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Vaccines against UTI’s

A vaccine against Urinary Tract Infections (UTIs) has been one of bioscience’s much sought-after dreams for quite a few years. However, it has proved to be remarkably elusive. To look at the reasons why it is helpful to discuss how vaccines work.

How Vaccination Works

Vaccines programme our immune systems to respond quickly when it encounters an ‘invader’. Once primed in this way, white blood cells are on the lookout, ready to respond.

When these white cells encounter the trigger (or ‘antigen’) they quickly begin to multiply, and release antibodies.

Antibodies are very, very specific to the antigen: even to parts of it. They bind to it, in an effort to inactivate it, and to signal its removal from our systems.

This is often referred to as our Specific or Adaptive immune system, and can provide long-lasting protection against specific pathogens or foreign substances.

Typical administrative routes include oral, intramuscular (most common), nasal sprays, subcutaneous and intradermal (rarest). [1]

REF: WHO http://vaccine-safety-training.org/route-of-administration.html

Many people have concerns about Vaccines based on the problem that vaccines do not just contain the ‘active’ ingredient (the antigen)

Typical components include adjuvants, diluents, stabilisers, preservatives and trace components.

The use of gelatine, in particular, as a stabiliser in some vaccines is of concern on religious and ethical grounds and also has the potential to cause anaphylactic allergy reactions, although this is considered rare. For more information on vaccine components see the NCIRS Factsheet [2]:

http://www.ncirs.edu.au/assets/provider_resources/fact-sheets/vaccine-components-fact-sheet.pdf

The Bladder has its own natural defences

The bladder and the urinary tract is a unique place in your body.

Your specific, adaptive immune system is certainly at work in the urinary tract. Compliment, which activates an immune response, white blood cells, and antibodies, can all be found in urine. [3]

However, there are some things that get in the way of your immune system working as effectively here as they would, say, in your blood stream,

  • It’s within, but not ‘inside’ your body. It is a little bit of ‘outside – in’.
  • Urine is not an ideal medium for white cells or antibodies to function in: as well as having a changeable pH, it’s a big volume that is regularly flushed out!
  • In the blood, antibody levels (or ‘titre’ as it’s often referred to) can build up as production by the white cells continues. In the bladder, they only have time to build up between emptying, making time for their build up limited.

So the classical immune system struggles to reach targets in the bladder as effectively as it can in other places within the body.

The body does have some other tricks to fight bacteria in the UT: The Tamm Horsfall Protein (THP, also known as uromodulin) is made in your kidneys and flows down with the urine. It has been shown to be a defence factor against E.coli [4] and other uropathogenic bacteria [5]. This glyco-protein is positively bristling with receptors, including mannose, which play a role in binding to bacteria and flushing them out. It is now known that some people lack THP.

D-Mannose is in fact acting in exactly the same way as your body does naturally: by using it you are just supplementing your natural defences without creating bacterial resistance and with no side effects.

How Vaccines are made: Targets

When making a vaccine these days it is often the case that a specific ‘target’ will first be identified. This may be a part of the pathogen which we want the resulting antibodies to attack.

(There are other approaches, discussed below in “cocktails: multistrain whole-cell/cell lysate vaccines”) In the case of uropathogenic E.coli (UPEC) a number of such targets have been identified and tried …

TARGET 1: Adhesins

Probably the most obvious thing to try. If we could interfere with the lectin ‘anchors’ on the bacterial fimbriae, we’d reduce its capacity to hang on and cause infections, right?

Unfortunately, things are not quite so clear cut in practice.

  • In 1999, MedImmune, Inc. (MA, USA) brought the UPEC type 1 fimbria subunit vaccine, FimCH, to Phase II clinical trials with women volunteers. MedImmune formally announced in early 2003 the discontinuation of further research and development of the FimCH vaccine, citing that the previous clinical trials failed to demonstrate a sufficient level of efficacy in prevention of UTIs to warrant additional larger Phase III studies [6,7] - From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498450/
  • In 2008 the University of Washington, Seattle published a study in “The Journal of Biological Chemistry” which looked at the molecular mechanism of the adhesin ‘catch-bond’. This study found that “In the presence of antibodies, the strength of bacterial adhesion to mannose is increased” [8,9] March 21, 2008 the Journal of Biological Chemistry 283, 7823-7833.

Further work by the same group, published in 2011 in “Infection and Immunology” [10] the journal of the American Society for Microbiology resulted in some rather startling facts …

  • “Antibodies raised against whole fimbriae enhance FimH-mediated binding” I.e. an immune response to fimbral adhesin actually increased the adhesion of E.coli to epithelial cells!
  • “FimH can shed the bound HAS-specific antibody” I.e. the adhesin can ‘shuck-off’ bound antibodies! Infect. Immun. October 2011 vol. 79 no. 10 3895-3904 - http://iai.asm.org/content/79/10/3895.long

Whilst these examples may sound counter-intuitive, it does explain the lack of success MedImmune had with their vaccine. The Washington team also demonstrated the mechanism for these same effects (discussed later).

And collaborative work between the Seattle team and the Genome Institute of Singapore in 2013 further confirmed these conclusions and the way it works. [11]

Ref PNAS (Proceedings of the National Academy of Sciences of the United States of America) vol. 110 no. 39 > Drew J. Schwartz, 15530–15537

So, targeting the adhesin ‘grappling-hooks’ it would seem is, counterproductive and unfortunately unlikely to provide the solution many hoped it would and may just replicate the problem with antibiotic therapy which is increased resistance.

Vaccine and Autoimmune systems

Uromune® containing an inactivated bacterial cell suspension of selected strains of Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Enterococcus faecalis is now being offered for recurrent cystitis, following a Spanish study on vaccines. Basically, these bacteria are introduced to the human body with the sole purpose of stimulating an immune response.

Because of course, the whole premise of vaccination is to intentionally provoke an immune response. This has the potential to overstimulate the immune system and it has been suggested that immune systems altered by vaccination are a potential cause for autoimmune diseases. A 2009 study on the potential links between Guillain-Barré and the Gardasil vaccine points out that:

“By their nature, immunisations are intended to stimulate the human immune system, and that stimulation could, at least theoretically, increase the risk of autoimmune diseases.”

Meanwhile the NCBI (The National Centre for Biotechnology Information advances science and health by providing access to biomedical and genomic information) advises caution in the use of vaccines:

“We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines.”

https://www.ncbi.nlm.nih.gov/pubmed/15196997 Eur J Dermatol. 2004 Mar-Apr; 14(2):86-90.

TARGET 2: Surface Polysaccharides

Like all Gram-negative bacteria the carbohydrate-rich cell surface of UPEC, contains an abundance of various polysaccharides. These again look like they would be a good target, but again, this turns out not to be the case …

  • There are a lot of them* and their expression is highly variable between UPEC strains (and even by a single strain at different times). * 167 ‘O’ antigens, 80 ‘K’ antigens have been identified REF - To quote the National Centre for Biolotechnology Information (NCBI) [8]: “designing a surface polysaccharide-based UPEC vaccine that can be effective against all UPEC serotypes is extremely challenging” [12].
  • Many of the surface polysaccharides are camouflage!
  • They mimic the host’s own cell surface markers, and are thus ‘overlooked’ by the immune system! [8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498450/

TARGET 3: Siderophores

This is a more recent line of investigation. Siderophores are iron ‘scavenging molecules’ released by UPEC, and they have active ‘portals’ – gateways through the bacterial cell wall to drag them + the iron back in. Blocking these could starve the UPEC of iron.

Encouraging results in studies on mice [13] have unfortunately not translated to success in humans. REF: Pathogens. 2015 Dec 31;5(1). pii: E1. doi: 10.3390/pathogens5010001.

This highlights another problem : studies comparing experimental UTI in the mouse and active human UTI have identified differences, indicating unsurprisingly that artificial infection of the mouse does not directly equate with natural infection in humans [14].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498450/

Cocktails: multistrain whole-cell/cell lysate vaccines

Vaccinating with whole or lysed fractions of inactivated pathogens can be an effective method to generate protective immunity, and a number of successful vaccines against human pathogens, including Bordetella pertussis (whooping cough), Vibrio cholerae (cholera) and Salmonella Typhi (typhus) contain killed whole bacteria [15].

One drawback of this approach is the potential for endotoxin toxicity and adverse side effects.

Another problem is that many of the UPEC’s surface antigens are mimics of the host’s own surface cell markers. These identify the cells as ‘self’ to the immune system, so they create a poor immunological response … you do not want to start making antibodies against yourself!

Dating back to the 1980’s there have so far been five standardized whole-cell/cell lysate-based vaccines that have been tried for UTI, but with limited success …

OM-89 / Uro-Vaxom

(OM Pharma, based in Switzerland) was developed in 1988 and is currently marketed by Terralab of Croatia in Europe, Canada, and other countries [8]. Notably not the USA.

Packaged into a once daily oral tablet, a full course requires three months to complete.

Only modest protection is afforded by this product [16].

Initial clinical studies, involving 601 female participants did appear to demonstrate protection against recurrent UTI [17].

However a more recent (2015, Justus-Liebig University, Germany) multicentre double blind control trial of 451 patients showed no significant difference in UTI rates between Uro- Vaxom® and placebo [18] Urologia internationalis. 2015; 95: 167-176.

Urovac

(Solco Basel AG, Birsfelden, Switzerland and Protein Express, Cincinnati, OH, USA) is a suppository vaccine containing a mixture of ten whole-cell, heat-killed uropathogens

Rodent studies were promising, and an early trial of 202 women appeared to show a reduction in recurrent infection in the 12 months following intramuscular injections. [19].

Subsequent trials delivered Urovac vaginally, to reduce the risk of endotoxin toxicity and adverse side effects, and to stimulate a more robust local immune response [20].

Phase II and extended Phase II clinical trials found that women who received six total doses of vaccine gained short-term protection from infection, having significant delays to reinfection during the first 8 weeks of the study in comparison with women who received placebos [21-24].

However, over the full course of the 6-month study, Urovac immunization did not provide significant long-term protection from UTI or increase mean levels of UPEC-specific serum, urinary or vaginal antibodies [21-24]

And even with a vaginal route of delivery, some of the women reported adverse side effects.

SOURCE : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498450/ Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine

Urvakol / Urostim Oral Tablets Pending Approval

Urvakol/Urostim is the product of a Czech and Bulgarian collaboration (BB-NCIPD Limited). They are seeking approval for a freeze-dried formulation of attenuated uropathogens in a daily oral tablet.

Data from animal and patient studies demonstrate that Urvakol and Urostim have immune-stimulating activity [25-27].

However, the ability of either vaccine to prevent recurrent UTI has not been established as well-structured clinical trials have yet to be completed. [8]

SOURCE : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498450/ Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine

Uromune outperforms antibiotics in 2013 study? (Syner-Med (PP) Ltd UK, Inmunotek S.L. Spain)

The vaccine contains an inactivated bacterial cell suspension of selected strains of uropathogenic bacteria, delivered via an oral tablet. A course of treatment is 3 months.

A 2013 study by the University of Salamanca [28], compared 159 patients treated with Uromune® for a period of 3 months (group A) and 160 with sulfamethoxazole/trimethoprim 200/40 mg/day for a period of 6 months (group B).

The patients receiving Uromune® (group A) experienced a highly significant reduction in the number of infections compared to patients on antibiotics (group B).

A significant reduction was also observed after 9 and 15 months.

REF: https://www.ncbi.nlm.nih.gov/pubmed/22806485

Int Urogynecol J. 2013 Jan;24(1):127-34. doi: 10.1007/s00192-012-1853-5. Epub 2012 Jul 18.

Uromune is currently only available in the UK on a ‘named patient’ basis.

A “First Experience” study involving 40 patients at the Royal Berkshire Hospital in Reading ( REF ) has

just been presented ( March 2017 ) at the 32nd Annual EAU Congress in London. [29]

This ongoing study does show promise, with 87% of women reporting no further UTI’s during the treatment and the subsequent follow-up period. However, that period is still very short to draw any long-term conclusions.

Further studies are required to evaluate the efficacy of this vaccine in a larger group of patients including comparing effectiveness against placebo and antibiotic prophylaxis.

An international multi-centre study is currently underway, and a Randomised Control Trial at the Royal Berkshire centre. The results from both of these studies are awaited.

REF: First experience in the United Kingdom with the novel sublingual vaccine Uromune® in the treatment of women with recurrent urinary tract infections

Eur Urol Suppl 2017; 16(3); e234

Yang B.1 , Foley S.2 1Royal Berkshire Hospital, Dept. of Urology, Reading, United Kingdom, 2Royal Berkshire Hospital Reading UK, Dept. of Urology, Reading, United Kingdom

http://www.eusupplements.europeanurology.com/article/S1569-9056(17)30206-3/pdf

So, we have had close to 30 years of vaccine development: a number of products, lots of trials, and although there are hopeful signs … we are definitely not there yet and we may never be there fully.

Challenges facing Vaccines

UPEC has some pretty neat tricks up its sleeve when it comes to protecting itself. It’s had millions of years to evolve survival strategies. Here’s a few we know about which are relevant to antibody attack, and therefore vaccination …

Molecular Mimicry: Camouflage: Many of UPEC’s surface polysaccharides mimic the host’s own cell surface markers, and are thus ‘overlooked’ by the immune system! [8]

REF https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498450/

Capsid Cloaking: UPEC can protect themselves from antibody attack.

Recent work suggests that the polysaccharides in UPEC’s capsid (outer layer) may ‘cloak’ the bacterial cell surface, obscuring it from recognition by host antibodies. [30].

Antibody Shedding: The lectin (FimH) has 2 shapes, or ‘conformations’. By switching the shape, attached antibodies become un-stuck! So, UPEC are able to ‘shake-off’ antibodies directed against these areas.

Even more bizarrely, many of the antibodies directed at the FimH seem to ‘lock’ it into a shape that has higher affinity for mannose, actually making it more likely to stick! [10,11]

Strain Diversity: Variability of expression of “virulence factors”: There are many, many factors which assist UPEC and other uropathogenic bacteria to cause infection. Hundreds have been identified already. The problem is, they are not expressed consistently, either by any one strain, or across strains.

“A required core set of virulence factors common to all UPEC isolates has yet to be identified” None offer “knock-out blows” [8]

REF https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498450/

Biofilm formation: UPECs can at times produce a ‘mucus’ of glyco-proteins and polysaccharides which physically protects them from outside attack. The host’s natural defences, white cells, antibodies, compliment, and even chemicals like antibiotics, find it hard to get through this sticky, protective layer. The biofilm can be a ’refuge’, from which they can re-emerge when conditions are less hostile. [31,32]

‘Hiding’ by epithelial cells: UPECs appear sometimes to persuade host epithelial cells to ‘engulf’ them, wrapping around them protectively. This apparently strange behaviour is little understood at this time.

Where does this Leave Us?

There’s already been a great deal of work in this quest, and we have a long way still to go.

UIT’s and specifically UPEC have an amazing repertoire of tricks and defences, … almost certainly more we haven’t discovered yet.

The search for an effective, safe, long-lasting vaccine is still going on.

Remember, though, that whilst the scientists continue their quest, there are simple, safe and cost-effective treatments available right now … Waterfall D-Mannose.

Author : Dermot Boylan - Mircobiologist

Dermot worked as a microbiologist in vaccine production for Hoechst before taking up a career in laboratory automation.

References

1. WHO http://vaccine-safety-training.org/route-of-administration.html

2. http://www.ncirs.edu.au/assets/provider_resources/fact-sheets/vaccine-components-fact-sheet.pdf

3. Li K1, Sacks SH, Sheerin NS. The classical complement pathway plays a critical role in the opsonisation of uropathogenic Escherichia coli. Mol Immunol. 2008 Feb;45(4):954-62. Epub 2007 Sep 17.

4. Bates JM, Raffi HM, Prasadan K, Mascarenhas R, Laszik Z, Maeda N, et al. Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int. 2004;65:791.

5. Tamm-Horsfall Protein Protects Against Urinary Tract Infection by Proteus mirabilis Hajamohideen S. Raffi, James M. Bates Zoltan Laszik, and Satish KumarJ Urol. 2009 May; 181(5): 2332–2338. Published online 2009 Mar 19.

6. Meiland R, Geerlings SE, Langermann S, Brouwer EC, Coenjaerts FE, Hoepelman AI. Fimch antiserum inhibits the adherence of Escherichia coli to cells collected by voided urine specimens of diabetic women. J Urol. 2004;171(4):1589–1593. [PubMed]

7. Medimmune, Inc. [Accessed on 6 June 2012];Annual Report. 2002 www.astrazeneca.com/Investors/Annual-reports.

8. Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine Ariel R Brumbaugh and Harry LT Mobley* NCBI - National Centre for Biotechnology Information Expert Rev Vaccines. 2012 Jun; 11(6): 663–676. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498450/

9. Integrin-like Allosteric Properties of the Catch Bond-forming FimH Adhesin of Escherichia coli*. Veronika Tchesnokova‡,1, Pavel Aprikian‡,1, Olga Yakovenko‡§,1, Christopher LaRock‡, Brian Kidd§, Viola Vogel¶, Wendy Thomas§∥,2 and Evgeni Sokurenko‡∥,3 Departments of ‡Microbiology and §Bioengineering and the ∥Nanotechnology Center, University of Washington, Seattle, Washington 98105 and the ¶Department of Materials, ETH Zurich, 8093 Zurich, Switzerland . March 21, 2008 The Journal of Biological Chemistry 283, 7823-7833. http://www.jbc.org/content/283/12/7823.short

10. Type 1 Fimbrial Adhesin FimH Elicits an Immune Response That Enhances Cell Adhesion of Escherichia coli ▿ † Veronika Tchesnokova1, Pavel Aprikian1, Dagmara Kisiela1, Sarah Gowey1, Natalia Korotkova1, Wendy Thomas2 and Evgeni Sokurenko1* 1.Department of Microbiology 2.Department of Bioengineering, University of Washington, Seattle, Washington 98195 B. A. McCormick, Editor. American Society for Microbiology. Infect. Immun. October 2011 vol. 79 no. 10 3895-3904 http://iai.asm.org/content/79/10/3895.long

11. Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation. Drew J. Schwartza, Vasilios Kalasa, Jerome S. Pinknera, Swaine L. Chenb,c, Caitlin N. Spauldinga, Karen W. Dodsona, and Scott J. Hultgrena,1. aCenter for Women’s Infectious Disease Research, Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; and bDivision of Infectious Diseases, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074; and cInfectious Diseases Group, Genome Institute of Singapore, Singapore 138672 - PNAS ( Proceedings of the National Academy of Sciences of the United States of America ) vol. 110 no. 39 > Drew J. Schwartz, 15530–15537 http://www.pnas.org/content/110/39/15530.abstract

12. Johnson JR. Virulence factors in Escherichia coli urinary tract infection. Clin Microbiol Rev. 1991;4(1):80–128. [PMC free article] [PubMed]

13. Development of a Vaccine against Escherichia coli Urinary Tract Infections. Mobley HL, Alteri CJ : Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Pathogens. 2015 Dec 31;5(1). pii: E1. doi: 10.3390/pathogens5010001.

14. Hagan EC, Lloyd AL, Rasko DA, Faerber GJ, Mobley HL. Escherichia coli global gene expression in urine from women with urinary tract infection. PLoS Pathog. 2010;6(11):e1001187. [PMC free article] [PubMed]

15. Rappuoli R, Bagnoli F. Vaccine Design: Innovative Approaches and Novel Strategies. Caister Academic; Norfolk, UK: 2011. Well-organized review of vaccine design strategies, including reverse vaccinology.

16. Bauer H.W., Rahlfs V.W., Lauener P.A., Blessmann G.S. Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: A meta-analysis of five placebo-controlled double-blind studies. Int. J. Antimicrob. Agents. 2002;19:451–456. doi: 10.1016/S0924-8579(02)00106-1. [PubMed] [Cross Ref]

17. Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. Prevention of recurrent urinary tract infections with immunoactive E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents. 2002;19(6):451–456. [PubMed]

18. A Randomized, Double-Blind, Parallel-Group, Multicenter Clinical Study of Escherichia coli-Lyophilized Lysate for the Prophylaxis of Recurrent Uncomplicated Urinary Tract Infections. Wagenlehner F.M.E.a • Ballarini S.c • Pilatz A.a • Weidner W.a • Lehr L.c • Naber K.G.b - aClinic for Urology, Pediatric Urology and Andrology, Justus-Liebig University, Giessen, and bTechnical University of Munich, Munich, Germany; cVifor Pharma, Geneva, Switzerland - Urologia internationalis. 2015; 95: 167-176.

19. Grischke EM, Rüttgers H. Treatment of bacterial infections of the female urinary tract by immunization of the patients. Urol Int. 1987;42(5):338–341. [PubMed]

20. Mestecky J. The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol. 1987;7(4):265–276. [PubMed]

21. Uehling DT, Hopkins WJ, Balish E, Xing Y, Heisey DM. Vaginal mucosal immunization for recurrent urinary tract infection: Phase II clinical trial. J Urol. 1997;157(6):2049–2052. [PubMed]

22. Uehling DT, Hopkins WJ, Beierle LM, Kryger JV, Heisey DM. Vaginal mucosal immunization for recurrent urinary tract infection: extended Phase II clinical trial. J Infect Dis. 2001;183(Suppl 1):S81–S83. [PubMed]

23. Uehling DT, Hopkins WJ, Elkahwaji JE, Schmidt DM, Leverson GE. Phase 2 clinical trial of a vaginal mucosal vaccine for urinary tract infections. J Urol. 2003;170(3):867–869. [PubMed]

24. Hopkins WJ, Elkahwaji J, Beierle LM, Leverson GE, Uehling DT. Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a Phase 2 clinical trial. J Urol. 2007;177(4):1349–1353. quiz 1591. [PubMed]

25. Koukalova D, Krocova Z, Vitek P, Macela A, Hajek V. Immunostimulatory activity of the vaccine used in the treatment of recurrent urinary infections. II. Bratisl Lek Listy. 1999;100(4):215–217. [PubMed]

26. Koukalová D, Reif R, Hájek V, et al. Immunomodulation of recurrent urinary tract infections with Urvakol vaccine. Bratisl Lek Listy. 1999;100(5):246–251. [PubMed]

27. Marinova S, Nenkov P, Markova R, et al. Cellular and humoral systemic and mucosal immune responses stimulated by an oral polybacterial immunomodulator in patients with chronic urinary tract infections. Int J Immunopathol Pharmacol. 2005;18(3):457–473. [PubMed]

28. Evaluation of a therapeutic vaccine for the prevention of recurrent urinary tract infections versus prophylactic treatment with antibiotics. Lorenzo-Gómez MF1, Padilla-Fernández B, García-Criado FJ, Mirón-Canelo JA, Gil-Vicente A, Nieto-Huertos A, Silva-Abuin JM. 1 Servicio de Urología, Complejo Asistencial Universitario de Salamanca, Paseo San Vicente 58-182, Instituto de Investigación Biomédica de Salamanca, 37007, Salamanca, Spain. Int Urogynecol J. 2013 Jan;24(1):127-34. doi: 10.1007/s00192-012-1853-5. Epub 2012 Jul 18.[Pubmed]

29. First experience in the United Kingdom with the novel sublingual vaccine Uromune® in the treatment of women with recurrent urinary tract infections. Yang B.1, Foley S.2 1Royal Berkshire Hospital, Dept. of Urology, Reading, United Kingdom, 2Royal Berkshire Hospital Reading UK, Dept. of Urology, Reading, United Kingdom. Eur Urol Suppl 2017; 16(3);e234 http://www.eusupplements.europeanurology.com/article/S1569-9056(17)30206-3/pdf

30. Russo TA, Beanan JM, Olson R, MacDonald U, Cope JJ. Capsular polysaccharide and the O-specific antigen impede antibody binding: a potential obstacle for the successful development of an extraintestinal pathogenic Escherichia coli vaccine. Vaccine. 2009;27(3):388–395.

31. Biofilm exclusion of uropathogenic bacteria by selected asymptomatic bacteriuria Escherichia coli strains. Ferrières L., Hancock V., Klemm P. Microbiology, 2007. 153:1711–1719.

32. The ferric yersiniabactin uptake receptor FyuA is required for efficient biofilm formation by urinary tract infectious Escherichia coli in human urine. Ferrières L., Hancock V., Klemm P. Microbiology 2008 154:167–175.

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