Immunostimulation with Vaccines

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Immunostimulation with Vaccines

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UTIs

• gt70-80 caused by uropathogenic E. coli (UPEC)
• affect 8 million women annually in the US
• high recurrence rate gt25 of all UTIs recur
  within 6 months
• Antibiotics primary means of prophylaxis
• Emergence of increasing numbers of drug-resistant
  bacteria
• Alternative prevention strategies
• Vaccines

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Contents

1. Pathophysiology of UTIs
2. Immunology of UTIs
3. Vaccines for UTIs

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UTI etiology

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

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Pathogenesis of cystitis
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COLONIZATION Establishment of bacteria on host
cell surfaces
Commensal State
Infection
Opportunists
Pathogens (Extreme range of virulence and
infectivity)
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The first step to colonization is adherence to a
host cell surface.
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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.

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Morphology of bacterial adhesins
Afimbrial adhesin
Type I fimbriae
Type IV fimbriae ( bundle forming pilus)
Curli
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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 Bacterium coli,
  Journal of Pathol Bacteriol, 70, 335, 1955.
• Found on a variety of gram-negative bacteria
  including saprophytes, commensals and pathogens.

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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
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Type 1 pili similar to P pili
Found in E. coli and most Enterobacteriaceae. Imp
ortant 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
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• 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

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Contents

1. Pathophysiology of UTIs
2. Immunology of UTIs
3. Vaccines for UTIs

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Mucosal
peripheral
central
NALT BALT GALT RALT





The secondary lymphoid organs can be sub-divided
into the Systemic () and Mucosal immune systems
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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

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Mucosal immune response
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Mucosal Inductive Sites
Effector Sites
MALT
Integrated system
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Contents

1. Pathophysiology of UTIs
2. Immunology of UTIs
3. Vaccines for UTIs

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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

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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)

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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

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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

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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)

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J Urol 20071771349-1353
75 paients, Urovac vaginal suppositories, 6 months
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Percent infection-free
E. coli
Any bacterial strain
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(No Transcript)
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No significant adverse events
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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)

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European Urology 200547542-548
9 EU countries 52 centers
1 year
N454
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(No Transcript)
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12 University hospitals, 50 female patients, 6
months
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(No Transcript)
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No significant adverse events
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Urvakol Urostim

• Urvakol
• inactivated, whole E. coli, P. mirabilis,
  Pseudomonas aeruginosa, E. faecalis
• Oral tablet daily for 3 months (mucosal
  immunization)
• Bratisl lek Listy
  1999100246-251
• 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 2000485325-329

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FimCH

• E. coli type 1 fimbrial adhesin (FimH) and its
  caperone protein (FimC)
• Parenteral intramuscular injection
• Animal (Cynomolgus monkey) study
• 
  J Infect Dis 2000181774-778
• 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

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Summary
Mucosal immunogen vaccine Adhesin vaccine
Urovac Uro-Vaxom Vaginal or Oral route induce protective antibodies on the mucosal surfaces of the vagina and bladder FimCH (type 1 fimbriae) PapDG (P pili) Parenteral route interrupt a key initial step of bacterial adhesion to the urogenital mucosa