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Immunostimulation with Vaccines

Immunostimulation with Vaccines. 이 승 주. UTIs. >70-80% caused by uropathogenic E. coli (UPEC) affect 8 million women annually in the US high recurrence rate: >25% of all UTIs recur within 6 months Antibiotics : primary means of prophylaxis

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Immunostimulation with Vaccines

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  1. Immunostimulation with Vaccines 이 승 주

  2. UTIs • >70-80% caused by uropathogenic E. coli (UPEC) • affect 8 million women annually in the US • high recurrence rate: >25% of all UTIs recur within 6 months • Antibiotics: primary means of prophylaxis • Emergence of increasing numbers of drug-resistant bacteria • Alternative prevention strategies • Vaccines

  3. Contents • Pathophysiology of UTIs • Immunology of UTIs • Vaccines for UTIs

  4. UTI etiology • Uropathogens from intestinal flora sequentially colonize mucosal surfaces of the vagina and urethra prior to establishing an infection on the bladder mucosa

  5. Pathogenesis of cystitis

  6. COLONIZATION Establishment of bacteria on host cell surfaces Commensal State Infection Opportunists Pathogens (Extreme range of virulence and infectivity)

  7. The first step to colonization is adherence to a host cell surface.

  8. Adherence Mechanisms • Adherence is required for extracellular colonization as well as internalization of bacteria. • Adhesins - General term for bacterial structures involved in adhesion. • Pili or fimbriae – Gram-negative bacteria • Non-pilus adhesins – Gram-positive and negative bacteria • Bacteria often have a variety of both types of adhesins.

  9. Morphology of bacterial adhesins Afimbrial adhesin Type I fimbriae Type IV fimbriae (= bundle forming pilus) Curli

  10. Fimbriae or Pili • Filamentous organelles expressed on the surface of gram-negative bacteria and mediate attachment to host tissues. • First described by Duguid et al. in 1955 • Duguid JP, Smith IW, Dempster G, Edmunds PN. Non-flagellar filamentous appendages (“fimbriae”) and haemagglutinating activity in Bacteriumcoli, Journal of Pathol Bacteriol, 70, 335, 1955. • Found on a variety of gram-negative bacteria including saprophytes, commensals and pathogens.

  11. P or Pap pili: Uropathogenic strains of E. coli associated with pyelonephritis Genes (11) in pap gene cluster (PapA- PapK) Thick, rigid filaments; Rod is composed of several thousand pilin units tightly wound in a right-hand helix to form a hollow cylinder with an outer diameter of ~7 nm and an inner diameter of 1.5 – 3 nm. Flexible, more narrow tip (fibrillum) with adhesin on distal end. ~ 1000-2000 nm long Adhesin binds to Gal(1,4)Gal moieties of glycolipids on uroepithelial cells

  12. Type 1 pili – similar to P pili Found in E. coli and most Enterobacteriaceae. Important virulence factor In cystitis-associated E. coli. Genes in Fim gene cluster (FimA-FimH) Fibrillum is shorter and stubbier. FimH also intercalates with rod at buried sites that may be exposed when breakage occurs at these sites. Adhesin (FimH) binds to mannose oligosacchaarides attached to uroplakin on surface of urinary bladder epithelium

  13. Adhesins recognize and bind to specific receptors on host cells. This may activate complex signal transduction cascades resulting in: • Activation of innate defenses • Subversion of cellular processes facilitating bacterial invasion • May activate expression of new genes in bacterial cell that are important in pathogenic process • Important UTI vaccine candidate

  14. Contents • Pathophysiology of UTIs • Immunology of UTIs • Vaccines for UTIs

  15. Mucosal peripheral central NALT BALT GALT RALT *** # *** # *** The secondary lymphoid organs can be sub-divided into the Systemic (***) and Mucosalimmune systems

  16. MALT (Mucosal Associated Lymphoid System) • Differs fundamentally from systemic immune responses in that: • major isotype in mucosal secretions is secretory IgA • most of the antibody-producing cells and effector T occur in the MALT • separate inductive and effector lymphoid sites

  17. Mucosal immune response

  18. Mucosal Inductive Sites Effector Sites MALT Integrated system

  19. Contents • Pathophysiology of UTIs • Immunology of UTIs • Vaccines for UTIs

  20. UTI vaccine • efficacy & safety • Ideally, the vaccine will increase patient resistance to the most common uropathogens without causing significant adverse effects. • administered easily • low cost • broad patient acceptance

  21. UTI Vaccines currently in development • Urovac®(SolcoBasel, Basel, Switzerland and Protein Express, Cincinnati, OH) • Uro-Vaxom®(OM Pharma, Myerin, Switzerland) • Urvakol(Institute of Microbiology; Olomouc, Czech Republic) • Urostim(Bulbio; National Center for Infectious and Parasitic Diseases, Sofia, Bulgaria) • FimCH(Medimmune, Gaithersburg, MD)

  22. Components of vaccine • Intact bacteria (whole cells) or crude lysates • contain a large number of urovirulence factors • potentially afford protection against many different strains of uropathogens • cause unacceptable adverse reactions by bacterial components such as endotoxin • Detoxified bacterial lysates or purified virulence factor • less toxic • decrease ability to protect against a wide range of pathogens

  23. Route of administration • Mucosal • Immunogen onto the mucosal surface that may infected or onto a distant mucosal site because of the integrated nature of the mucosal immune system • Parenteral • Induce lower amounts of specific antibody in mucosal secretions

  24. Urovac® • Inactivated whole-cell; 10 uropathogens • six E. coli strains • Proteus mirabilis, Proteus morganii, Klebsiella pneumoniae, Enterococcus faecalis • Final concentration: 1 x 109 bacteria/dose • Intramuscular injection (initially in 1987) • Vaginal suppository; primary + monthly booster (mucosal immunization)

  25. J Urol 2007;177:1349-1353 75 paients, Urovac vaginal suppositories, 6 months

  26. Percent infection-free E. coli Any bacterial strain

  27. No significant adverse events

  28. Uro-Vaxom® • Extract from 18 uropathogenic E. coli strains • Induction of antibody to Proteus, Klebsiella,Enterococcus species • Oral capsule; daily for 3 months + three 10-day boosters (mucosal immunization)

  29. European Urology 2005;47:542-548 9 EU countries 52 centers 1 year N=454

  30. 12 University hospitals, 50 female patients, 6 months

  31. No significant adverse events

  32. Urvakol &Urostim • Urvakol • inactivated, whole E. coli, P. mirabilis, Pseudomonas aeruginosa, E. faecalis • Oral tablet; daily for 3 months (mucosal immunization) Bratisl lek Listy 1999;100:246-251 • Urostim • freeze-dried excipient plus lysates of killed E. coli, P. mirabilis, K. pneumoniae, and E. faecalis • Oral tablet; daily for 6 months (mucosal immunization) Adv Exp Med Biol 2000;485:325-329

  33. FimCH • E. coli type 1 fimbrial adhesin (FimH) and its caperone protein (FimC) • Parenteral; intramuscular injection • Animal (Cynomolgus monkey) study J Infect Dis 2000;181:774-778 • Phase 1 trial, 48 adult women • Intramuscular injection at 0, 1, and 4 months • Increases in anti-FimH antibodies in serum, urine, or vaginal secretions Personal communication of Dr. Uehling

  34. Summary

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