tract infection in women: results from the first North American clinical experience study. Can Urol Assoc J. 2024; 18(2):25-31. Medline, Google Scholar 7. . Prospective multicentre randomized double-blind placebo-controlled parallel group study on the efficacy and tolerability of StroVac in patients with recurrent symptomatic uncomplicated bacterial urinary tract infections. Int Urol Nephrol. 2023; 55(1):9-16. Crossref, Medline, Google Scholar 8. Non-Antibiotic Prophylaxis for Recurrent UTIs in Neurogenic Lower Urinary Tract Dysfunction (NAPRUN): study protocol for a prospective, longitudinal multi-arm observational study. Methods Protoc. 2023; 6(3):52-61. Crossref, Medline, Google Scholar 9. Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial. Lancet Infect Dis. 2017; 17(5):528-537. Crossref, Medline, Google Scholar 10. Uropathogenic Escherichia coli infection-induced epithelial trained immunity impacts urinary tract disease outcome. Nat Microbiol. 2023; 8(5):875-888. Crossref, Medline, Google Scholar Recusal: Dr Siemens, editor of The Journal of Urology®, was recused from the editorial and peer review processes due to affiliation with Queen's University. Funding/Support: No funding was provided for the preparation of this JU Forum article. Conflict of Interest Disclosures: Dr Nickel has acted in an advisory role with Inmunotek, OM Pharma, and Red Leaf Medical. No other disclosures were reported. Ethics Statement: In lieu of a formal ethics committee, the principles of the Helsinki Declaration were followed. Author Contributions: Conception and design: Doiron, Nickel. Data acquisition: Doiron, Nickel. Data analysis and interpretation: Doiron, Cotechini, Nickel. Critical revision of the manuscript for scientific and factual content: Doiron, Cotechini, Nickel. Drafting the manuscript: Doiron, Nickel. Supervision: Nickel. © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 6June 2024Page: 797-799 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Keywordsurinary tract infectionvaccinesimmunotherapyimmunomodulationMetrics Author Information R. Christopher Doiron Corresponding Author: R. Christopher Doiron, MD, MPH, FRCSC, Department of Urology, Queen's University, 76 Stuart St, Kingston General Hospital, Victory 4, Kingston, ON K7L 2V7, Canada ( ([email protected]) More articles by this author Tiziana Cotechini More articles by this author J. Curtis Nickel More articles by this author Expand All Recusal: Dr Siemens, editor of The Journal of Urology®, was recused from the editorial and peer review processes due to affiliation with Queen's University. Funding/Support: No funding was provided for the preparation of this JU Forum article. Conflict of Interest Disclosures: Dr Nickel has acted in an advisory role with Inmunotek, OM Pharma, and Red Leaf Medical. No other disclosures were reported. Ethics Statement: In lieu of a formal ethics committee, the principles of the Helsinki Declaration were followed. Author Contributions: Conception and design: Doiron, Nickel. Data acquisition: Doiron, Nickel. Data analysis and interpretation: Doiron, Cotechini, Nickel. Critical revision of the manuscript for scientific and factual content: Doiron, Cotechini, Nickel. Drafting the manuscript: Doiron, Nickel. Supervision: Nickel. Advertisement Advertisement PDF downloadLoading ...

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