13. Immunomodulation Vaccines
Induces the host adaptive immune system
Uropathogens share similar surface antigens, which therefore allows for a broad-spectrum defence when the immune system is stimulated by antigen from one bacteria group
RCT data available for:
Uro-Vaxom ®(OM Pharma, Myerlin, Switzerland)—oral tablet
Urovac ®(Solco Basel Ltd, Basel, Switzerland)—vaginal vaccine
ExPEC4V (GlycoVaxyn AG, Schlieren, Switzerland)—IM injection
Uromune ®(Syner-Med (PP) Ltd UK, Inmunotek S.L. Spain) is a newer sublingual (under the tongue) spray which is effective but has only prospective and retrospective trials published. No RCT available to date
13.1 Introduction and Mechanism of Action
Vaccines are the current hot topic in recurrent UTI prevention. These new immune-modulators stimulate the body’s own immune system to more effectively fight off any bacterial invasion.
The urinary tract fights against uropathogens using both an innate and adaptive mucosal-immune system, which is part of a larger Mammalian lymphoid organ system. This system works by having receptors to recognise invading bacteria, binding onto them and stimulating the body’s immune system to then kill it off. In the body, the mucosal immune system comprises of 80% of all immunocytes (cells used by the body to fight off infection).
Immunocytes transit throughout the body through various Mucosal associated lymphoid tissue (MALT), meaning stimulation and activation of the Toll-Like Receptors at one MALT site disseminates immunity to other MALT sites by allowing them to also recognise the surface antigens on the bacterium.
Vaccines work by introducing one or more common bacteria that cause UTI to the body’s immune system. This can be done either with the bacteria’s surface antigens or by using the whole inactivated bacterium, thus allowing for the induction of the host immune system without risking an actual infection. This exposure activates both the innate and (later on) the adaptive immune response.
This pre-sensitisation means when an actual virulent uropathogen attempts to invade the urinary tract, the body has already “learnt” previously how to deal with this bacteria and thus can mount a significantly faster adaptive host immune response, which when activated, promotes an more effective targeted immune reaction to clear the pathogen before any symptoms occur.
As most uropathogens share similar surface antigenic properties between themselves, stimulation with one (or more) uropathogens results in a broad-spectrum immune response against both the listed uropathogens and also other pathogens not solely limited to the bacteria within the vaccine itself .
13.2 Clinical Evidence
UroVaxom®, originally called OM-89, is an oral tablet composed of bacterial extracts from 18 strains of Escherichia coli. It is given daily in an oral tablet form for 90 days. Its use has been reported in the literature since 1986. Since then, there have been 6 RCTs, which on meta-analysis, found that UroVaxom® did reduce UTI recurrence rates (risk ratio [RR] 0.67, 95% CI 0.57–0.78). The maximal effect was seen by 3 months.
Current EAU guidelines recommend this treatment for immuno-prophylaxis in women with recurrent uncomplicated UTIs .
Urovac® is a vaginal suppository vaccine delivered as a weekly dose for 3 weeks. It is composed of ten inactivated uropathogen strains including six E. coli strains and one Proteus mirabilis, Morganella morganii, Enterococcus faecalis and Klebsiella pneumoniae. After the initial 3 week treatment period, three follow up booster doses are then given at 6, 10 and 14 weeks.
Urovac® has also been shown in a recent meta-analysis of 3 RCTs to effectively reduce UTI recurrence rates (RR 0.75, 95% CI 0.63–0.89) .
ExPEC4V is an intramuscular vaccine delivered as a single injection. It is composed of the O-antigens from four E. coli serotypes.
Whilst effective in initial trials, to date there has been only one published RCT, which in 93 women reported no reduction in UTI recurrence rates. (RR 0.82, 95% CI 0.62–1.10) However the trial did show ExPEC4V induced a significant host immune response, with significant rises in the immunoglobulin (IgG) levels specific to all four O-antigens. A phase II trial is currently underway to investigate whether this rise in immunity translates to a clinical benefit in preventing UTIs .
Uromune® (Syner-Med (PP) Ltd. UK, Inmunotek S.L. Spain) is a newer immunomodulating vaccine which has reported good efficacy. However the lack of any published RCTs means to date, the EAU are unable to list this treatment in their guidelines.
Uromune® is a sublingual vaccine composed of Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris and Enterococcus faecalis in equal proportions. It is currently pre-licence.
Two large retrospective Spanish studies comparing Uromune® and antibiotic prophylaxis in 669 and 319 women found a significant decrease in UTI recurrence. [Risk reduction 90.28% (87.18–93.38)] The authors also reported no side effects [3, 4].
A recent 2018 prospective UK observational study found that in 77 women, after 3 months of daily administration, 78% of women developed no further UTIs in the 12-month follow-up period. For those who still developed UTIs despite treatment, proportionally more were seen in postmenopausal women, suggesting Uromune is more effective in pre-menopausal women, though it still displayed a marked effect in post-menopausal women too. [UTI free patients—Pre-menopause: 88%, Post-menopause 72%]. There were very few significant side effects with only one woman in the study stopping treatment due to a rash .